Physiol Rev 96: 647– 693, 2016

Published March 9, 2016; doi:10.1152/physrev.00010.2015

CELLULAR AND SYSTEM BIOLOGY OF MEMORY:

TIMING, MOLECULES, AND BEYOND
Martin Korte and Dietmar Schmitz

Zoological Institute, Division of Cellular Neurobiology, Braunschweig, Germany; Helmholtz Centre for Infection
Research, AG NIND, Braunschweig, Germany; and Neuroscience Research Centre, Charité Universitätsmedizin
Berlin, Berlin, Germany

Korte M, Schmitz D. Cellular and System Biology of Memory: Timing, Molecules,

L
and Beyond. Physiol Rev 96: 647– 693, 2016. Published March 9, 2016;
doi:10.1152/physrev.00010.2015.—The storage of information in the mammalian
nervous systems is dependent on a delicate balance between change and stability of
neuronal networks. The induction and maintenance of processes that lead to changes
in synaptic strength to a multistep process which can lead to long-lasting changes, which starts and
ends with a highly choreographed and perfectly timed dance of molecules in different cell types of
the central nervous system. This is accompanied by synchronization of specific networks, resulting
in the generation of characteristic “macroscopic” rhythmic electrical fields, whose characteristic
frequencies correspond to certain activity and information-processing states of the brain. Molec-
ular events and macroscopic fields influence each other reciprocally. We review here cellular
processes of synaptic plasticity, particularly functional and structural changes, and focus on timing
events that are important for the initial memory acquisition, as well as mechanisms of short- and
long-term memory storage. Then, we cover the importance of epigenetic events on the long-time
range. Furthermore, we consider how brain rhythms at the network level participate in processes
of information storage and by what means they participating in it. Finally, we examine memory
consolidation at the system level during processes of sleep.

I. INTRODUCTION 647 rons in neuronal networks, which is so important for ani-

II. CELLULAR BIOLOGY OF MEMORY 649
III. SYSTEMS BIOLOGY OF MEMORY 673
IV. PERSPECTIVES 681
I. INTRODUCTION
“There is nothing like future and past (ь ь ь). There is only
the presence of the past, the presence of the presence, and
the presence of the future. These three I see in the soul, but
I cannot see them independent of it: present is the memory
of the past, present is the perception of the presence, and
present is the expectation of the future” (Augustine, Con-
fessions, Chapter 20 in Book 11).
Life is in many respects a remembrance of things of the past.
In this context, information storage works on different time
scales in the genome (evolution and epigenetic), on behav-
ior, and in the nervous system. One of the most intriguing
questions is how does the brain capture and store informa-
tion in such an efficient and long-lasting way? To do so, the
brain has to perform a tremendous task: it has to process a
continuous input from our sensory organs and at the same
time it must be able to store memories, sometimes even for
a lifetime (and sensory processing does not stop when we
store or retrieve information). What is the cellular founda-
tion of this long-term information storage capacity of neu-
mals in general and for humans specifically?
It became evident in the last decades that neurons in memory
relevant areas of the mammalian brain are highly plastic. This
means that the activity patterns generated by experience can
modify neuronal function and structure. Especially prominent
to learning and memory events are processes of synaptic plas-
ticity, which include activity-dependent alterations of the effi-
cacy of synaptic transmission (functional plasticity) and
changes in the structure and number of synaptic connections
(structural plasticity). But in addition to processes of synaptic
plasticity, it also became evident that the storage of informa-
tion is highly influenced by activity patterns of neuronal
networks and any approach which tries to explain the cel-
lular foundation of memory storage needs to take the net-
work level into account. In addition, the timing of network
activities is as important as the history of prior events,
which influences the propensity of neurons to be plastic and
by this means to change its input-output characteristic.
Therefore, in this review, we will summarize the knowledge
about the interplay of different types of neurons and the
rhythm of their activity to prepare a network of neurons to
receive and to store information. In addition, we would like
to report about these network events and follow them all
the way to the molecular level, which have to finally imple-
ment the necessary plastic changes that are needed for the

0031-9333/16 Copyright © the American Physiological Society 647

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 BIOLOGY OF MEMORY EVENTS
processes of memory and recall. In particular, we will focus
on neuron-related timing events that are important for the
initial steps of memory acquisition. We will then consider
cellular processes modulating the input and output charac-
teristics of a neuron due to changes in neuronal activity
(synaptic plasticity). Next, we will examine the importance
of epigenetic events on the long-range time scale of months
and years, and finally, we will focus on hypothesis to ex-
plain how brain rhythms are organized at the network level
to assist in, or being central, to information storage before
examining memory consolidation at the systems level. In
this context, the timing of single events is important, since
the encoding of a memory trace on the behavioral level
requires time scales that differ substantially from those re-
quired for processes of synaptic plasticity and the review
will address the question of which cellular or network
mechanisms allow bridging these different time scales.
To give the reader a sense of what we consider the major issues
emerging in the research about learning and memory mecha-
nisms, we have been highly selective in the topics we cover and
in the number of papers we can cite. This selective approach is
bound to exclude a large body of work on memory processes.
We can only focus on several major questions (related to our
own research fields) that we consider particularly challenging
and that have recently evolved into a broader focus. This is a
huge field to cover, in time (from nanoseconds to years) and
space (from nanometers within the synaptic cleft to centime-
ters of neuronal networks), and therefore, we had to limit
ourselves to some aspects of the events in neuronal networks,
neurons, synapses, and signaling pathways.
Throughout this review we will stress that learning and
memory processes are the result of the interplay between
synaptic plasticity and orchestrated network activity that
finally culminates in the long-term storage of information.
Overall, information storage is a dynamic and interactive
process that starts with the encoding of new information
and progresses to the rather fragile short-term/intermediate
memory, before a memory trace (engram) is stored in dif-
ferent forms of long-term memory (191). At this stage the
engram might be either consolidated for a lifetime, destabi-
lized, or even restabilized in the course of memory retrieval.
These neuronal dynamics start and end with synaptic and
cellular plasticity and extend to more distributed larger neu-
ronal networks and can be observed at the behavioral level.
Although synaptic plasticity has been found in most regions
of the vertebrate brain (and for that matter in all other
neuronal networks of all other animal species), most of the
research on activity-dependent synaptic plasticity in mam-
mals has been performed on a brain region called the hip-
pocampus.
The hippocampus is an evolutionarily old part of the cere-
bral cortex, lying bilaterally in the depth of the cerebral
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hemispheres (FIGURE 1). In particular, the hippocampus is
essential for the formation and also for recall of spatial,
contextual, and episodic memory (99, 327, 412) by inte-
grating sensory and spatial information from the entorhinal
cortex (EC) to create context-specific representations (225,
279, 423). In humans, the hippocampus plays a major role
in processes related to declarative memory, the type of
knowledge that comprises facts about the self and the sur-
rounding world. Famous cases of hippocampal lesions, as
the case of the patient H.M., impressively show the impor-
tance of the hippocampus in memory-related functions.
After a bilateral surgical removal of the hippocampus (hip-
pocampectomy), H.M. suffered from permanent antero-
grade amnesia and partial retrograde amnesia (387). Very
old memories could be retrieved, demonstrating the fact
that the hippocampus is not the storage site for long-term
memories but serves for the processing of memories by con-
necting pieces of information and preparing them for inde-
pendent long-term storage in higher cortical brain regions.
Rec.
Stim.
CA1
CA2
DG
CA3
FIGURE 1. Anatomy of the hippocampus. Anatomically, the mouse
hippocampus is formed by the dentate gyrus (DG) and the ammon’s
horn (cornu ammonis, CA). The CA region can be subdivided into
CA1, CA2, and CA3. Information is delivered from the starting point
at the entorhinal cortex (EC) via the perforant path (green axonal
projection) into the DG and the CA3 region or (pink) to the CA1
pyramidal cells. From the DG, signals are transferred via mossy
fibers (violet) to the CA3 region and after that via the Schaffer
collaterals (yellow) to CA1 pyramidal cells before they are delivered
back to the EC (blue). For the analysis of synaptic plasticity, stimulus
electrodes (Stim.) are employed for activating axon fiber bundles
from Schaffer collaterals and the signals are recorded from apical or
basal dendrites of CA1 pyramidal cells using a recording electrode
(Rec.).
 MARTIN KORTE AND DIETMAR SCHMITZ
Its highly organized network structure renders it to an ideal
model for investigation of specific synaptic contacts be-
tween groups of neurons. The hippocampal formation is
organized in transverse lamellae. Herein, axons are project-
ing in line with pyramidal cells so that slices can keep the
neurons and most of their projections alive. It comprises the
dentate gyrus (DG) and the ammon’s horn (CA, lat. cornu
ammonis). The hippocampal formation includes three sub-
regions with distinct populations of excitatory neurons,
forming a trisynaptic circuit between excitatory neurons
(see FIGURE 1). Information enters the hippocampus from
the EC, terminating on granular cells of the DG. These
neurons send axons, the mossy fibers to pyramidal neurons
of the area CA3, and these in turn connect by the Schaffer
collaterals to CA1 pyramidal neurons. In addition to excit-
atory neurons, there are highly diverse populations of in-
hibitory interneurons in all subregions mediating feedback
and feed-forward inhibition within an area and shaping
rhythms of activity by grouped discharge predisposing the
network for alterations. In all subregions, modification and
interconnection take place, and at each of the stations, con-
nections can be altered. The hippocampal CA3-CA1 syn-
apse is the best-specified synapse in the mammalian brain in
terms of synaptic plasticity. Interestingly, the morphologi-
cal and physiological characteristics of the CA3 region are
essential in the encoding of novel information involving
associations between cues and spatial locations, and the
CA3-CA1 connection is mandatory for processes of recall
and pattern completion (for review, see Ref. 209). But re-
cently, also the CA2 region received some attention: it is a
fairly small region between the CA3 and CA1 subregion.
CA2 neurons get their input from DG cells and project to
CA1 pyramidal neurons (228). In addition, it might also get
input from the EC. The CA2 region might have its own
specific function, since it could be shown that mice, in
which the CA2 subregion was specifically inactivated,
showed deficits in social learning (168).
II. CELLULAR BIOLOGY OF MEMORY
Many different molecular players have to be orchestrated to
play in order to store and retrieve memory events. In this
section, we will discuss the cellular level, including pre- and
postsynaptic processes, as well as the role of extracellular
matrix, glia cells, and modulatory inputs that are essential
for memory formation. It can be assumed that the brain of
animals and humans alike encodes internal as well as exter-
nal events as spatiotemporal activity patterns that are pro-
cessed in a neuronal circuit. The output of such a neuronal
circuit (sometimes also called a neuronal ensemble) is de-
fined by the weight of synaptic connections between neu-
rons in such a functional entity. An experimentally well-
supported hypothesis is therefore that information storage
is defined as a change in the pattern of synaptic strength in
a specific neuronal circuit involved in the learned behavior.
This is described in the synaptic plasticity and memory
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(SPM) hypothesis formulated by Morris and colleagues and
which is used as a road map for this part of the review:
“Activity-dependent synaptic plasticity is induced at appro-
priate synapses during memory formation, and is both nec-
essary and sufficient for the information storage underlying
the type of memory mediated by the brain area in which
that plasticity is observed” (284).
A. Processes of Timing on the Cellular Level:
Storage of Information
On the cellular and molecular level, timing and the orches-
tration of memory events is crucial. With respect to timing,
“Hebb’s rule” is by far the best-known example for the role
of timing events as a central mechanism for information
storage. The key concept postulated by D. O. Hebb tempo-
rally links neural activity representing aspects of informa-
tion processing and storage to neuronal assemblies (165).
Hebb postulated that not a single cell but networks of neu-
rons, which change the strength of their connections and
therefore their input/output characteristics, can be used to
store information. Hebb also suggested that the timing of
events is crucial for the learning and memory processes in
the brain (165): “When an axon of cell A is near enough to
excite a cell B and repeatedly or persistently takes part in
firing it, some growth process [structural changes] or met-
abolic change [functional changes] takes place in one or
both cells such that A’s efficiency, as one of the cells firing B,
is increased.” In the Hebbian rule, timing (associativity) and
input specificity are of upmost importance. In other words,
memories are stored not in single cells but in networks of
neurons where the information is stored by altering the
contact sites between nerve cells. These changes take place
at synapses and are therefore called activity-dependent syn-
aptic plasticity. Hebb’s postulate also includes an important
rule, predicting that synaptic weights change when the pre-
and postsynaptic neurons show coincident activity (associa-
tivity), thus changing the input/output characteristic of neu-
ronal assemblies. In 1973, such an enhancement of synaptic
strength was finally observed for the first time by Timothy
Bliss and Terje Lømo. After they applied a short train of
high-frequency pulses under in vivo conditions to a hip-
pocampal pathway (see FIGURE 1 and sect. I), they could
observe a long-lasting strengthening in the electrophysio-
logical response properties of the recorded neurons (36), a
phenomenon that is now termed long-term potentiation
(LTP). LTP is defined as an increase in synaptic strength
that lasts for at least 1 h (36). It consists of an induction
phase, including processes that trigger the alterations lead-
ing to the changes in synaptic efficacy followed by the ex-
pression or maintenance phase of LTP. LTP can be divided
in different types: at 1-3 h, it is independent of transcription
and translation (early or E-LTP); if it lasts longer than 3 h,
it is generally dependent on altered gene expression and
referred to as late LTP (L-LTP) (35, 196).
649
 BIOLOGY OF MEMORY EVENTS

Hebb’s postulate for the requirements of synaptic strength-
ening asks for coincident neuronal activity at the pre- and
postsynapse and for a subcellular mechanism of detection in a
narrow time window. In 1986, a cellular implementation of
this requirement was found. Wigström and Gustafsson (462)
showed a strong potentiation of synaptic responses in a hip-
pocampal slice preparation by simultaneously activating an
axon bundle of CA3 neurons and a postsynaptic neuron in the
CA1 region (see also sect. I). In many excitatory synapses, a
specific role for the induction of plastic alterations is exerted
by the N-methyl-D-aspartate (NMDA) receptor, an iono-
tropic glutamate receptor. This was shown by the inhibition
of LTP induction in area CA1 by application of a receptor
antagonist for the NMDA receptor. Regular (basal) synaptic
transmission is mediated predominantly by ionotropic ␣-ami-
no-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)
receptors, which allows Na⫹ influx in response to glutamate
binding (FIGURE 2). The NMDA receptor is a ligand-coupled
ion channel, permeable for Na⫹ and Ca2⫹. Under resting
membrane condition, the ion channel pore is occluded by
Mg2⫹ ions; therefore, binding of glutamate is not sufficient
to open the channel pore for Ca2⫹ or Na⫹. Only the depo-
larization of the postsynaptic terminal releases the Mg2⫹
block in addition to glutamate binding allowing influx of
Na⫹ and most importantly of Ca2⫹ into the cell (167) (FIG-
2⫹
URE 2A). Elevation of the Ca concentration within the
postsynaptic neuron then triggers several intracellular reac-
tions via the activation of kinases. The requirement for
postsynaptic depolarization during glutamate binding de-
mands precise timing and coordinated activity of the pre-

A
FIGURE 2. Basic cellular processes re-
sulting in long-term potentiation (LTP) or
long-term depression (LTD). A: under basic
synaptic conditions, AMPA receptors (AM-
PAR) regulate the Na⫹ influx in the postsyn-
aptic dendritic spine depending on the
amount of released glutamate. Ion chan-
nels of NMDA receptors (NMDARs) are
AMPAR NMDAR Mg2+ blocked by Mg2⫹ ions (left). If the postsyn-
Mg2+
aptic membrane is depolarized, the Mg2⫹
block of the NMDA receptor channel is re-
moved and Ca2⫹ and Na⫹ ions enter the
Na+ Na+ Ca2+ spine (right). B: under baseline synaptic
Na+
conditions (top), AMPA receptors cycle be-
tween intracellular compartments and the
Depolarization outer membrane of the postsynapse. This
is accomplished through lateral mobility of
the AMPA receptors out of the postsyn-
apse into endocytose-active zones. Here
AMPA receptors are included into early en-
B AMPAR NMDAR dosomes, which then are transferred to
recycling endosomes, then they return to
the cell membrane via exocytosis, followed
by lateral movement into the synapse
LTP LTD where they are retained. After LTP induc-
Exo- Endo- tion by tetanic stimulation (bottom left), en-
cytosis cytosis
hanced AMPA receptor exocytosis occurs
and these receptors are then stabilized at
the synapse through a Ca2⫹-mediated pro-
Recycling cess that includes protein kinases (e.g.,
CaMKII) and the fusion of recycling endo-
somes mediated by Rab11a. After the in-
NMDAR AMPAR duction of LTD by low-frequency stimulation
NMDAR AMPAR
(bottom right), endocytosis of AMPA recep-
tors is increased, and it occurs at extrasyn-
aptic sites in a process that is Ca2⫹ depen-
CaMKII
dent and included the activation of protein
Endo- Ca2+ phosphatases [e.g., protein phosphatases
cytosis Calcineurin
Ca2+ 1 (PP1) or calcineurin]. After the induction
PP1
of LTD, AMPA receptors are retained
Exocytose within the cell and are stored in endosomes
Endocytose or degraded.
Rab11a

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 MARTIN KORTE AND DIETMAR SCHMITZ
and postsynaptic side. By this means, the NMDA receptor
acts as a molecular switch, a real “molecular coincidence
detector.” Only when the postsynaptic cell or a stretch of
dendrite is already (or still) active and the Mg2⫹ block is
expelled from the NMDAR channel while presynaptic glu-
tamate is released, an intracellular Ca2⫹ signal is generated.
The requirement for presynaptic activity, i.e., glutamate
release, underlines a key feature of LTP: input specificity.
This means that LTP is restricted to synapses, which have
been activated (or are very close to activated synapses, see
Ref. 104) rather than to all of the synapses on a given
neuron. This was experimentally proven by the induction of
LTP using intracellular depolarization of a neuron while
applying single low-frequency pulses to axons converging
onto that neuron, which without this postsynaptic depolar-
ization did not show LTP (463; see also Ref. 104). Bliss and
Lomo (36) could achieve the same effect by high-frequency
stimulation of axons. Here, the postsynaptic depolariza-
tion, caused by repeated transmitter release, summed up to
exceed the voltage threshold for the activation of the
NMDA receptor. This mechanism ensures the second im-
portant characteristic of LTP: cooperativity. To confine
plastic alterations to stimuli representing either simultane-
ous heterosynaptic information or strong (homosynaptic)
inputs, these have to pass a certain intensity threshold due
to effects of cooperativity (37; for a review, see Ref. 146).
With these means, cooperativity and specificity, changes in
synaptic strength are largely confined to active connection.
On glutamatergic synapses, the postsynaptic elements are
located on small membrane protrusions with bottle-neck
connections to the dendrite, so-called dendritic spines. The
geometry of these spine-necks, together with the passive
signal propagation in dendrites, ensures that electric and
ionic alterations, especially local alterations of cytosolic
Ca2⫹, stay largely confined to the active part of the dendrite
(for a review, see Ref. 484). Here, the fast kinetics of the
AMPA receptors and the local extrusion by Na⫹/Ca2⫹
pumps ensure restriction of synaptic alterations. The spec-
ificity, however, is not absolute; part of the depolarization
spreads to nearby portions of dendrite (see Ref. 104). This
contributes to the phenomenon of cooperativity, permit-
ting that inputs converging in close spatial vicinity can be
potentiated if they are active together, but it also explains
the third feature of LTP: associativity. A weak synaptic
connection can be potentiated if it coincides with a stron-
ger one, because the depolarization from nearby active
synapses helps to surpass the threshold of the NMDA
receptor or of voltage-dependent Ca2⫹ channels (219).
So, new connections between previously unrelated inputs
can be formed, if one of them surpasses the induction
threshold within a narrow time window (374; but see also
the clustered plasticity model in Ref. 146).
In fine-tuned electrical circuits, you also expect to find
mechanisms that weaken synaptic input and not only
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strengthen it. And indeed, synaptic depression (termed
long-term depression, LTD) constitutes a necessary coun-
terpart of LTP. By reducing synaptic efficacy, LTD estab-
lishes the necessary differences in strength between syn-
apses, and at the same time, it helps to prevent excessive
synaptic activity. An earlier notion was that LTD is a cor-
relate of forgetting by weakening unused connections, but it
is now undisputed that also activity-dependent reduction of
synaptic strength is directly involved in learning. A common
theory is that LTP establishes connectivity within a net-
work, whereas LTD accomplishes the fine-tuning of these
connections (272). LTD was first described by Dudek and
Bear (95) and Mulkey and Malenka (310). These groups
observed that prolonged low-frequency stimulation can in-
duce a long-lasting reduction of synaptic responses, at the
same synapses that are capable to show LTP. Even more
surprisingly, it was found that the same molecular players
that mediate LTP were also involved in LTD. However,
they act in opposite directions. While AMPA receptors are
internalized during the induction of LTD, they are in-
serted into the membrane which contribute to the induc-
tion of LTP (FIGURE 2B). Some forms of LTD are initiated
by activation of NMDA receptors, by prolonged low-
frequency stimulation (LFS; 1 Hz for 15 min is a typical
protocol) resulting in a modest increase of cytosolic Ca2⫹
levels (whereas Ca2⫹ levels after tetanic stimulation in-
crease strongly). Instead of resulting in the activation of
kinases, a modest increase in Ca2⫹ levels leads predomi-
nantly to activation of phosphatases, due to their higher
affinity for Ca2⫹ (250; for a review, see Ref. 409). Espe-
cially the phosphatase calcineurin (also alternatively ab-
breviated as PP2B) is involved here, as well as PP1 (FIG-
URE 2B). NMDA receptor-dependent LTD is easier to
induce in the hippocampus during development of the
nervous system, and the likelihood of induction decreases
with age, concomitantly with a switch between NMDA
receptor subunits with different opening kinetics. During
development, the expression of the NMDA receptor sub-
unit 2B (NR2B) decreases (which helps to mediate LTD),
whereas the expression of the NR2A subunit rises in-
creasing the likelihood for LTP expression (18, 22, 63).
In addition, a form of NMDAR-independent LTD was dis-
covered, which relied on the activation of metabotropic
glutamate receptors (mGluR) (19, 176). This third type of
glutamate receptors is not linked to an ion channel but
instead to G proteins. The mechanism of mGluR-dependent
LTD is much less clear. As it is blocked by the postsynaptic
injection of Ca2⫹ chelators, its induction seems to rely on
postsynaptic mechanisms. However, it results in a de-
creased frequency but not amplitude of miniature excit-
atory postsynaptic potentials (mEPSPs), indicating a pre-
synaptic phenomenon that can be observed with the patch-
clamp techniques. This suggests a presynaptic locus of
expression (for a review, see Ref. 12). Occlusion studies
indeed indicate that LFS-induced LTD (NMDAR depen-
651
 BIOLOGY OF MEMORY EVENTS

dent) can still be induced after mGluR-dependent LTD is
saturated. This confirms that the two forms of LTD rely on
independent signaling mechanisms and that the activation
of the two receptor types occurs independently. NMDA
receptor-dependent LTD is readily induced in juvenile, but
not in adult mice, suggesting that its main task is to refine
the young neuronal network by targeted pruning of less
significant contacts during late phases of development.
mGluR-dependent LTD is still inducible in the adult system
(176) and thus seems to be one of the main mechanism
needed to keep the balance of synaptic weights in the adult
hippocampus.
B. Spike-Timing Dependent Plasticity
LTP and LTD can be induced via alterations of stimulus
frequency of the presynaptic neuron alone or via pre- and
postsynaptic stimulation. As outlined above, Hebb postu-
lated that coincident activation of the pre- and postsynapse
leads to a strengthening of these specific synapses,
whereas noncoincident synaptic activity will lead to the
weakening of the connectivity. In this context of timing,
spike-timing dependent plasticity (STDP) is an interest-
ing concept, since it confirms Hebb’s rule and offers an
explanation for the time dependency of storage events in
the brain taking into account the opening time of the
NMDA receptor (FIGURE 3; reviewed in Ref. 79). Exper-
imentally, STDP can be induced by paired triggering and
synaptic weight
recording of precisely timed spikes in pre- and postsyn-
aptic neurons (280). In the presynaptic neuron, the elec-
trical stimulation causes well-timed neurotransmitter re-
lease; in the postsynaptic neuron, electrical stimulation
generates a back-propagating action potential (bAP) run-
ning from the soma into the dendritic compartment. If
presynaptic activity precedes the postsynaptic spike by
5–15 ms (representing a situation in which a presynaptic
neuron contributes to firing the postsynaptic neuron), the
strength of the active synapses will be enhanced (LTP).
On the contrary, if the postsynaptic spike occurs shortly
before transmitter release and binding, uncorrelated ac-
tivity is mimicked and synaptic strength is reduced (in-
ducing LTD). As a consequence, according to this model,
inputs on a given neuron compete for grouped activity to
form stronger connections, leaving less precisely timed
inputs to be weakened. STDP was observed so far on
more than 20 neuronal connections in different brain
areas (109) and may represent an important instructor of
the developing brain (79) as well as a crucial mechanism
for memory storage in the mature brain (109).
Functionally, Hebbian STDP strengthens synaptic connec-
tions whose activity is causal for the postsynaptic spike and
does weaken noncausal synaptic activity (1). Additionally,
the opposite phenomenon called Anti-Hebbian-STDP has
been observed. In this case of Anti-Hebbian-STDP, synaptic
neurotransmitter release (presynaptic spike) precedes the

tpre – tpost [ms]

FIGURE 3. Spike-timing-dependent synaptic plasticity

l
tia

(STDP). Coordinated timing of presynaptic activity and post-

sy

n
n

te

synaptic back-propagating action potential (bAP) cause de-

ap

po
tic

polarization and activation of spines, subsequent Ca2⫹ in-

n
in

tio
pu

flux, and finally, can lead to the induction of LTP or LTD.

ac
t

spine
depolari-
sation

Ca2+ influx

LTP/LTD

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 MARTIN KORTE AND DIETMAR SCHMITZ
postsynaptic spike and will lead to LTD (whereas the oc-
currence of the postsynaptic spike before presynaptic trans-
mitter release will lead to LTP). This phenomenon has been
detected at excitatory synapses on medium spiny neurons
(which are inhibitory themselves), on cholinergic interneu-
rons (118), as well as on GABAergic interneurons (241,
242). In most cases it is associated with LTD (for details, see
Ref. 109).
An attractive candidate for mechanisms to regulate the tim-
ing of pre- and postsynaptic spikes is phase-phase coupling,
or phase synchronization (429). Here, spike times are de-
termined by the oscillation frequencies of the neuronal as-
semblies of which the pre- and postsynaptic neurons are a
part (further details will be outlined in sect. IIIB). By this
mechanism, an oscillatory input that impinges on a cluster
of rhythmic discharging neurons might meet either the cri-
teria of Hebbian STDP (“in-phase” rhythmic activity of
input and target assembly) or those of anti-Hebbian STDP
(“out of phase” rhythm of input and target assembly; for a
review, see Ref. 110).
C. Cellular and Molecular Mechanisms of
STDP
Normal Hebbian STDP is most likely implemented via
NMDA receptor function, as described above in the context
of LTP at the CA3-CA1 hippocampal synapses. The same
would hold up for LTD; here the NMDA receptor activa-
tion leads to a moderate Ca2⫹ influx (in contrast to the high
Ca2⫹ entry via the NMDA receptor during strong stimula-
tion). The induction of LTP or LTD leads to the removal or
to the insertion of AMPA receptors into the postsynaptic
membrane, respectively (177, 276). At other synapses, dif-
ferent mechanisms of LTP/LTD are realized, e.g., at the
hippocampal mossy fiber-CA3 as well as at the parallel fiber
synapses in the cerebellum, as the induction and expression
mechanisms are presynaptic (for a review, see Ref. 321).
For STDP it is mechanistically important that Ca2⫹ entry
into the cell via the NMDA receptor or voltage-sensitive
Ca2⫹ channels (VSCC) is timed precisely. VSCC are acti-
vated via the bAP leading to a nonlinear increase in the
cytosolic Ca2⫹ when paired with a synaptic response. Al-
ternatively, activation of mGluR resulting in the release of
Ca2⫹ from intracellular stores plus Ca2⫹ entry via VSCC,
again activated via the bAP, fulfill the same purpose (227).
For the implementation of this supralinear Ca2⫹ entry, tim-
ing is important. The bAP needs to activate VSCC and by
this means depolarizes the membrane in spines, which leads
to the removal of the Mg2⫹ block inside the channel of
NMDA receptors resulting in the maximal Ca2⫹ entry. At
some hippocampal synapses, phospholipase C (PLC) is used
as a coincidence detector instead of the NMDAR. Here
release of endocannabinoids (neuromodulatory lipids) are
induced by either depolarization or activation of G protein-
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coupled receptors, and it is significantly boosted by the
coincidence of depolarization and receptor activation. At
these synapses, the PLC serves as the coincidence detector of
presynaptic activity (which activates mGluR and conse-
quently the release of Ca2⫹ from intercellular stores) and
postsynaptic activation of VSCC via the bAP (for further
details, see Ref. 163).
Taken together, precise timing develops on the one hand
from molecular coincidence detectors (NMDA receptor,
PLC) and on the other hand from the dynamics of electrical
signaling in dendrites and spines (this includes the AMPA
receptor-mediated signals and the bAP).
Different induction mechanisms for changing synaptic
properties (and consequently the characteristics of neuronal
networks) are not restricted to synapses between different
neuronal types or even brain regions in the CNS. Even
within the same neuron, synapses may be ruled by different
regimes: bAPs are short lasting and propagate with decre-
ment. The bAP loses already 50% of its magnitude in the
first 100 ␮m from the soma and disappears completely in
the more distal parts of dendrites of pyramidal neurons
(411). In layer 5 pyramidal neurons of the cortex, Hebbian
STDP can induce LTP only in proximal synapses, whereas
distal synapses show no LTP under these conditions (for
further details, see Ref. 400). This mechanism is also pres-
ent in phylogenetically older palaeocortical structures like
the piriform cortex (188). De facto, this implies that the
rules for synaptic plasticity change between different zones
within a single pyramidal neuron in the neocortex, piriform
cortex, or hippocampus. In other words, the molecular
mechanisms and the timing requirements for modifying the
connectivity of neuronal networks might be defined by dif-
ferent synaptic plasticity thresholds (146, 411). This means,
in simple terms, that proximal synapses will be affected by
the bAP and will most likely implement STDP-LTP. Conse-
quently, this LTP will not or to a lesser extent depend on the
firing rate and on synaptic cooperativity. In contrast, syn-
apses at the distal part of large dendritic trees will be prone
to show STDP-LTD (129) or even anti-Hebbian-LTD
(399). Furthermore, the proximal synapses will depend to a
larger extent on firing rate and cooperativity. The most
distal synapses may be completely outside the STDP regime
depending on cooperativity and firing rates largely by
neighboring inputs (an example is given in Ref. 143).
Taken together, depending on the localization at the den-
dritic tree, different plasticity thresholds and diverse timing
rules are implemented to increase or decrease the influence
of STDP on different forms of synaptic plasticity.
Recent studies have questioned the necessity of bAP for the
induction of plastic changes under all circumstances (158,
257, 396). One has especially to consider that synaptic
strength changes are not exclusively determined by den-
653
 BIOLOGY OF MEMORY EVENTS
drites; they are also implemented by molecular mechanisms
and biophysical properties of synapses themselves. As out-
lined above, the relevance of STDP seems to vary between
different types of synapses and their distance from the
soma. Additionally, one of the most important parameters
for the induction of synaptic plasticity is the strength of
postsynaptic depolarization. Here, STDP is only one out of
several variables influencing the physical properties of den-
dritic membranes (which include AMPA receptor-mediated
depolarization, spike timing, spike frequency, and postsyn-
aptic depolarization) within a multifactorial plasticity pa-
rameters (for a review, see Ref. 158). A limitation of STDP
has been so far the fact that under experimental conditions
bAPs are usually generated by somatic current injection,
whereas in vivo, action potentials are most likely the result
of an strong excitatory input (reviewed in Ref. 257). “To
‘naturalize’ STDP, it will be important to focus on the mul-
tiple natural sources of synaptic depolarization rather than
on artificially induced spikes” (158). For instance, the de-
polarization achieved via the AMPA receptor channel al-
ready has a major impact on Ca2⫹ influx. In addition, the
strength of synapses is influenced via Ca2⫹ spikes in spines,
which are active before, during, and after the dendritic spike
(bAP). Here, an intriguing idea is that form and function
depend on each other; the morphology of spines could have
a significant effect on synaptic function, e.g., changing the
diameter of the spine neck could affect Ca2⫹ diffusion out
of the spine into dendrites and by this means the effectivity
of a bAP into spines might be influenced (271, 323).
It is speculated that STDP is not only important as a cellular
learning rule, but it is also of utmost importance for the
implementation of topographic maps and receptive fields
during the development of the sensory systems of the brain
(410). Additionally, it might assist in sharpening the com-
petition between convergent inputs (1). In the adult nervous
system, Hebbian STDP supports learning of temporal se-
quences (356). The logic goes as follows: sequential, recur-
rent activation of a neuronal network would drive LTP in
the so-called forward direction, and LTD would be driven
in the reverse route. It would also be mandatory for the
prediction of future events from stimuli experienced in the
past. And indeed, with the use of the tadpole visual system,
experimental evidence has been provided for an STDP
mechanism in vivo (105, 114). In addition, it should be
noted that some psychophysical experiments with human
visual perception do support the timing rules of STDP
(480). STDP was also observed via the variation of the
stimulus timing for the perception of retinotopic position
(130). This could also be observed for higher-order visual
processing: in an experiment concerning face perception, in
which a rapid series of two faces (100 pairings over 2 min)
are presented to test persons, a bias for the perception of the
second presented face was observed. Following the STDP
prediction, strict timing requirements have to be fulfilled,
since it only works for pairing delays up to 60 ms (291).
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These findings support the hypothesis that STDP-like plas-
ticity indeed occurs in the human CNS and is instrumental
for sensory perception. Overall, at least for simple visual
perceptions, stimulus-timing dependent plasticity changes
the orientation and also spatial position perception with a
time regime compatible with STPD rules. Also, data ob-
tained in humans using transcranial magnetic stimulation
(TMS) are in line with timing requirements predicted from
STDP rules (259, 469). Finally, for hippocampal place cells,
it could be shown that the sequence learning of spatial po-
sitions is compatible with Hebbian-STPD-LTP on the cel-
lular level (293). Moreover, the rate and timing dependent
STDP model fits to results obtained by Bush et al. (49) to
explain spatial sequence learning of place cells with over-
lapping place fields.
Taken together, timing between pre- and postsynaptic neu-
rons is certainly an important feature of plasticity events in
neuronal networks. The relatively new concept of STDP has
significantly broadened the understanding on how this tim-
ing can be achieved and directed the focus on the functional
involvement of the postsynaptic neuron in general and bAPs
in particular. But despite the conceptional strength of
STDP, several important questions remain: how important
is the absolute level of postsynaptic depolarization and
Ca2⫹ entry, despite the relatively moderate effects of bAPs?
And in which way do trans-synaptic signaling and other cell
types contribute to plasticity and how can this be related to
STDP? In this respect, STDP has improved the tools and the
theoretical analysis of learning-related plasticity in neuro-
nal networks. But for future explorations it seems to be
more important to focus on the weight of postsynaptic de-
polarization (74, 258) and an increase in cytosolic Ca2⫹
concentration (396). For this, bAPs are important, espe-
cially considering that bAP evoked Ca2⫹ transients can be
enhanced by neuronal activity (189). However, they are not
the only current source to reach a high degree of depolariza-
tion or to mobilize Ca2⫹. STDP focuses heavily on the impor-
tant contribution of the postsynaptic neuron as an instructor
for the early events in inducing synaptic plasticity. But in ad-
dition to postsynaptic events, a more general view also has to
include presynaptic changes in function and structure, trans-
synaptic signaling at the synaptic cleft, and the role of astro-
cytes as members of the so-called tripartite synapse (for re-
views, see Refs. 169, 329). A detailed description of the mo-
lecular players taking place in the different cellular
compartments of neurons and glia cells will be given in the
following sections.
D. Well-Timed Molecular Events Underlie
Processes of Synaptic Plasticity
The initiation of many synaptic plasticity events in the hip-
pocampus seems to be orchestrated by the postsynaptic
compartment, which in excitatory neurons is the spine. As
outlined above, a spine constitutes a distinct subcompart-
 MARTIN KORTE AND DIETMAR SCHMITZ
ment (almost like an organelle) at dendrites that detects
timing coincidence. The spine utilizes the electrical asym-
metry (“easy in, hard to get out”) implemented by the ge-
ometry of the spine neck to act as a processing machinery
for incoming signals. The geometry of the narrow spine
neck isolates the small volume protrusion, and this has two
important functional consequences for processes of synap-
tic plasticity: 1) bAPs invade the spine without decreasing in
amplitude, and 2) minimal amounts of ion flux over the cell
membrane result in significant depolarization (5, 171). The
asymmetry in electric signal propagation becomes clear by
considering the direction of current flow from the spine
(high impedance) to the dendrite (low impedance): a spine-
generated EPSP is highly attenuated when it flows into the
branch of a dendrite (10, 37, 271). Therefore, the spine can
be studied as a separated functional unit (for a detailed
discussion, see Ref. 158). This supports the fact that the
spine is not just a little protrusion of the dendrite, but
instead a densely packed compartment itself filled with
actin, actin binding proteins (70, 119, 174, 492), and
postsynaptic molecules (214, 393). These molecules need
to interact in a precise spatial-temporal pattern to induce
and to maintain changes in the strength of neuronal con-
nectivity (FIGURE 4 – 6). In this spatial-temporal interplay
at glutamatergic synapses, the depolarization achieved
by AMPA receptors is the first sensitizing event which
depolarizes the postsynaptic membrane and thus allows
coincidence detection of the activity of the pre- and post-
synapse via the NMDA receptors. This AMPA receptor-
mediated depolarization can also be important for the
additive activation of VDCC, when a bAP enters the
spine (compare sect. IIB) (131, 132, 170).
E. From the Pre- to the Postsynapse:
Events in Time
An integrated view at the paradigmatic CA3-CA1 hip-
pocampal synapse (see sect. I) could be envisioned like this.
Activity-dependent increase in intracellular Ca2⫹ levels in
the postsynapse, the common crucial step for converting
electrical signals into biochemical activity, is achieved by
three sources: opening of NMDA receptor channels, VGCC
activity, and/or release from internal stores (388). The in-
crease in Ca2⫹ levels induces a cascade of events involving
the activation of kinases (372) and ultimately leading to
the amplification of synaptic transmission (FIGURE 4).
The concentration of cytosolic Ca2⫹ is a good predictor
of the magnitude of synaptic potentiation (319). High
Ca2⫹ levels activate different effector kinases, like PKA,
Ca2⫹/calmodulin-dependent protein kinase II (CaMKII),
Fyn, Scr, and protein kinase Mzeta (PKM␨, an atypical
PKC isoform). These kinases initiate processes to main-
tain an increase in synaptic strength acting in various par-
allel and serial signal transduction pathways (for a review,
see Refs. 197, 372). One of the first kinases discovered in
this respect is CaMKII, which is highly concentrated in
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spines of excitatory neurons and its inhibition prevents LTP
induction (273). One of the first events after the rise of Ca2⫹
levels in the postsynaptic compartment is the activation of
calmodulin upon binding of Ca2⫹, and the resulting com-
plex activates CaMKII (FIGURE 4). As a consequence, CaM-
KII autophosphorylates and is now constitutively active,
independent of Ca2⫹ or calmodulin. CaMKII translocates
to the postsynaptic density (PSD), a meshwork of densely
packed postsynaptic proteins juxtaposed to the presynaptic
active zone (134, 277). At the PSD, CaMKII phosphorylates
amino acid residues on the AMPA receptor subunit GluR1,
thus increasing its opening probability. It also activates fur-
ther signaling molecules, which mediate the insertion of
more AMPA receptors into the postsynaptic membrane
(265; for a review, see Ref. 177).
A possible site at which CaMKII (and also for PKA) phos-
phorylates the AMPA receptor subunit GluR1 is a serine at
position 831 (Ser831). If Ser831 is phosphorylated, the
opening probability of the AMPA receptor increases (27,
406), thus resulting in an increase in the EPSP size at this
particular synapse. But the phosphorylation of AMPAR
subunits has an even more important effect on the receptor
insertion into the postsynaptic membrane. It induces the
delivery of GluR1 subunit to the PSD at a higher rate (FIG-
URE 4) (48, 87, 274, 409; for a review, see Ref. 177). AMPA
receptors are tetramers (GluR1-GluR4) and are delivered in
pairs of subunits (367; for a review, see Ref. 177). Mostly,
GluR1/R2 and GluR2/R3 AMPA receptor compositions/
assemblies are inserted into the postsynaptic membrane
(460). Under baseline synaptic conditions, GluR1 subunits
undergo a cycle of membrane insertion and removal with a
slow rate, whereas GluR2/R3 subunits cycle at a constantly
higher rate (164, 340, 395; for a review, see Refs. 71, 177).
During elevation of intracellular Ca2⫹, GluR1/R2 insertion
increases, probably caused by exocytosis of endosomes lo-
cated in the spine. This event involves the small G protein
Rab11a inserting GluR1/R2 into the spine membrane, most
likely at extrasynaptic sites. Therefore, the synaptic strength
increases only if lateral diffusion delivers these AMPA recep-
tors to the PSD (for a recent review, see Ref. 177). Incorpora-
tion into the PSD is mediated by a specific TARP, the accessory
subunit stargazin, which mediates the interaction of AMPA
receptors with PSD95 (one of the most prominent scaffolding
proteins in the PSD) (382). Phosphorylation of stargazin leads
to a decrease in AMPA receptor mobility trapping the recep-
tors at the PSD. By this plethora of highly regulated mecha-
nisms, the composition and total number of postsynaptic
AMPA receptors change after LTP induction. In addition to
the direct posttranslational modifications of AMPAR, it is cur-
rently debated if another crucial step for LTP induction is the
phosphorylation of transmembrane AMPA receptor regula-
tory proteins (TARPs), which would then alter AMPAR inser-
tion, membrane clustering, and traffic (434, 435; for a discus-
sion of this issue, see Ref. 177).
655
 BIOLOGY OF MEMORY EVENTS

A B
PRESYNAPTIC PRESYNAPTIC
Neurotransmitter
NEURON molecules AXON
TERMINAL
Synaptic
Depolarization vesicle

Neurotransmitter
Synaptic Vesicle uptake
vesicle 1 mobilization
SYNAPTIC Endocytosys
2 B Neu- PSA-
CLEFT Glutamate
Activ A C rexin NCAM NCAM
Na+ Mg2+ e zone EphrinB
Ca2+ Ca2+ release Docking and SYNAPTIC
Na+ Fusion and CLEFT
Na+ priming
VSCC axocytosis
Kainate 6
AMPA NMDA AMPAR Retrograde
receptor receptor receptor P NMDAR messenger
P (BDNF, NO, endo-
PSA- cannabinoids)
NCAM
EphB Neuro- NCAM
P login
Calcium PSD
Depolarization AMPA influx
receptor Lateral
PKA diffusion Exocytosis
trafficking POSTSYNAPTIC
Adenyl DENDRIC
cyclase AMPAR
Endocytosis SPINE
cAMP
PKC Degradation
P
Intracellular instead of
MAPK Ca2+ Calmodulin International

CaMKII
CREB

POSTSYNAPTIC
Protein synthesis NEURON

FIGURE 4. Events and signaling pathways mediating functional synaptic plasticity. Different events partici-
pate in the strengthening of a synapse and in the manifestation of LTP. A: signaling from the pre- to the
postsynapse: action potentials arriving at the presynaptic terminal initiate Ca2⫹ influx through VSCCs resulting
in the release of glutamate at the active zone. After activation by binding of their ligand glutamate, postsynaptic
AMPA and kainate receptors conduct Na⫹ initiating the depolarization of the postsynaptic membrane. Upon
depolarization, Mg2⫹ ions are removed from NMDA receptors channels allowing the Ca2⫹ influx into the
postsynaptic cytosol resulting in the activation of Ca2⫹-dependent enzymes (e.g., CaMKII, PKC, adenyl cyclase).
Activation of the CaMKII cascade facilitates AMPA receptor trafficking by the phosphorylation of specific
AMPAR subunits. B: retrograde signaling from the post- to the presynapse: diffusible retrograde signaling
messengers like BDNF, NO, and endocannabinoids are released by the postsynapse. Retrograde messengers
bind to their receptors in the presynaptic membrane modulating the neurotransmitter release facility by, e.g.,
modulating the Ca2⫹ influx into the presynapse. Increased Ca2⫹ concentrations are followed by an extensive
vesicle mobilization resulting in the augmented vesicle docking and priming and finally in vesicle fusion and
neurotransmitter release. Vesicles are recycled by endocytosis and neurotransmitters are regained by specific
transporters. Retrograde messengers cause changes in the release probabilities of neurotransmitters at the
presynaptic side, by this means the strengthening of the synapse would be ensured via presynaptic mecha-
nism, including a higher mobilization of vesicles (indicated as 1), and the release probably could be increase
(indicated as 2). Trans-synaptic signaling (6): presynaptic neurexins (NX) and postsynaptic neuroligins (NL)
cross the synaptic cleft transducing signals to the respective compartment. Cadherins transmit signals in a
Ca2⫹-dependent manner and immunoglobulins like NCAM and PSA-NCAM contribute to the adhesion between
pre- and postsynapse. Extracellular matrix (ECM): the netlike ECM contains proteoglycans and glycoproteins
and is considered to maintain stabilized structures. It might control the lateral diffusion of various receptors in
their cell membrane and for this contribute to processes of synaptic plasticity.

The functional effects of AMPA receptor insertion into the
spine membrane are gradual for most synapses, but for
some synapses they are extreme. Prior to LTP induction, the
so-called silent synapses have no transmission at all (307).
Their functional significance and characteristics are still
controversial, overlapping with the debate of the pre- or
postsynaptic locus for LTP induction in the hippocampus.
But some experimental evidence points to the fact that
strong postsynaptic depolarization leads to the insertion of
AMPA receptors into the postsynaptic membrane of silent
synapses which so far only contained NMDA receptors.
This insertion implies that EPSPs appear after LTP induc-
tion when no depolarization was detectable before (138,
307). Furthermore, the terminology is imprecise and con-
fusing, because synapses lacking AMPA receptors are not
really silent, but “mute” as opposed to a truly silent syn-
apse, which would not undergo any transmitter release and
thus not “speak.” Speaking of “mute” synapses would in-

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 MARTIN KORTE AND DIETMAR SCHMITZ

A
LTP
Presynaptic Presynaptic

LTD
AMPAR

NMDAR

Synaptic
vesicles
Spine head Spine head

docked synaptic vesicles

AMPAR content

Number of
PSD size

Spine volume PSD size

B polymerization
G-actin F-actin G-actin F-actin

barbed polymerization
G-actin F-actin end polymerization

F-actin
pointed depolymerization ↓↓
end
depolymerization ↓↓ F-actin stability ↑↑
depolymerization ↑
↑
F-actin stability G-actin depolymerization F-actin stability ↑↑

C
N-cadherin
Vezatin

syndecan-2

5-HT2AR
integrin α5

integrin α3
TSPAN7
GluA2

EphB2

TrkB

PAK
Par-1 ka
p190RhoGAP

n
a t eni PICK1 GIT1 CASK ka
lir ERK1/2 Rac1 lir
in
β-c αPIX
FAK in Tiam1 PAK
PAK3

spine enlargement

FIGURE 5. Structural plasticity and actin dynamics. A: structural plasticity induced via activity-dependent
synaptic plasticity can lead to a growth in the postsynaptic density (PSD) and the whole spine volume (after LTP),
or to a shrinkage (LTD) accompanied by the change in the number of AMPA receptors in the PSD and
presynaptically the number of docked presynaptic vesicles. B: actin filament plays a major role in the regulation
of the spine dynamics. Upon LTP induction, actin polymerization increases close to the PSD and the G-actin to
F-actin ratio shifts towards the filamentous F-actin resulting in spine head enlargement. LTD induction leads to
the shrinkage of the spine head and increased actin depolymerization. C: depicted is a set of molecules that
interacts with the actin cytoskeleton. This graph highlights the main PSD-95-associated membrane or scaf-
folding molecules, which are involved in the regulation of spine formation and changes of in spine shape.

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 BIOLOGY OF MEMORY EVENTS

Folded
m7G protein LOCAL
5 Ubiquitin DEGRADATION
40S
eEF2 Ub Ub
60S Ub Ub

Nascent
polypeptide Proteasome

40S
elF4E m7G

elF4G 40S 3 Met-i

elF2
PABP Degraded
GTP
protein
2

elF4E PABP

4EBP

1 RBPS
RBPS

LOCAL
TRANSLATION

RNA trafficking Synapse to nucleus signal

FIGURE 6. Local protein synthesis and degradation in dendrites and spines. mRNAs for spine-localized
proteins are transcribed in the nucleus and transported into spines by specific transport granules (RNA
trafficking). Here, the 3’UTR of the mRNA is bound by CPEB until the translation is initiated by synaptic
activation. Now, CPEB is phosphorylated and recruits the poly(A) increasing machinery. After PABP binding,
the translatory factors are captured and the local translation is performed. Proteins supposed to be specifically
degraded in proteasomes of spines after ubiquitin-dependent labeling in an activity-dependent manner. CPEB,
cytoplasmic polyadenylation element binding protein; eIF4G, eukaryotic translation initiation factor 4 gamma;
eIF4E, eukaryotic translation initiation factor 4E; PABP, poly(A) binding protein; Ub, ubiquitin; 3’UTR, 3’
untranslated region; arrows indicate where neuronal activity changes and alter the dynamic the system.

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 MARTIN KORTE AND DIETMAR SCHMITZ
dicate that transmitter release is not initially absent, but the
amount of postsynaptic AMPA receptors is not sufficient to
induce postsynaptic responses (452, 453).
In the context of AMPA receptor cycling in and out of the
cell membrane of spine, it is noteworthy that evidence is
accumulating showing also NMDA receptors cycle in and
also out of the postsynaptic membrane (for a detailed dis-
cussion, see Ref. 202).
Finally, it should be considered that the so far described
early LTP (E-LTP), lasting for 1–3 h, does not necessarily
lead to long-term changes in synaptic strength (376). It is
generally believed that distinct changes at the synapse lead
either to LTP, which lasts 1–3 h (E-LTP), or to L-LTP,
which lasts for 3–10 h and probably even longer. Distinc-
tive inducing stimuli trigger very different but partially
overlapping biochemical pathways depending on how long
the plasticity changes at synapses are maintained. Notably,
induction of L-LTP leads to activation of signaling path-
ways including PKA and MAPK (also known as ERK) (317,
318). In addition, several transcription factors [e.g., cAMP/
Ca2⫹-responsive-element binding protein (CREB), Elk-1]
which are expressed constitutively are phosphorylated and
by this means activated to strengthen transcription of
downstream elements that most likely mediate structural
and functional changes of the synapses (196, 486). In recent
years, two prominent candidates, the brain-derived neu-
rotrophic factor (BDNF) and the brain-specific, atypical
PKC isoform PKM␨ have emerged as key molecular players
for maintaining L-LTP and processes of long-term memory
(333, 341, 373). The overall excitability of a neuron on a
larger time scale also depends on neuromodulatory neu-
rotransmitters acting via different metabotropic receptors
to activate signaling cascades, which boost or maintain the
initial NMDA receptor-mediated plasticity (30). These
modulatory inputs have to be taken into account, because
they give input to excitatory as well as inhibitory neurons in
addition to glutamatergic or GABAergic transmission.
Therefore, the picture of molecular timing events would not
be complete without considering metabotropic G protein-
coupled receptors (GPCRs). GPCRs exist for many ligands
with a variety of subtypes for each ligand coupled to differ-
ent signaling pathways (30). GPCRs are highly clustered in
the vicinity of synaptic membranes and provide a sort of
modulation attuned to a wide range of different input sce-
narios. Overall, one of the most important functions of the
metabotropic receptors is the modulation of synaptic
strength in response to previous synaptic activity. Just to
give an example, there are at least three different metabo-
tropic dopamine receptors that interact with heterotrimeric
G proteins generally promoting LTP (57), and there are at
least two other dopamine receptors that activate other G
proteins that generally promote LTD (57). The ensemble of
GPCRs, G proteins, and cellular signal transduction com-
ponents at a particular synapse varies with age, epigenetic
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status, and history of neuronal activity at a particular syn-
aptic side. GPCR regulatory signaling primarily works to
control a network of interacting protein kinases that cata-
lyze the transfer of phosphoryl groups to definite serine and
threonine residues in regulatory target proteins. This sets
the scene for future events quite powerfully; it has been
estimated that a third of all cytoplasmic proteins are subject
to kinase regulation (421). However, reviewing the actions
of these important molecules is beyond the scope of this
review; see the following excellent and recent reviews: Ref-
erences 12, 23, 139, 263, 272, 309, 415.
F. From the Post- to the Presynapse:
Retrograde Signaling
So far we have described the prototypic CA3-CA1 LTP
induction mechanism as being implemented in the postsyn-
apse, but the mechanisms underlying synaptic plasticity are
pleiotropic and include different cell types and cell compart-
ments. Directly following the postsynaptic actions which
initiate LTP induction at CA3-CA1 hippocampal synapses,
presynaptic changes due to retrograde signaling have to be
taken into account (169, 196). Retrograde trans-synaptic
signaling occurs via diffusible retrograde messengers [can-
didates are endocannabinoids, BDNF, nitric oxide (NO),
and arachidonic acid]. Depending on the activation pattern,
as well as on the type of neuronal circuit in different brain
areas, different signaling systems might be activated. In ad-
dition, or alternatively, to the NMDA receptor also
metabotropic glutamate receptors (mGluR9) or endocan-
nabinoid type 1 receptor (CB1) signaling mediate different
forms of plasticity (447).
1. Endocannabinoids
As a paradigmatic example for a retrograde signaling sys-
tem involved in processes of synaptic plasticity, endocan-
nabinoids (endogenous cannabinoids, eCB) and their recep-
tors will be presented here (66, 89, 126, 237, 348, 465).
Endocannabinoid signaling influences the propensity of the
synaptic network for plasticity alterations by modifying
GABAergic inhibitory contributions or by regulating re-
lease probabilities of excitatory synapses (494), thereby re-
alizing a form of metaplasticity (4). Metaplasticity means
that the previous history of synapses changes the rules of
synaptic plasticity (see sect. IIO).
From the molecular viewpoint, eCBs, the ligands of CB1
receptors, are hydrophobic lipids and do not need to be
packed into vesicles. They are produced out of glycerophos-
pholipids and are directly released from the cell membrane
after the activation of the appropriate enzymes (205). It is
now well recognized that postsynaptic neurons in the hip-
pocampus and several other brain regions release eCBs in
response to a rather strong depolarization. This might also
occur after the activation of G protein-coupled receptors
659
 BIOLOGY OF MEMORY EVENTS
(e.g., mGluR or muscarinic receptors). This results in the
activation of presynaptic CB1 receptors inhibiting neurotrans-
mitter release at either excitatory or inhibitory synapses (FIG-
URE 4). CB1 receptors are one of the most abundant G pro-
tein-coupled receptors in the CNS and are predominantly lo-
calized on axon terminals (205). In the hippocampus, eCBs are
for example mandatory for a certain form of LTD at inhibi-
tory as well as excitatory synapses, thereby restricting LTP
(65, 403). They also regulate the heights of LTP directly (305).
2. Presynaptic release machinery
An important presynaptic parameter to change/affect syn-
aptic strength is the release probability. The process of neu-
rotransmitter release is highly regulated, and in principle,
each of the highly controlled events leading to neurotrans-
mitter release would be suitable for change due to altered
neuronal activity, namely, vesicle recycling, storage and
mobilization, docking at the presynaptic membrane, prim-
ing, and fusion (184, 398). Good candidates for presynaptic
regulatory elements are synapsins, which can be phosphor-
ylated via kinases regulated by neuronal activity. Their
phosphorylation alters the tethering of the actin cytoskele-
ton with synaptic vesicles and regulates vesicles in the read-
ily releasable pool (61). And indeed, synapsin-deficient/
knockout mice do have a reduced number of vesicles in the
reserve pool and show behavioral abnormalities in learning
tasks (365). Further on the regulation of the different vesi-
cles pools, also the docking and fusion of synaptic vesicles is
highly regulated. Here, vesicles undergo a maturation pro-
cess to become fusion competent. In this process, SNARE
proteins (soluble NSF attachment protein receptor) come
into close contact with the plasma membrane and with
Ca2⫹ channels. The active zone of the presynaptic mem-
brane where the vesicles release their neurotransmitters is
organized by the cytomatrix at the active zone (CAZ),
which is a likely a candidate for activity-dependent changes
in the release machinery (150). A particularly good example
is the study by Matz et al. (288) performed in hippocampal
cultures. This study provides good evidence that the num-
ber of CAZ-related proteins present at individual active
zones changes fast in response to alterations in neuronal
activity (150, 288, 398). At the level of individual signaling
pathways, pharmacological as well as genetic analyses
show that an increase in presynaptic cAMP is mandatory
for mossy fiber synaptic plasticity. The same holds true for
cerebellar parallel fibers (reviewed in Ref. 398). Indeed, a
couple of independent studies implicated that adenylate cycla-
ses and subsequent PKA activation result in the phosphoryla-
tion of CAZ-related proteins leading to the presynaptic induc-
tion of LTP at hippocampal mossy fiber terminals (reviewed in
Ref. 321). In line with this is the finding that voltage-depen-
dent Ca2⫹ entry into the presynaptic terminal triggered by
high frequencies of action potentials might directly activate the
adenylate cyclase/PKA pathway. This results in the phos-
phorylation of proteins like synapsins (reviewed in Ref.
321). Presynaptic mechanisms for the induction of LTP also
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include “turning on” mute synapses, as has also been
shown in hippocampal granule cell autapses (chemical syn-
apse formed by the axon on its dendrites of the same neu-
ron) (436). Recordings of Ca2⫹ transients in the postsyn-
apse implied that presynaptic release sites, which have been
silent previously, can be switched on following LTP induc-
tion (360).
Taken together, even if NMDA receptor-dependent forms
of LTP have been in the spotlight of experimental research
for LTP induction, also presynaptic components have to be
considered and could further increase the cellular instru-
ments to implement fine-tuned changes in synaptic strength.
In addition to the induction mechanisms that are imple-
mented directly at excitatory or inhibitory synapses, also
other cell types (astrocytes or microglia cells) and neuro-
modulators (such as dopamine, acetylcholine, and sero-
tonin) may be major components of the transition from
short- to long-term memory processes (96, 141, 142, 426).
G. Trans-synaptic Signaling at the Synaptic
Cleft Contributing to Synaptic Plasticity
There is also accumulating evidence indicating that the
space surrounding neurons (peri-neuronal net, PNN) and
the extracellular space between synapses (synaptic cleft)
must be considered as players in processes of activity-de-
pendent neuronal plasticity. The tiny space between the pre-
and the postsynapse (20 nm) is densely packed with cell
adhesion molecules (CAMs), and it is not an empty space
through which neurotransmitters and neuromodulators dif-
fuse. The most important CAMs are neurexins, neuroligins,
cadherins, and CAMs with immunoglobulin domains
(478).
1. Neuroligin/neurexins
The importance of cell adhesion became evident for the
heterotypic interaction between the presynaptically ex-
pressed cell adhesion protein neurexin (NX) and its post-
synaptically expressed counterpart neuroligin (NL). Due to
a large variety of splice variants, these molecules were orig-
inally thought to provide the potential for a highly specific
trans-synaptic combinatorial code during the development
of the nervous system (239). It became evident that they
also act as modulators of synaptic plasticity. The two NL
isoforms, NL1 and NL2, are targeted specifically to excit-
atory (NL1) and inhibitory (NL2) synapses, respectively
(44). NL1 has the ability to modulate synaptic transmission
via NMDA receptor activation (81) and by this means con-
trols synaptic plasticity. NL1 is in particular mandatory for
the maintenance of synaptic plasticity in the amygdala at
synapses that express NMDA receptors (194, 215). Here,
NL1 knockdown in rats show impaired STDP in thalamic
inputs to the amygdala, whereas cortical inputs were not
affected. These defects in synaptic plasticity result in im-
 MARTIN KORTE AND DIETMAR SCHMITZ
pairments in contextual and cued fear conditioning. Dele-
tion of NL1 also impairs hippocampal CA1 LTP (39, 78).
These alterations in synaptic properties after NL1 knock-
down in rats (194) are accompanied by impaired spatial
memory in a Morris water maze task (215). Interestingly,
impaired learning in two water maze tasks following NL1
overexpression in mice and also impaired hippocampal
CA1 LTP were observed too (78). Changes in synaptic ac-
tivity might induce the transport of NX as well as NL to and
from individual synapses. Evidence for this comes from the
observation that induction of LTP can be achieved via the
application of forskolin (an activator of adenylate cyclases,
leading to PKA activation), and this results in trafficking of
NL1 to the cell membrane, whereas the opposite, induction
of chemical LTD by stimulation with 3,5-dihydroxyphenyl-
glycine (DHPG, a mGluR agonist), causes the internaliza-
tion of NL1 (380).
It can be concluded that the expression of the right amounts
of NL1 is crucial for the proper synaptic function and for
the fine tuning of synaptic plasticity.
2. Cadherins
The cadherin family of adhesion molecules participates in
processes of synaptic development and plasticity (324, 413;
for a review, see Ref. 424). During the early development,
mostly E-cadherins (epithelial cadherin) are expressed,
whereas in the development of the nervous system N-cad-
herins (neural cadherin) are expressed at higher levels (for a
review, see Ref. 424). Cadherins form, and this is a very
interesting feature with respect to synaptic plasticity, Ca2⫹-
dependent homophilic bonds in the synaptic cleft (50, 181,
425, 450); indeed, cadherins are named with reference to
“calcium-dependent adhesion.” The main question is how
cadherins sense changes in neuronal activity and if they
might be able to transmit signals from the extracellular
space to the cytosol. With respect to these questions, it is
noteworthy that Kim et al. (217) could visualize via genet-
ically encoded fluorescence resonance energy transfer
(FRET) the spatiotemporal dynamics of the interaction of
N-cadherins across the synaptic cleft. The results revealed a
fast and partial loss of homophilic interactions upon chela-
tion with an increased level of extracellular Ca2⫹. The usage
of a version of the cadherin molecule with a deteriorated
adhesive activity showed a faster loss of homophilic inter-
actions. This approach could also tackle the question of
how the signal might be transmitted to the cell interior, by
showing that the Ca2⫹-sensitive modulation of cadherin
interactions is transmitted via intracellular ␤-catenin. These
cadherin-␤-catenin complex by this means link synaptic ac-
tivity with processes of synaptic plasticity. Cadherins are
therefore molecules that are responsible for transmitting
dynamic information about the extracellular environment
to both cells that form a synapse. This can occur on a fast
time scale in minutes. The highly conserved cytoplasmic
localized cadherins are associated with the cytoskeleton (3,
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192), and this ensures a direct signaling mechanism to struc-
tural changes at synapses. Tang et al. (428) found that LTP
is compromised if N- and E-cadherin function is disturbed
via antibodies or specific peptides against the extracellular
domains of cadherins.
Taken together, cadherins are well suited to act as trans-
synaptically active sensors of neuronal activity for the pre-
and postsynaptic neuron to enhance or restrict synaptic
plasticity, depending on the precise code of expression and
the precise type of neuronal activity.
3. Immunoglobulin superfamily
In addition to the Ca2⫹-dependent regulation of cadherins,
also Ca2⫹-independent cell-cell adhesion molecules are im-
portant determinants of synaptic plasticity. Here, members
of the immunoglobulin superfamily are important. The
most abundant is the neural cell adhesion molecule (NCAM)
and a molecule named L1. Function blocking antibodies
against NCAM and also for L1 were able to prevent LTP in the
hippocampus if applied prior to the inducing stimulus (267).
NCAM can be modified posttranslationally through the addi-
tion of polysialic acid residues (PSA). PSA-NCAM to NCAM
ratio changes due to neuronal activity, and this alters homo-
philic adhesion, a higher PSA-NCAM content increases the
distance between synapses and therefore allows remodeling
and growth of the synapse (24, 474, 478). PSA-NCAM is
less adhesive compared with NCAM alone. And indeed,
removal of PSA from NCAM, which is naturally occurring
via the enzyme EndoN (an endoneuraminidase), interferes
with the induction of LTP as well as LTD (390).
Taken together, the interesting point of regulation is here,
that the strength of adhesion can be calibrated via the re-
moval or addition of PSA, regulated via an activity-depen-
dent enzyme.
4. Extracellular matrix
In addition to CAMs, the extracellular matrix (ECM) is
another factor influencing synaptic plasticity. Most syn-
apses are surrounded by a dense meshwork of ECM. The
ECM contains proteoglycans and glycoproteins of glial or
neuronal origin. A remarkable feature of the ECM in CNS
is its netlike appearance (PNN) (60), which is constructed
postnatally in the first 5 wk of mouse development (229).
The ECM is considered to be a stabilizer and is most likely
important for the maintenance of a memory engram in the
adult CNS possessing inhibitory effects on structural rear-
rangements and axonal outgrowth (128, 140). Depending
on its precise composition, ECM might control the diffu-
sion of receptors in a lateral manner inside the cell mem-
brane and therefore regulates the proportion of synaptic
and/or extrasynaptic receptors (92, 151). With this means
the netlike structure of the ECM might represent an addi-
661
 BIOLOGY OF MEMORY EVENTS
tional determinant for synaptic plasticity by restricting pro-
cesses of plasticity, which could in the end also support the
expression of stable engrams.
H. BDNF: It Is the Modulator That Mediates
Important Aspects of Long-Term Storage
In addition to classical neurotransmitters, also neurotro-
phins might be important players in promoting the likeli-
hood of plastic changes in neuronal networks. Most of all,
BDNF is implicated in processes of synaptic plasticity. The
transcription of BDNF and its release have been shown to
be activity dependent (252, 262; for reviews, see Refs. 431,
432). BDNF is also a major player in changing functional
synaptic properties during the development of the CNS as
well as in the adult nervous system (for reviews, see Refs.
144, 337). There is also evidence that BDNF affects neurite
outgrowth and the differentiation of certain neuronal sub-
types. Taken together, BDNF was hypothesized to be a
major player for the transformation of functional into
structural changes (231, 289, 427). Genetic approaches elu-
cidated that BDNF knockout mice exhibit a significant re-
duction in synaptic plasticity, most of all in the induction
and maintenance of LTP (232, 343, 351). Remarkably, this
impairment in hippocampal LTP could be rescued by the
virus-mediated local expression of BDNF (233) or via the
application of recombinant BDNF to hippocampal slices
from BDNF knockout mice (343). In a gain of function
experiment, the application of BDNF to wild-type slices
increased synaptic strength and by this means increased the
probability of LTP induction (145, 199, 201). Likewise,
weak electrical stimulation (which alone would not lead to
LTP) together with the local application of BDNF, con-
verted short-term plasticity into LTP (235). Also synap-
totagmin-IV knockout mice, which release higher amounts
of BDNF, show enhanced LTP (82). In addition to these
slice experiments, there is also evidence that BDNF is me-
diating learning behavior in vivo as it is upregulated in brain
areas that are involved in a specific learning task (433).
Furthermore, BDNF⫹/⫺ mice and conditional tropomyo-
sin-related kinase receptor B (TrkB, which binds BDNF)
knockout mice show deficits in hippocampus-dependent
learning (298). Notably also studies on humans indicate
that BDNF is involved in processes of learning and infor-
mation storage. Here the genetic evidence comes from a
common single-nucleotide polymorphism in the human
BDNF gene which leads to the substitution of a methionine
(Met) for the valine (Val) at codon 66 (Val66Met). This has
the consequence that BDNF secretion is impaired (97, 161,
468). This is most likely due to misfolding of the BDNF
protein and leading to a less efficient sorting of the
proBDNF protein into the Golgi apparatus, impairing espe-
cially the activity-mediated release of BDNF. The Val-Met
genotype leads to a compromised performance in hip-
pocampus-dependent learning tasks in humans (97, 161,
468).
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What is a possible mechanism for BDNF to increase the
likelihood of synapses to undergo activity-dependent
strengthening? The signaling cascade seems to involve
the receptor for BDNF, that TrkB receptor. And indeed,
if the interaction of BDNF with its TrkB receptor is
blocked by TrkB-receptor bodies (116) or via anti-BDNF
antibodies (62), hippocampal LTP is strongly impaired.
Using a Cre-deleter mouse line to delete the TrkB recep-
tor from the genome only postnatally and only in the
forebrain region, CA3-CA1 LTP was impaired (297,
298). Furthermore, it was asked if BDNF is an acute
mediator of synaptic changes or if it is a permissive mod-
ulator (337, 350)? BDNF is not needed under all circum-
stances and stimulus protocols (see, e.g., Ref. 473). With
respect to the discussion about the nature and function of
“mediators” and “modulators” of synaptic plasticity,
BDNF is an instructive example. In our view, depending
on the brain area, the type of neuron, the local connec-
tivity, and the required learning task, BDNF most likely
plays a dual role: it acts both as a mediator and as a
modulator of plasticity. It is noteworthy that quite in
contrast to the findings of the TrkB receptor signaling,
which mediates LTP, the pan-neurotrophin receptor
p75NTR, which also binds BDNF, supports negative syn-
aptic plasticity like LTD (366, 470).
There is no “exclusive memory molecule,” and also BDNF
is working in concert with other molecular signaling path-
way. In addition, it is a relevant question if BDNF indeed
belongs to a group of molecules which are major players
(instructive mediators) or if BDNF is more like a permissive
modulator with a more or less supporting role. By this
means it would only be expressed in neurons to support
indirectly processes of synaptic plasticity. If this would be
the case, BDNF would not be directly incorporated in a
rather linear signaling line, leading to functional or struc-
tural activity-dependent changes. With respect to these
thoughts, experiments in which endogenous BDNF is
blocked during the induction period of LTP are telling.
Two studies have been published which used a TrkB-IgG
fusion protein (TrkB-Fc), which scavenges (and by this
means neutralizes) BDNF with high affinity, and function
blocking TrkB receptor antibodies have been used to
block binding of BDNF to the receptor. In both cases,
LTP was impaired in acute slices (116, 201). The inter-
pretation was complicated by the fact that other neu-
rotrophins NT3 and NT4/5 can also bind to the TrkB.
This was resolved by Chen et al. (62), who used specific,
monoclonal antibodies against BDNF or alternatively
against NT3 at the time point of LTP induction. Under
these circumstances, only anti-BDNF antibodies were
able to impair LTP. This is supported by experiments in
which endogenous BDNF was inactivated by “uncaging”
a BDNF-function-blocking antibody (monoclonal) with
a light stimulus (which released the antibody-inactiva-
tion compound from the antibody) right at the time of
 MARTIN KORTE AND DIETMAR SCHMITZ
LTP induction. Only when the BDNF-function blocking
antibody was uncaged by a light stimulus was LTP im-
paired (62). These observations showed that indeed
BDNF directly affects synaptic plasticity, and it strength-
ened the view that indeed it might be an instructive me-
diator, and not just a permissive modulator.
In addition, it could be shown that BDNF does not only
increase the likelihood of LTP induction but supports also
L-LTP maintenance and by this means long-term memory.
Experiments here include studies with BDNF knockout
mice (234) as well as results from experiments in which
BDNF was applied directly (201), experiments involving
TrkB-Fc (116) and conditional TrkB knockout mice (298).
The long-lasting effects of BDNF might be mediated via its
effect on local dendritic translation, and this might produce
proteins that promote cellular processes of memory consol-
idation (46).
However, BDNF action might not be restricted to glutama-
tergic synapses; it might also be involved in changing the
excitation-inhibition balance (for a thorough review, see
Refs. 144, 338). This might be achieved due to the fact that
the GABAergic influence on excitatory neurons is weak-
ened.
Taken together, BDNF seems to be not part of the core
mechanism of LTP induction (even complete BDNF knock-
out mice show residual LTP), but to maintain LTP (L-LTP)
and to fully potentiate a synapse (heights of LTP) BDNF
seems to be an important modulator of synaptic plasticity
(491; for reviews, see Refs. 144, 338, 488). The functions of
BDNF in orchestrating molecular events leading to memory
storage are depending on the developmental stage, the spe-
cific cell type, and also the brain region (488). Overall,
BDNF is most likely an instructive player in the process of
functional strengthening of synapses.
It should also be noted that modulators of synaptic plastic-
ity are as important as mediators. Examples for this state-
ment are modulatory neurotransmitter systems like acetyl-
choline, serotonin (5-HT), dopamine, and epinephrine
(noradrenaline), which are involved in attention and moti-
vational aspects of behavior and have a great influence on
the capacity of long-term memory storage.
I. Local Protein Synthesis and Degradation
In addition to posttranslational modifications like phos-
phorylation and dephosphorylation of plasticity associ-
ated proteins occurring very fast, long-lasting memory
storage also needs the synthesis or the degradation of a
specific set of proteins. New synthesis can occur either via
transcription (signaling to the soma, synthesized proteins
are transported back to the activated synapses) or via
local translation in dendrites. Local mRNA translation is
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an elegant way to solve the problem of how a neuron with
10,000 synapses can maintain changes in a few specific/
selected synapses without affecting others (417, 418).
But how does a neuron know which synapse shows
changes in synaptic strength and has been activated? One
solution would be that a tag is set to specifically mark a
certain synapse. Alternatively but not exclusively, the
proteome of dendrites and spines might be changed lo-
cally at the site of synaptic plasticity alteration via local
protein translation in dendrites. The presence of protein
translation in dendrites was first proposed after polyri-
bosomes had been observed in dendrites (416). In addi-
tion, several forms of LTP are protein synthesis depen-
dent and could still be maintained, when the soma was
cut off from dendrites, but not if translation was phar-
macologically blocked (176, 200). In addition, it was
reported that mRNAs in the soma can bind to proteins,
which shuttle them into dendrites (211, 212). These pro-
teins include Staufen, ZBP1 (Zipcode binding protein 1),
and hnRNPA2 (heterogeneous nuclear ribonucleopro-
tein A2). They form together with the mRNA a kinesin-
dependent transport granule that is transported along
microtubules into the dendrites (211). How the final des-
tination is determined is an open question. It might also
be possible that the transport is not directed to specific
spines, but that the transport granule is stopped and sta-
bilized at activated postsynaptic sites (211).
The mRNAs are not only transported (or captured) close to
active spines, they also need to be translationally regulated,
adding another layer of complexity and regulation to local
protein synthesis in dendrites. One possible scenario is de-
picted in FIGURE 6. mRNA is transported into dendrites,
where cytoplasmic polyadenylation element binding pro-
tein (CPEB) binds to its 3’ untranslated region (3’UTR),
thus inhibiting its translation (FIGURE 6). After the synaptic
activation of specific signaling cascades, CPEB can be phos-
phorylated and now recruits the protein machinery neces-
sary to increase the length of the poly(A) tail of the mRNA
(7). This enables PABP [poly(A) binding protein] to bind to
the mRNA, and this recruits a new group of proteins to
foster local translation (FIGURE 6) (7). Among these trans-
lation promoting molecules are eukaryotic translation ini-
tiation factor 4 gamma (eIF4G) and eukaryotic translation
initiation factor 4E (eIF4E), which initiate the translation of
proteins in a combined effort right at the side of increased
synaptic activity (363, 418).
In the following we present a small list of molecules that
have been instrumental to understand how protein transla-
tion is shaping processes of functional and structural plas-
ticity.
1. Arc/Arg3.1
One of the first discovered examples of activity-regulated
gene transcription and translation is Arc/Arg3.1 (419, 420).
663
 BIOLOGY OF MEMORY EVENTS
It could be shown that indeed Arc/Arg3.1 likely contributes
to L-LTP and to processes of memory consolidation (349,
394). Its translation is robustly induced within the spine by
plasticity-promoting stimulation, and the protein is specif-
ically targeted to stimulated synaptic sides. Arc/Arg3.1 gene
targeted mice fail to form long-term memories. This holds
true for implicit as well as for explicit learning tasks. This is
in contrast to short-term memory which stays intact (349).
This mechanism to support long-lasting plasticity is medi-
ated by local translation of plasticity-relevant proteins, like
Arc or CaMKII protein (459, 472). Interestingly, the
mRNAs encoding GluR1 and GluR2 (AMPA receptor sub-
units) have both been found in dendrites of pyramidal neu-
rons of the hippocampus, and they are indeed regulated by
synaptic activity (148, 193). An interesting twist here is that
local eEF2-dependent translation of cytoskeletal regulator
Arc and its mRNA trigger endocytosis of AMPA receptors
during mGluR-mediated hippocampal LTD (67, 458).
2. miRNAs
In addition to the inactivation of mRNA interacting pro-
teins that usually inhibit translation, also microRNAs
(miRNAs) seem to play an elegant role in the regulation of
local protein synthesis. Each miRNA, only 22 nucleotides
long, can in principle regulate literally many hundred tran-
scripts and might therefore orchestrate the expression of
many genes. The mechanism of miRNAs action is rather
simple: via base-pairing with complementary sequences
within coding mRNA they inhibit translation at ribosomes
of particular proteins (383). The relatively higher abun-
dance of miRNAs in the brain, some are even restricted to
the brain, points to their important role in the CNS (for a
review, see Ref. 383). miRNAs are particularly well suited
to control distally localized mRNAs and their translation.
Components of the RNA-induced silencing complex (RISC)
machinery have been found in dendrites and synapses and
can be altered by synaptic activity (14).
3. Degradation
In addition to transcription and translation, which lead to
an increase in the amount of certain proteins in synapses,
protein degradation can reduce the copy numbers of specific
proteins. This has been shown for the proteasome-depen-
dent alterations in the composition of proteins in the post-
synaptic density (PSD) of principal neurons in the hip-
pocampus after LTP induction (98). Like dendritic transla-
tion, protein degradation can also be regulated by changing
the local proteome. The ubiquitin proteasome system may
be the key regulator of protein degradation, and its compo-
nents exist in dendrites and also at synapses (FIGURE 6). In
addition, proteasomes seem to relocate from dendritic
shafts into spines within minutes possibly altering AMPA
receptor trafficking and degradation within spines (for a
review, see Ref. 269). In 2004 it was discovered that a
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delicate balance of protein degradation and synthesis is
mandatory to transform E-LTP into L-LTP (123).
In summary, net production of new proteins via local trans-
lation in dendrites, possibly right at the side of activity-
dependent changes at synapses, is as important for informa-
tion storage as is the regulated degradation of certain regu-
latory components of signaling cascaded in synapses and
dendrites.
J. Synaptic Tagging and Capture Hypothesis
In addition to processes of local protein synthesis (transla-
tion), transcription in the nucleus has also been shown to be
mandatory for long-term memory storage (196). But this
leads to the following puzzle: on the one hand, long-term
memory storage needs transcription in the nucleus (196),
and on the other hand, it requires a local specificity for
stimulated synapses (320). But how do the gene products
generated in the nucleus find the appropriate synapse? A
pyramidal neuron in the hippocampus might have up to
10,000 synapses, and during a certain learning event, plas-
ticity is induced only in a subset of these synapses. One
solution to this problem is provided by the synaptic tagging
and capture (STC) hypothesis (127, 283). This hypothesis
was formulated as a consequence of the results of experi-
ments recording from two hippocampal pathways at the
same time (127). For this, two CA3 synaptic inputs, shown
to be independent from each other and to converge on the
same population of CA1 hippocampal neurons are em-
ployed. A weak tetanus (a stimulation normally leading to
E-LTP) is converted into L-LTP, if shortly after its applica-
tion a second, independent pathway is stimulated with a
strong tetanus. These observations are the core of the STC
hypothesis and can be explained as follows. The first syn-
aptic pathway by itself is not able to activate local protein
synthesis in the respective dendritic spine as it received te-
tanic stimulation that induced E-LTP. But the induction of
E-LTP is able to form a “tag” marking the activated synapse
in a specific manner. For a distinct time period, this tag can
“capture” the newly synthesized plasticity-related proteins
(PRPs). The activation or synthesis of PRPs is stimulated
when LTP is induced in a neighboring synapse. By this
means, certain amounts of the PRPs can enter the tagged
synapse so that E-LTP is converted into L-LTP (378). In a
nutshell, a synaptic “mark” or “tag” induced via a transient
event, sequesters PRPs from a nearby strong synapse to
consolidate changes in synaptic weight at stimulated syn-
apses (and by this means maintains synaptic input specific-
ity) (127). This concept is so far to our knowledge the most
comprehensive model to explain late associativity in pro-
cesses of activity-dependent synaptic plasticity (15).
1. Molecules involved in synaptic tagging
It is noteworthy that in hippocampal neurons BDNF was
shown to regulate the local translation of PRPs, including
 MARTIN KORTE AND DIETMAR SCHMITZ
Arc/Arg3.1, which is in part involved in controlling the
turnover of the actin cytoskeleton (294, 481; see also for
a review, Refs. 46, 175). These results suggest that BDNF
is indeed a major PRP, which also stimulates the produc-
tion of other PRPs. This notion is supported by experi-
ments from Barco et al. (16). This group performed a
STC-type two-pathway experiment in hippocampal slices
of BDNF heterozygous knockout mice having only a lim-
ited amount of BDNF (16). They stimulated two indepen-
dent inputs to the same part of the CA1 region and found
evidence that synaptic tagging and capture was signifi-
cantly impaired in the BDNF heterozygous knockout
mice (16). Following up on these results it could be
shown that BDNF is only mandatory in specific forms of
long-term memory formation and that its role is highly
specific and indeed instructive for synaptic plasticity
(375). The authors used a version of L-LTP, which is
induced locally (175) and by this means allows the inves-
tigation of a synapse-specific L-LTP achieved by a weak
tetanus that does not activate transcription in the nu-
cleus. This form of locally induced L-LTP is exclusively
achieved via BDNF-mediated local protein synthesis
(175). Under these circumstances the newly synthesized
PRPs can only be used within small dendritic portion and
will not be shared with more distant compartments
(375). This indicates that PRPs can be spatially restricted
to a cluster of synapses, e.g., on a certain dendritic
branch. Surprisingly, theta-burst stimulation (TBS)-in-
duced LTP is prone to cross-capture, a process that shows
a positive associative interaction of LTP with LTD, in
which PRPs are shared between these different mecha-
nisms of synaptic plasticity (317). In addition, the tag
that is set during E-LTD induction exploits BDNF as a
PRP for LTD maintenance, whereas other signaling path-
ways involved in synaptic plasticity relied on the activity
of PKM␨, but not on BDNF, as has been shown in Ref-
erence 317.
In this context, experiments are needed for addressing the
question of how different dendritic compartments with a
specific plasticity threshold act as functional units for stor-
ing long-term memory in the neuronal networks. The term
plasticity threshold refers to the capacity of a synaptic unit
to process incoming information. It was shown that hip-
pocampal neurons have different synaptic compartments
and that independent “synaptic units” or “clusters” exist
within these compartments (146, 375). Now, it becomes
clear that future experiments should not exclusively con-
centrate on a certain synapse but rather on synaptic com-
partments.
2. PKM␨
In addition to BDNF, the atypical protein kinase PKM␨ is
discussed to act as a synaptic tag for stimulated synapses. In
particular, it could be shown that PKM␨ inhibition in the
hippocampus hours after learning prevents the retention of
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spatial memory (248, 451). It could even be shown that
once the PKM␨ inhibitor has been removed, the memory is
still erased, but new spatial memories can be formed and
stored (341). Thus PKM␨ is the first identified molecular
component of the storage mechanism of associative long-
term memory in the mammalian brain (373). Besides
PKM␨, several kinases act in concert to activate new protein
synthesis for L-LTP and the formation of long-term mem-
ory. For example, selective inhibitors of protein kinases like
CaMKII, MAP kinases, PKA, and mammalian target of
rapamycin (mTOR) block the synthesis of PKM␨ in LTP
(364).
3. Sensorin
Overall, there is indeed good evidence for a mechanism in
which generally available proteins enter the activated syn-
apses only after synaptic stimulation (330). Synaptic stim-
ulation could induce protein synthesis restricted exclusively
to the activated synapse, thus forming the “tag” (146, 418).
But this scenario requires that specific mRNAs undergo
locally restricted translation at stimulated synapses only
during processes of long-lasting synaptic plasticity. To ad-
dress this issue, Wang et al. (457) have used the well-estab-
lished system of Aplysia sensory neurons co-cultivated with
motor neurons (196). This monosynaptic connection is a
central part of the gill-withdrawal reflex in Aplysia. Here,
the repeated application of 5-HT can lead to a long-term
facilitation (LTF), the Aplysia equivalent to LTP, whereas
the application of the neuropeptide FMRFamide leads to
synaptic depression (LTD). To monitor local translation
during the conversion of short- to long-lasting synaptic
plasticity, the researchers generated an elegant translational
reporter utilizing the mRNA from sensorin, a sensory neu-
ron-specific peptide neurotransmitter the mRNA of which
localizes to distal neuronal processes. Sensorin is enriched
at synapses, and its translation is necessary for 5-HT-in-
duced LTF. Indeed, the authors only used the 5’ and
3’UTRs of sensorin mRNA that were fused to the coding
region of the photoconvertible fluorescent protein dendra2
(152). By this means, the authors could show that in neu-
rites, disconnected from the soma, green dendra2 became
visible only at stimulated synapses that underwent LTF af-
ter local 5-HT superfusion, but not at unstimulated syn-
apses and not when LTD was induced. One central finding
of this study was that regulation of local translation re-
quires chemical synaptic transmission. Furthermore, this
study also shows an example in which Ca2⫹ changes in the
postsynaptic compartment are correlated with local protein
translation in the presynapse. Therefore, a trans-synaptic
signal is required for translational regulation in the presyn-
aptic side. It will be interesting to see what the hunt after the
retrograde signaling will bring to light and if such mecha-
nisms are used in hippocampal and other CNS structures of
mammals as well.
665
 BIOLOGY OF MEMORY EVENTS
Local and precisely targeted protein synthesis is one solu-
tion to the riddle of synapse specificity of learning events.
Another, not mutually exclusive, alternative explanation
would be to target ubiquitous available proteins into the
stimulated synapse only. This latter idea was tackled by
Okada et al. (330). Under resting conditions, Vesl-1S
(Homer 1a), one of the PRPs required for long-term fear
memory, was absent from the postsynaptic side of a stimu-
lated synapse (in primary cultures of hippocampal neu-
rons). Okada et al. (330) used a fluorescence marker tagged
to Vesl-1S to detect the movement of the corresponding
protein. Only after NMDA receptor activation, Vesl-1S
could enter spines in an input specific manner. Also Wang et
al. (457) could show that the entry of proteins into spines is
tightly controlled by molecules that function as synaptic
tags. This finding opens the possibility of a synaptic tag as a
“molecular gatekeeper” and how it can “sense” the spatial
and temporal strength of the incoming information. It will
be exciting to see if molecules located at the spine neck, like
synaptopodin (84), could fulfill this function (see, e.g., Ref.
230).
Overall, these studies could demonstrate that translation
and transportation can indeed be restricted to specific syn-
apses. However, data from acute slices of mice support the
view that, under a more complex network situation, there is
additional cross-talk and interaction between synapses like
cross-tagging (377) or competition for PRPs (122, 376).
Experiments presented here (330, 457) are so far the most
convincing studies how synapse specificity can be main-
tained during the implementation of associative memory
storage along the line of the synaptic-tagging and capture
hypothesis.
K. Stabilization
Change of synaptic function and structure is one side of
the coin, but how can change last and how can an engram
be stabilized in an ever-changing neuronal network?
Long-term memory storage requires on the one hand the
activation of positive regulators, which favor informa-
tion storage, and on the other hand the removal of re-
straining, negative-acting factors preventing it (2). Inhib-
itory pathways act at different levels all the way from
synapses to the nucleus of a neuron. Following synaptic
receptor activation, downstream signal amplifiers, such
as PKA, are controlled by an inhibitory subunit. Also the
transactivation function of some transcription factors can
be reduced by inhibitory regulators. These “memory sup-
pressor genes” (2) are good checkpoints for long-lasting
memory storage. These molecules might function as hubs
determining the rate, the occurrence, and the specificity at
which changes in neuronal connectivity are either imple-
mented, maintained, or prevented. Thus memory control-
ling proteins ensure that only relevant features of an event
are stored (filter function) and that the synaptic weight
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changes are maintained for a long period of time (consoli-
dation). This memory barrier is of special importance, since
it is a hallmark of animal and human cognitive abilities to
select salient information to separate this from a noisy back-
ground. Moreover, it might be even more important to
consolidate the most important facts and features and pro-
tect them from change, like it is indeed happening during
processes of reconsolidation (314).
1. Nogo-A
Among the molecules known to restrict neuronal plastic-
ity are the pan-neurotrophin receptor p75NTR (366, 470),
adhesion molecules (392), endocannabinoids (64, 305),
part of the ephrin family (224), semaphorins (342), and
the myelin-associated neurite growth inhibitor family
and their receptors (385). As an example we would like
to focus on the myelin-associated neurite growth inhibi-
tor Nogo-A and its receptors NgR1 (Nogo-66 receptor 1;
Ref. 124), S1PR2 (sphingosine 1-phosphate receptor 2;
Ref. 208), or PirB (reviewed in Ref. 385). They are ex-
pressed pre- and postsynaptically (207, 251, 261). Re-
cently, they have been shown to restrict neuronal archi-
tecture (346, 490) and to control synaptic plasticity in
the developing and also in the mature CNS (83, 208, 249,
299, 353). Moreover, NgR1 has been shown to limit
experience-driven plasticity in the visual cortex (290).
Furthermore, there is accumulating evidence that it also
regulates experience-dependent dynamics of spines as
well as the axonal varicosities in the somatosensory cor-
tex (8). Indeed, Nogo-A might acutely regulate structural
plasticity due to its influence on the actin cytoskeleton
dynamics via Rho/Rock signaling to restrict plasticity at
individual dendritic spines of hippocampal pyramidal
neurons within minutes (386).
However, it is not enough to concentrate on single mol-
ecules promoting stabilization, but of course one has to
take into account that there might be an extensive cross-
talk between signaling pathways promoting plasticity
and those that promote stability (or restrict possible plas-
tic changes). Indeed, there are experiments suggesting an
opposing interaction between inhibitors of plasticity and
neurotrophic factor signaling pathways. Pretreatment of
dissociated hippocampal neurons with BDNF signifi-
cantly reduces the inhibitory effect of myelin, and this is
phospho-CREB dependent (136). On the other hand,
Nogo⌬20 (one domain of the Nogo-A molecule) reduces
CREB activation (190) and decreases pAKT (86). In line
with this, the other Nogo-A domain, Nogo66, reduces
the BDNF-mediated activation of pAKT (353). In an-
other study it has been shown that the BDNF/TrkB acti-
vated Erk1/2 signaling pathway is increased in NgR1
knockout hippocampal neurons (353), and NgR1 knock-
out neurons are also more sensitive to another growth
factor pathway, namely, to FGF2-FGFR signaling (249).
It is also noteworthy that growth factor and Nogo-A
 MARTIN KORTE AND DIETMAR SCHMITZ
signaling pathways affect the mTOR complex 1
(TORC1) in an antagonistic fashion (for details, see Refs.
344, 353). Specifically mTOR-dependent protein trans-
lation is regulated in an antagonist fashion via phospho-
CREB, promoting or inhibiting transcription (344, 353).
Finally, Nogo-A in concert with its receptors (NgR1,
S1P2R, PirB) limits activity-dependent plasticity and
growth-dependent processes, thereby leading to the sta-
bilization of neuronal assemblies (either developmentally
or during processes of memory consolation in the mature
nervous system) (for recent reviews, see Refs. 386, 489).
Taking away the molecular synaptic plasticity brakes al-
lows the induction of extensive structural and functional
rearrangements and promotes compensatory growth
processes after an injury of the CNS. However, it is im-
portant to keep in mind that this could be a dangerous
endeavor, since it might facilitate unwanted and unnec-
essary (and probably even maladaptive) neuronal con-
nections.
Also of note, at some glutamatergic connections, synaptic
plasticity is rather difficult to induce, and it is suggestive to
speculate that this might be linked to expression of plastic-
ity-limiting molecules at the end of CNS development. For
example, within the entorhinal cortex, many different pro-
tocols failed to induce LTP, whereas other studies showed
LTP like effects (76, 361, 483).
Molecules that limit synaptic plasticity may therefore play a
central part in processes of memory formation, especially
when it comes to regulating the association between events
or facts. The inhibitory processes might be activated in sit-
uations of CNS injury (e.g., infection, stroke) to prevent
that the ongoing remodeling processes might endanger es-
tablished structures and functions of adjacent neuronal net-
works (385). They are in a way reminiscent of tumor sup-
pressor genes that integrate a variety of molecular signals
into a single cellular response and help to control cell divi-
sion.
L. The Tripartite Synapse
So far we have considered the storage of information as a
solely neuronal endeavor. But indeed, the orchestration of
memory manifestation is even more complex than “just”
the CA3-CA1 excitatory synaptic connection. In addition
to the pre- and postsynaptic side of a synapse, the inhibitory
and modulatory inputs to the pre- and postsynaptic neurons
and the myriads of molecules therein, also glia cells (astrocytes
and microglia cells) have to be considered as regulatory ele-
ments in changing synaptic strength and during the mainte-
nance of functional and structural changes (FIGURE 7) (for a
review, see Ref. 335).
Here we would like to consider glia cells and their contri-
bution to information storage. First of all astrocytes should
be considered.
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1. Astrocytes
Astrocytes got their name indeed from their star-shaped
morphology. The interest in their involvement in processes
of synaptic plasticity comes from the fact that processes of
protoplasmic astrocytes completely enwrap synapses in the
grey matter of the CNS. In the hippocampus, astrocytes
enwrap ⬃57% of all synapses (467). As far as it is known,
usually a single astrocyte enwraps literally thousands of
synapses (up to 6,000 synapses; Ref. 210). Astrocytes signal
to neurons via glioneurotransmitters, like D-serine, a coago-
nist of the NMDA receptor. And indeed, it could be shown
that the release of D-serine is a necessary ingredient to pro-
mote hippocampal LTP induction (166, 479). In addition,
astrocytes express a large array of neurotransmitter recep-
tors, like glutamatergic, purinergic, GABAergic, cholin-
ergic, and adrenergic receptors (for a review, see Ref. 106).
Specifically, astrocytes express AMPA and NMDA recep-
tors at their surface, and the removal of astrocytic AMPA
receptors leads to the retraction of astrocyte processes from
synapses and to pronounced deficits in motor coordination
in the adult brain (371). Also, in astrocytes the activation of
typical neurotransmitter receptors can lead to Ca2⫹ waves
within and between astrocytes. An increase in the intracel-
lular Ca2⫹ concentration boosts the release of D-serine and
coactivates NMDA receptors (179, 244). As a side note, this
has the potential to explain why there is a correlation be-
tween glial coverage of synapses and LTP in the supraoptic
nucleus of mice (29, 332).
However, increases in Ca2⫹ in the cytosol of astrocytes
following neuronal activity leads to the release of a whole
plethora of signaling molecules, most prominently ATP,
glutamate, and also tumor necrosis factor (TNF)-␣ (31,
111, 345, 414). In return, neurons can supply D-serine
(204, 300). The signaling between neurons and astro-
cytes can also influence the morphology of astrocytes. In
this context, it has been shown recently that astrocytes
also undergo structural rearrangements after LTP induc-
tion, especially at the perisynaptic astrocytic processes
(29).
In addition, subtypes of astrocytes and microglia cells are
involved in structural changes of synapses, e.g., in synapse
elimination and pruning (69, 336). On the signaling level it
could be shown that the tyrosine kinase EphA4 on the side
of excitatory pyramidal cells of the hippocampus interacts
directly with the ligand ephrin-A3, which is located directly
on processes at synapses from astrocytes (311; see also Ref.
117).
2. Microglia
In addition, there is increasing evidence that also microglia
cells, the immune cells of the brain, are involved in the
elimination of synapses (339). Also oligodendrocytes have
been implicated in processes of plasticity, since the myeli-
667
 BIOLOGY OF MEMORY EVENTS

nation of axons can change due to changes in neuronal M. Function Follows Form? Structural
activity even in the mature CNS and might therefore further Plasticity and Memory Consolidation
increase the cellular arsenal of plasticity mediating cells in
the CNS (113, 405). One essential arena for future experi- Until this point we have mainly considered the singular
ments is to determine how specific glia cell-secreted mole- contributions of molecular, cellular, as well as network
cules can cross-talk with the neuronal signaling to regulate, events that are correlated to functional Hebbian plasticity
promote, or restrict activity-dependent plasticity. In addi- by which synaptic strength is modulated during and after
tion, it would be important to elucidate how glia cells re- the learning events. However, synaptic networks are not
spond to changes in neuronal activity to secrete molecules only changed and rearranged due to functional modifica-
that are important for functional or structural changes at tions, they are also modified at the structural level, and
synapses. therefore, neuronal connectivity can be remodeled through-

A B
Nucleus
PRESYNAPTIC CRE CRE
TERMINAL
ASTROCYTE
PROCESS
P
Substance SYNAPTIC cAMP MAP
release
CLEFT kinase kinase
Glutamate
transporter
ECM PSA-
cAMP
Calcium PSA- NCAM
rise NCAM

NCAM Adenylyl
PRESYNAPTIC NCAM cyclase
Neuro-
Neuro- POSTSYNAPTIC
AXON login
login
DENDRIC
POSTSYNAPTIC TERMINAL EphBx
TERMINAL
EphB
Endo-
SPINE
cytosis
Neurotransmitter
uptake
Degradation PRP
Neuro- Fusion and (plasticity-
transmitter related
exocytosis proteins)
molecules
Intracellular
NMDAR PSD AMPAR
Regulators
VSCC
zone

Vesicle Exo- Endo-

mobilization Docking cytosis cytosis
and priming
C Synaptic
e

vesicle P
Activ

AMPAR
Neurotransmitter PRESYNAPTIC AMPAR
molecules AXON
Synaptic TERMINAL
vesicle
Lateral
diffusion
Neurotransmitter
Vesicle uptake
mobilization Substance Calcium
release rise
Endocytosis
B PSA-
Neuro- NCAM
A
Activ C EphB login NCAM
e
zone
ASTROCYTE
Docking and Fusion and
priming exocytosis SYNAPTIC
VSCC CLEFT ASTROCYTE
AMPAR
PROCESS
NMDAR

PSA-
P EphB Neuro-NCAM NCAM
login
Lateral PSD
diffusion
Exocytosis POSTSYNAPTIC Modulatory
DENDRIC input
AMPAR SPINE
Endocytosis (Dopamin, ACH, 5'TH)

Degradation

Intracellular
pool
Inhibitory
modulation
(e.g at the soma)
Local Trancription/
translation Translation
(Soma)

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 MARTIN KORTE AND DIETMAR SCHMITZ

out life. These structural changes include not only the for-
mation of new synapses and their stabilization but also their
elimination. Structure and function of neurons have a re-
ciprocal relationship, and spines on dendrites are a partic-
ularly good example of this fact. Inside the spine, actin
filaments (F-actin) are highly enriched providing the struc-
tural base for stability as well as for changes in morphology
(115, 286, 287). In turn, the actin cytoskeleton is linked via
a complex network of proteins to extracellular signals to
tightly control spine morphology including the coupling of
functional synaptic changes to structural changes at den-
dritic spine, presynaptic release side (boutons), dendrites
themselves, and axons (reviewed in Refs. 59, 379, 487).
Changes in the morphology initiated by activity-dependent
synaptic plasticity events are termed structural plasticity.
These changes are of functional and behavioral conse-
quence, and they remodel the fine-grained architecture of
neurons and therefore also the connectivity of networks or
subsets of neuronal nets throughout life.
1. Structural spine plasticity
We will focus here on structural changes of spines (for
extended reviews, see Refs. 43, 379). Activity-dependent
synaptic plasticity includes changes in the size and shape
of dendritic spines as well in the overall number of spines,
and these structural changes are highly correlated to
learning processes (103, 275, 437; for reviews, see Refs.
59, 172). Moreover, increasing evidence indicates that
functional changes at synapses such as LTP and LTD are
associated with spine shrinkage or spine growth (427) or
even the growth of new spines (103, 275, 437) possibly
containing functional synapses (243, 315, 495) (FIGURE
5). With respect to the interdependence of functional and
structural changes, it is noteworthy that LTP induction
and maintenance (133, 236, 238) indeed depend on the
specific modulation of actin dynamics within dendritic
spines (331). And the induction of LTD resulted in spine
retractions (301), whereas LTP induction evoked growth
of spines (301) (FIGURE 5). The highly concentrated actin
in dendritic spines provides a skeleton for dynamic re-
modeling of spine size and shape (114; reviewed in Ref.
367). Actin is highly enriched in the head of spines and
shows a high degree of dynamics (114, 165; reviewed in
Ref. 41). In line with this, inhibition of LTP also pre-
vented changes in the dynamics of actin polymerization
in spines (255). Moreover, processes of activity-depen-
dent synaptic plasticity leading to LTP induces a shifts
from G-actin (globular actin, monomers) to F-actin (fil-
amentous, linear polymer microfilament). This change in
the G/F-actin ratio goes hand in hand with an enlarge-
ment of the spine head, whereas processes that lead to
LTD shift the ratio to G-actin resulting in destabilization
of the actin cytoskeleton and spine shrinkage (133, 255,
331, 493, 286, 427). Under in vivo conditions it was
shown in the murine motor cortex that intensive motor
learning leads to structural changes in dendritic spines as
well (477). The extent of these changes can even be highly
correlated with the behavioral improvement in the spe-
cific task, suggesting a crucial role for structural plastic-
ity during learning processes (477). In this context, it is
an interesting notion that BDNF supports LTP expres-
sion by increasing the dynamics of cytoskeletal changes
of spines (348). In addition, the BDNF-TrkB signaling
pathway induces the local dendritic synthesis of several
proteins known to regulate the cytoskeleton, like Arc,
Homer, and LIMK1 (384, 481).

FIGURE 7. The tripartite synapse. A: role of the extracellular matrix (ECM) and of astrocytes in processes of synaptic plasticity. In addition to
pre- and postsynaptic effects, glia cells contribute to the activity of various synapses by signaling via glioneurotransmitters like D-serine (coagonist
of NMDA receptors). Astrocytes themselves express various neurotransmitter receptors on their surface like AMPA or NMDA receptors
monitoring the synaptic activity and responding to changes by influencing Ca2⫹ level-dependent astrocytic processes like signaling molecule
release (D-serine, ATP, glutamate, TNF-␣) and NMDA receptor activity contributing to plasticity processes of the synapse. B: in addition to core
events, translation and transcription must be controlled as well via synaptic plasticity. In addition, astrocytes have to be taken into account, and
the influence of astrocytes on processes of synaptic plasticity are depicted. Changes in neurotransmitter vesicle cycling are prominent features
of presynaptically mediated neuronal plasticity. In general, the release of neurotransmitter starts with the filling of synaptic vesicles with
neurotransmitters. These vesicles are then docked to the plasma membrane and undergo a priming process at the active zone. When the action
potential arrives at the presynaptic side, it induces an influx of calcium ions through voltage-sensitive calcium channels (VSCCs). This triggers
vesicle fusion with the plasma membrane and exocytosis. The neurotransmitter vesicles are then recycled by the means of local reuse (a; “kiss
and stay”), or via fast recycling (b; “kiss and run”), or clathrin-mediated endocytosis (c). Vesicle fusion can be precisely controlled when neuronal
activity changes as exemplified by the regulation of synapsin phosphorylation (1) or the control of RIM protein phosphorylation (2). On the other
side of the synapse, AMPA receptor trafficking can be altered postsynaptically. AMPA receptors, synthesized in the nucleus or via local dendritic
protein translation, can enter a pool of endosomes which are involved in constitutive and regulated membrane trafficking. During processes of
synaptic strengthening, membrane receptor insertion increases the number of AMPA receptors at the synapse (3), where they are anchored
by interactions at the PSD. During processes of synaptic weakening, AMPA receptors have a high likelihood to be endocytosed (3). The
preferential site of exocytosis and endocytosis is most likely extrasynaptic. Within the plasma membrane, lateral diffusion between the synapse
and the point of insertion or removal controls AMPA receptors. Extrasynaptic diffusion of AMPA receptors increases with higher neuronal activity
(4). AMPA receptor trafficking is controlled by phosphorylation of receptor subunits (5), which determines the interaction with intracellular
scaffolding proteins. C: in addition to glia cells, events happening at the prototypic CA3-CA1 synapses and the role of the ECM, also modulatory
and inhibitory inputs from other neurons play a mayor in the modulation of neuronal plasticity. The neuromodulatory neurotransmitters (e.g.,
acetylcholine, serotonin, dopamine) influence the synaptic activity and signaling events of a specific neuron. NMDA, N-methyl-D-aspartate
receptor; TNF-␣, tumor necrosis factor-alpha.

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 BIOLOGY OF MEMORY EVENTS
2. Spine neck plasticity
Structural changes do not only affect the spine head, but
also the spine neck, which connects the spine head with the
dendrite, restricts the diffusion of ions, and influences the
electric signal propagation due to its geometric characteris-
tics (485). There is evidence that the resistance between the
spine neck and the underlying dendritic branch is changed
after the induction LTP and that this is due to changes in the
dynamics of the cytoskeleton in spines (38, 438). These
studies added the novel concept that spine neck resistance is
not constant and that structural alterations in the cytoskel-
eton change the diffusion constant of ions and probably
also electric signal propagation from spines to dendrites.
Here, Tønnesen et al. (438) used high-resolution stimulated
emission depletion (STED) imaging to provide direct evi-
dence for morphological changes of the spine neck upon
LTP induction. This study could show that the spine neck is
a highly dynamic structure, which becomes shorter and
wider upon activity, possibly facilitating diffusion of second
messengers from the dendrite into the spine. The biophysi-
cal effects of spine neck changes are quite different from the
biochemical effects. Whereas diffusion from dendrites into
spines will most likely be boosted, the biophysical proper-
ties indicate that these morphological changes lead to a
substantial drop in spine head EPSP. Therefore, on the bio-
physical side, the resistance of a spine neck is increasing
after LTP induction and is decreased if synaptic activity is
blocked for a longer period of time (438).
3. Actin-binding proteins
To enable structural plasticity, the underlying actin fila-
ments (F-actin) have to be assembled or disassembled on a
fast time scale (seconds to minutes) in a process tightly
regulated via numerous actin-binding proteins (ABPs). The
main task is the transformation of receptor-mediated sig-
nals into the cytosol via the action of ABPs. This view de-
mands that the most dynamic pool of F-actin is located
close to the postsynaptic membrane at the tip of the spine to
promote or restrict growth processes (173, 174; for a re-
view, see Ref. 70) (FIGURE 5B). Since LTP occurs within 1
min after high-frequency stimulation and needs to be stabi-
lized in the following 10 –30 min, rapid changes in the actin
organization are necessary (268). Increased polymerization
of G-actin to F-actin is mandatory for the stabilization of
LTP and pharmacologically induced depolymerization of
F-actin caused a decrease in spine head volume and elevated
internalization of glutamate receptors (133, 268). Overall,
it can be summarized that inhibiting spine head enlarge-
ment, LTP induction was not possible (133, 213, 238, 354,
362). Two recent studies used time-lapse two-photon imag-
ing of fluorescently labeled synaptic marker proteins com-
bined with electron microscopy to analyze the spatiotem-
poral changes in synaptic morphology upon LTP. Meyer et
al. (295) demonstrated that in persistently enlarged spines,
the sizes of spine, PSD and bouton are correlated. Bosch et
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al. (42) monitored the remodeling of spine structures during
LTP in single spines and observed that proteins translocate
into the spine through three sequential phases in four dis-
tinguishable patterns. The initial phase is characterized by
rapid actin remodeling and followed by immense trafficking
of the ABP cofilin into the spine. After that, cofilin forms a
stable complex with F-actin and contributes to long-term
spine stabilization.
4. CaMKII
On the molecular side, an interesting connecting partner
between function and structural plasticity is the kinase
CaMKII, which is needed after LTP induction due to an
increase in intracellular Ca2⫹ concentration (see sect. IIE
and FIGURE 4). In addition to its role in functional syn-
aptic plasticity, CaMKII in its inactive form can also bind
to F-actin, thereby limiting the access of APBs to F-actin
thus stabilizing the shape and size of spines (216). Ca2⫹-
mediated activation of CaMKII via autophosphorylation
leads to its dissociation from F-actin. This now allows
F-actin remodeling via the now possible interaction with
ABPs. The dissociation of CaMKII from F-actin is fol-
lowed by a fast inactivation of CaMKII leading again to
the binding to F-actin thus restabilizing the newly formed
spine structure.
In summary, it is commonly accepted that the immense
capacity of the central nervous system to store information
depends on the precise refinement of synapse structure. Syn-
apses are considered today as the single, most fundamental
processing units within neuronal networks, the majority of
which are located on dendritic spines, which can change
their structure due to changes in the actin cytoskeleton
(379).
N. Changes in Gene Expression and
Epigenetic
In addition to events that occur at the site of communica-
tion between neurons, when it comes to long-term storage
of information also the communication between the syn-
apses and the nucleus of a particular neuron has to be con-
sidered (as already mentioned in sect. IIJ). Whereas synaptic
events that lead to memory storage focus on protein
switches, more enduring processes of long-lasting memory
storage also have to include RNAs (translation) and also
events at the DNA level (transcription). Therefore, the
sometimes long distance between a particular set of syn-
apses and the nucleus must be overcome by signaling cas-
cades. The fastest routes use Ca2⫹ signaling, either via li-
gand or voltage-gated Ca2⫹ channels, or Ca2⫹ release from
internal stores. By this means Ca2⫹ signals could lead to
transcriptional changes of specific genes involved in plastic-
ity processes genes (160; for a review, see Ref. 13), like the
expression of immediate early genes after the induction of
 MARTIN KORTE AND DIETMAR SCHMITZ

LTP (419, 456), which have been acknowledged to be im-
portant prerequisites of long-term memory storage (for a
review, see Ref. 197). In this context hundreds of activity-
regulated changes have been discovered, including MEF2,
CREB, and NPAS4 Greer (147).
This means that by posttranslational changes, e.g., acetyla-
tion or phosphorylation of certain histone domains or
methylation of DNA elements, the long-lasting transcrip-
tion of specific genes involved in processes of long-term
information storage can be up- or downregulated.

In addition to immediate changes in gene transcription via
the activation/repression of transcription factors, the over-
all long-lasting (months to years) expression of genes can
also be changed via epigenetic regulation of chromatin
structure. The term epigenetic is used for the heritable and
self-perpetuating modifications to DNA and DNA-associ-
ated proteins (e.g., histones), without changes in the DNA
base pairs sequence itself (FIGURE 8). The epigenetic foot-
print on the DNA or histones can lead to a specific pattern
of gene expression and can be considered as a persistent
form of cellular memory, which can even be transferred
from mothers to their offspring. Epigenetic mechanisms are
used to define the expression pattern of cells in a specific
organ of the body, and the adult nervous system is using this
program for processes of long-term memory storage (253).
Conceptually this means that after a learning event, the
molecular modifications (up- and downregulation of cer-
tain genes) necessary to implement the long-lasting change
in the expression of plasticity-related proteins is mediated
via alterations at the level of the chromatin structure (with-
out changes in the order of DNA base pairs). By this means,
long-lasting changes in response properties of particular
neurons can be conserved to store an engram for months or
even years. This is supported by the fact that chromatin
acetylation is of importance for high-level gene expression
precisely at a chromosomal region of active transcription of
plasticity-related genes (253, 266). Acetylation is catalyzed
via the histone acetyltransferase (HAT) and de-acetylation
is mediated via the histone deacetylase (HDAC). The effect
of acetylation on gene expression is explained by the fact

A Gene expression

Acetylated chromatin
Ac Ac
CREB-1
P P
CBP
TBP

CRE TATA Ac C/EBP

POL II FIGURE 8. Epigenetic mechanisms. Epi-

mRNA genetic mechanisms mediate long-term
storage of memories (cellular event of
memory consolidation). The most promi-
nent molecular events of epigenetic regu-
lation are depicted: acetylated chromatin
B Gene repression (A) and methylated DNA and processes of
deacetylation (B). Ac, acetyl residue; CBP,
Methylated DNA CREB binding protein; C/EBP, CCAAT-en-
hancer-binding proteins; CRE, cAMP re-
CREB-1 Ac Ac sponse element; CREB, CRE binding pro-
P P tein; DMNT, DNA methyltransferase;
CBP DNMT HDAC, histone deacetylase; Me, methyl
Me
TBP residue; Me-CpG-BP, methyl-CpG binding
protein; P, phosphate residue; Pol II, RNA
CRE TATA Ac C/EBP polymerase II; TATA, TATA box; TBP, TATA
box binding protein.
POL II
mRNA
De-acetylated chromatin

Me-CpG-
CREB-
HDAC

TA

Me
TA

CRE C/EBP

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 BIOLOGY OF MEMORY EVENTS
that it removes positive charges on histone proteins, and by
this means it decreases the contact of histones with nega-
tively charged phosphate groups of DNA. This results in a
less condensed “relaxed” chromatin and increases the ac-
cess of transcription factors to DNA sections close to the
acetylated sides and increases transcription (149). In partic-
ular, DNA methylation has emerged as an important mech-
anism for epigenetic changes involved in long-term memory
storage. Here DNA methyltransferases (DNMT) detect se-
quences of CpG island sites within the DNA. “CpG” means
“-C-phosphate-G-” (cytosine and guanine linked by a phos-
phate), as it occurs in the structure of the DNA or RNA
nucleotide “backbone” of a single nucleotide strand. The
methylation of these CpG sites can directly control the rate
of transcription of certain genes via the alteration of the
local chromatin structure (253, 266). CpG islands can be
found in 40% of the promoters for mammalian genes (108).
It is currently believed that DNA methylation is a major
epigenetic mechanism that potentially contributes to long-
lasting alterations in the expression pattern of a whole series
of activity-regulated genes (32, 203, 245). At least two sub-
types of DNMT enzymes (DNMT 1, DNMT 3) are differ-
entially expressed in neurons in an activity-dependent man-
ner.
How can this be studied? Here, an example for the epige-
netic control of the bdnf gene is instrumental. BDNF has
been described earlier in this review as being a mediator of
activity-dependent synaptic plasticity and is discussed as an
important mediator especially of long-term memory stor-
age. It has been shown that the expression of BDNF de-
pends on neuronal activity (266). And not only that, there is
also behavioral evidence which implies that bdnf gene ex-
pression is activated in the hippocampus after contextual
and spatial learning (see, e.g., Ref. 157). In addition, the
bdnf-gene activation is vital for learning and memory events
(17, 157, 301). The bdnf gene itself is therefore rather com-
plex, to fulfill all the regulatory needs. It consists of nine 5’
noncoding exons each linked to individual promoter re-
gions, and a 3’ coding exon encoding the pre-protein amino
acid sequence. Some of the BDNF-promoter regions are
activity dependent determining the temporal and spatial
expression pattern of specific isoforms of bdnf transcripts
(for a review, see Ref. 47). After contextual fear condition-
ing, it could be shown that bdnf exons I, II, and VI are
methylated and the related mRNA transcripts reduced in
their expression, whereas exon IV is demethylated and the
corresponding mRNA expression increased. In this context,
it could be shown that methylation of bdnf DNA in the
hippocampus is changed by infusions of zebularine (a DNA
methyltransferase inhibitor). Overall, these changes lead to
different levels of exon-specific bdnf mRNAs and indeed to
a different performance in learning tasks related to long-
term memory storage (203). This indicates that changes in
DNA methylation are sufficient to trigger a differential bdnf
transcript regulation affecting long-term information stor-
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age. It is noteworthy that a NMDA receptor blocker can
prevent the synaptic plasticity-associated alterations in
bdnf DNA methylation (203, 266).
Taken together, activity-dependent changes can lead via
epigenetic mechanisms to a changed expression of the bdnf
gene, and this might be utilized for long-lasting memory
storage. In general, evolutionary ancient mechanism of epi-
genetic switches changing chromatin structure and by this
means the long-lasting expression pattern of a series of
genes can be utilized by neurons to change their long-term
behavior. Therefore, to store memories for a long period of
time, signaling molecules have to be activated (e.g., cAMP,
Ca2⫹) as well as kinases (protein switches), and in the end,
translational and transcriptional switches in addition to cy-
toskeletal switches are needed to transform short-lasting to
long-lasting events. Therefore, a different set of “molecular
switches” is needed (245), some of them transient, some of
them in the end long-lasting, and these could well include
changes in gene expression via activity-dependent epige-
netic changes in chromatin structure. This makes epigenetic
changes part of the molecular toolbox to consolidate infor-
mation storage for month and years (and some of them for
a life time).
O. Homeostasis and Metaplasticity
So far we have considered the timing of cellular events from
changes of neuronal activity under leaning conditions to
synaptic plasticity events to maintain these changes for
long-term storage. This includes changes in the postsynap-
tic spine, retrograde signaling to the presynaptic side, and
changes that happen there, signaling into the dendrites and
to the nucleus of a neuron, which leads sometimes to long-
lasting changes in gene expression. But also neuronal activ-
ity that happens before a particular learning event has an
influence on the probability of a specific synapses of a neu-
ron to undergo plasticity changes. The amount of informa-
tion a neuron “perceives” is changing all the time as it might
be involved in different neuronal assemblies that store dif-
ferent information. The ability of a neuron to modify its
ability to change over time has indeed been described and
named metaplasticity (4, 178) or synaptic scaling as a ho-
meostatic mechanism to calibrate the overall excitability of
a neuron (444).
1. Metaplasticity
The principal idea behind the concept of metaplasticity is
that the previous history of a nerve cell determines its future
ability to undergo synaptic changes; a neuron might be less
prepared to change its synapses or it may be more prone to
changes in response to a stimulus. For example, depending
on the previous input to a synapse or to a group of synapses,
LTP or LTD might have a higher (or lower) induction rate.
These mechanisms depend on the current “state” of a group
 MARTIN KORTE AND DIETMAR SCHMITZ
of functionally connected synapses (a synaptic unit), which
is influenced via current extrinsic factors, like the activity of
synaptic inhibition and the actual level of neuromodulators
acting on a subset of synapses. There is also some evidence
that synapses during processes of functional plasticity are
not changed gradually, but rather that they could be in
discrete states (306). These different states could be silent,
active, potentiated, recently silent, or depressed. Therefore,
the coming and the future states will be influenced by the
status gained during the previous activity level. Not much is
known about the molecular nature of metaplasticity, but it
is of great theoretical importance in brain and cognitive
science and it adds another layer of complexity to the mod-
ulation of synapses (306).
2. Excitation-inhibition balance and synaptic scaling
In relation to a remark made by the late Walter Cannon,
one can say: “Somehow the unstable stuff of which neurons
are composed of has learned the trick of maintaining stabil-
ity.” Homeostatic synaptic scaling is a form of synaptic
plasticity that adjusts the strength of all of a neuron’s excit-
atory synapses up or down to stabilize its firing. It was first
observed in dissociated cortical cultures (446), which
showed compensatory adjustments in their synaptic
strength upon perturbations of the activity in the neuronal
network. The adjustments returned in the end firing rates
back to baseline values. This suggests that nerve cells detect
changes in their own firing rates and regulate, e.g., receptor
trafficking accordingly so that synaptic strength is either
increased, if the overall firing rate of a neuron is very low, or
decreased if the overall firing rate is very high (for a review,
see Ref. 445).
On the molecular level, in addition to Ca2⫹-dependent sen-
sors (for a review, see Ref. 445), BDNF might orchestrate
the plasticity threshold of an entire cluster of synapses and
might therefore be involved in processes of metaplasticity
and homeostasis. Indeed, BDNF contributes to homeostatic
processes, especially to synaptic scaling of inhibitory neu-
rons, as was shown for cortical circuits in culture, which are
also modulated by GABA-releasing interneurons (356). In
the rodent as well as in the primate visual cortex, activity
blockade results in a decrease in the expression of GABA.
This indicates that neuronal activity is in principle able to
adjust the strength of cortical GABA-mediated inhibition.
In this context it is noteworthy that neuronal activity regu-
lates the expression of BDNF as well. In addition, BDNF
influences the differentiation and the phenotype of
GABAergic interneurons. Blocking spontaneous activity in
neuronal cultures leads to a reversible decrease in the num-
ber of GABA-expressing neurons without affecting neuro-
nal survival (356). Patch-clamp analysis of inhibitory cur-
rents indicates that blockade of neuronal activity also leads
to a decrease in inhibition mediated by the release of GABA
onto pyramidal neurons, which results in an increase of the
firing rates of these neurons (356). These effects could be
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counteracted if BDNF, but not the other neurotrophins,
was applied during the activity blockade (356). Overall,
these results indicate that the synaptic activity level controls
cortical inhibition and that BDNF plays a major role in the
regulation of cortical excitability. In a followup study, it
could be shown that the effects of neuron activity blockade
are mediated by changes in the quantal amplitude of EPSPs
and that this amplitude is regulated via BDNF (370). These
data demonstrate that synaptic scaling is of major impor-
tance for the homeostatic control of excitatory as well as of
inhibitory circuits and in the regulation of the balance of
cortical inhibition and excitation (443).
Taken together, the induction of processes that lead to
changes in synaptic weight is a long-lasting sequence, which
starts and ends with a highly choreographed and perfectly
timed movement of molecules in different cell types, which
operates over a long range of temporal and spatial scales.
But for sure the journey into molecular mechanisms of long-
lasting memory storage will go on “ѧ as it happens to the
coastwise voyager, who finds no end to his journey, for
behind each headland of clayey dune he conquers, fresh
headlands and new distances lure him on” (Thomas Mann,
Joseph and His Brothers).
III. SYSTEMS BIOLOGY OF MEMORY
Although synaptic plasticity processes contribute to mem-
ory formation, they have to be integrated into neuronal
networks within different brain areas as well as different
brain states. In this regard, synchronicity of circuits seems
to be of particular relevance. In this section, we review both
the encoding of new information during awake states as
well as the consolidation of fresh memories during sleep
from the prospective of the network level of information
processing.
A. Encoding: Role of Temporal Compression
As described above, the mammalian hippocampus was very
early on identified as critical for explicit memory (296).
Memory trace encoding on the behavioral level requires
time scales on the order of hundreds of milliseconds or even
seconds. Thus timing of learning differs substantially from
those required for synaptic plasticity rules, which is on the
order of only a few milliseconds (see above). Which cellular
and/or network mechanisms allow to bridge these different
time scales? In the following sections, we discuss a potential
network mechanism, the so-called “phase precession.” We
will describe some of the features of place cells, present
findings on oscillatory activity, and outline the phenome-
non of phase precession and its hypothetical function in
encoding via temporal compression.
673
 BIOLOGY OF MEMORY EVENTS
B. Place Cells
The activity of many hippocampal pyramidal neurons is
closely related to the animal’s position in the environment
during spatial navigation. These “place cells” show a rise in
their firing rate if the animal navigates through a specific
region of the environment, the so-called place field, and
become virtually silent when the animal is completely out-
side the respective place field (FIGURE 9). When an animal is
placed into a completely new environment, place fields are
established within a few minutes and stay stable for long
periods of time if the environment does not change. Never-
theless, the place fields of different cells may overlap, which
is an important condition for learning of spatial sequences
(100, 328, 391).
The topographical relationship of the place fields is inde-
pendent of their anatomical representation (359). Fur-
thermore, the relation between place fields varies be-
tween environments, i.e., cells with neighboring place
fields in a certain environment might have place fields
apart from each other in another one (358). Not all hip-
pocampal pyramidal neurons show place field activity,
e.g., only ⬃10 –25% of the CA1 cells show this firing
pattern (326, 327). Also, the fraction of active place cells
in a specific environment is even smaller and independent
of other environments (326, 327).
The underlying circuits for place fields very likely have
important implications for information storage, as they
provide the spatial context for memories and past expe-
riences. Place cells show a large variety of properties, but
only a few of those most important in the given context
are mentioned here (see Ref. 358 for more details). On
repeated paths (e.g., linear or rectangular tracks), place
fields are direction specific, i.e., the same cell that is firing
when the rat runs in one direction is silent when it runs
the opposite way (292). On the other hand, in an open
field environment where the rat can move freely, neuro-
nal activity does not completely depend on the direction
in which the rat is moving through a specific region (Fig-
ure 1.3B in Ref. 281).
Later experiments showed that place fields of CA1 pyramidal
neurons extend opposite to the running direction when the
animal is frequently running on a linear track. The field may
become asymmetric thereby, i.e., the relationship between po-
sition and firing rate gets negatively skewed over time (293).
Such asymmetric place fields are hypothesized to emerge by
NMDA receptor-dependent long-term plasticity of synapses
from CA3 to CA1 (100, 293, 391). Familiar environments are
also made up of symmetric and positively skewed place fields
(180). It has been reported that place cells exhibit a high vari-
ability of activity within the place field (112). This might indi-
cate that place cells encode other information than the ani-
mal’s location in the environment, e.g., texture underfoot,
odor, or stage of task. Furthermore, the running speed of the
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rat has been suggested to be encoded by the firing rate (100,
180, 328, 391). However, the correlation between action po-
tential firing rate and running speed, though higher than be-
tween firing rate and other parameters, is low and varies be-
tween cells. In addition, place cell activity correlated to previ-
ous spatial behavior has been shown to be recapitulated in
different types of sleep (264, 247).
C. Network Oscillations: Theta Rhythm
The activity of the place cell is accompanied by hippocampal
theta oscillations (4 –12 Hz) during exploratory behavior and
certain phases of sleep (REM) (325, 328). Summative evi-
dences indicate that theta rhythm is crucial for learning, e.g.,
spatial learning and navigation.
Exploratory behavior can be observed, e.g., when an animal
is placed in a rather novel environment and does whisking
and sniffing. The characteristic sniffing pattern of a rat is
also associated with theta activity (327).
1. Hippocampal theta rhythm
In principle, the hippocampal theta electroencephalogra-
phy (EEG) is very prominent and regular in frequency,
but it shows important differences depending on the re-
cording site. The amplitude as well as the phase of the
theta rhythm change between different hippocampal lay-
ers. The phase of the theta shifts backward with increas-
ing depth: from Stratum oriens, which is the layer above
the CA1 pyramidal layer, to the hilus, beneath the DG
granule cell layer. The amplitude is maximal at the hip-
pocampal fissure between Stratum lacunosum-molecu-
lare, the lowest layer in CA1, and Stratum moleculare,
the uppermost layer in DG (see also Ref. 52). The under-
lying mechanism of the hippocampal theta rhythm is un-
known. The “classic” model of theta generation is de-
scribed as follows (52). The medial septum and the diag-
onal band of Broca (MS-DBB) have been assumed to yield
the theta pacemaker input to the hippocampus by di-
rectly innervating CA1 pyramidal cells and interneurons
using acetylcholine as a transmitter. Additionally, the
basket cells (a type of inhibitory hippocampal neurons)
receive rhythmic GABAergic input, which they transmit
to the pyramidal cells. The pyramidal cells receive further
rhythmic input from the EC (layer III). This “classic”
model does not seem to reflect the reality very well for
several reasons. It has been suggested that two indepen-
dent theta generators are present in the hippocampus
(226). This suggestion arises from the finding that two
types of theta activity can be distinguished: atropine re-
sistant and atropine sensitive (52). The atropine-resistant
theta component is expected to be mediated by the EC to
the hippocampus, and the atropine-sensitive theta origi-
nates intrinsically in the hippocampus in the area of CA3
neurons. The latter theta oscillator requires cholinergic
 MARTIN KORTE AND DIETMAR SCHMITZ
activation, which is expected to be mediated by the sep-
tum (121). In the model presented by Kocsis et al. (226),
rhythmic input from EC layers II/III is transferred to both
hippocampal interneurons (basket and chandelier cells)
and directly to pyramidal and granule cells, while the
intrinsic CA3 theta generator is assumed to be suppressed
in the intact hippocampus (226).
Recent findings suggest that an intrahippocampal theta os-
cillator is located in the network of CA2/CA3 pyramidal
cells (120). In this model, the hippocampal subfield does not
obtain extrinsic oscillating input, and the septum is expected
to provide simply constant cholinergic input. The remaining
hippocampal network is assumed to adopt the oscillatory
pacemaker activity of area CA2/CA3. In fact, the mechanism
underlying the theta oscillations in the hippocampus remains
still unknown, despite the alternative ideas (for a review on
hippocampal theta activity and alternative solutions, see also
Refs. 52, 75, 308).
Corresponding to the extracellular theta, intracellular
membrane potential oscillations at theta frequency have
been shown to emerge in pyramidal cells (195, 482). The
activity of pyramidal cells, or more precisely place cells,
during spatial behavior is highly related to the theta rhythm
as will be outlined in the next section in more detail.
Riding on top of the theta rhythm, a neuronal activity with
the characteristic frequency of the gamma band (40 –100
Hz) is observed in the EEG (45). Theta and gamma rhythms
are recordable throughout the whole entorhinal-hippocam-
pal system, including the subiculum, and are tightly cou-
pled. The phase of theta scales the amplitude of gamma
oscillations. This phase-amplitude (or cross-frequency)
coupling of theta and gamma oscillations has been first
described (for a review, see Ref. 52) and later confirmed for
the hippocampus (407, 439) and other brain areas (58, 85,
440). More recently, it was reported (2012) that also an-
other theta-gamma coupling phenomenon is observed in
the hippocampus (26): phase-phase coupling (429). Here,
the phases of both rhythms are correlated (for a review, see
Ref. 110).
In summary, theta-oscillations are very robust synchronous
activities observed during exploratory behavior and are
thought to be crucial during encoding.
D. Phase Precession
The firing of single place cells in hippocampus is specifically
related to the theta rhythm of hippocampal neurons. This
spiking takes place at distinct points of the phase of the
theta cycle and can show variations in spiking-phase rela-
tionship.
In 1993, O’Keefe and Recce (328) observed the phenome-
non of hippocampal phase precession by investigating the
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timing of hippocampal pyramidal cell spiking in relation to
the theta rhythm while the rat crosses the neurons’ place
field. They recorded CA3 and CA1 pyramidal cells extra-
cellularly and found that during locomotor behavior, place
cells do not fire spikes randomly distributed over the whole
theta cycle, but rather discharge spikes that are pooled into
several bursts. O’Keefe and Recce (328) investigated the
temporal relationship between the theta rhythm and those
bursts and uncovered that such spike bursts do not occur at
a constant phase but shift to lower phases as the rat crosses
the cell’s place field. A graphical illustration of this phenom-
enon is given in FIGURE 9 (see also Figure 5 in Ref. 328). The
earliest action potentials, when the rat goes into the place
field, occur at constant phases, but the subsequent spikes
advance to lower phases. The phase precession continues
throughout the whole place field traverse so that the phase
has shifted through roughly an entire theta cycle when the
animal leaves the field.
A phase recession, i.e., shift to higher phases, has never been
observed. The linear correlation of the firing phase with the
position was stronger than with time. Though focusing on a
linear relation between phase and position, they mentioned
that occasionally position versus phase curves had sigmoi-
dal shapes indicating nonlinear dependencies (328). Later
on, it was described by recording only CA1 pyramidal cells
that phase precession shows more complex dynamics (402).
The spikes do not shift to lower phases linearly with posi-
tion; instead, the shift may accelerate at the end of the place
field, yielding curved phase versus position plots with ver-
tically expanded clusters for low phases (Figure 7 in Ref.
402). Yamaguchi et al. (475) analyzed these features more
thoroughly and described the data by two Gaussian func-
tions. They saw that the first Gaussian component belongs
to the early part of the place field, thus to high theta phases
(⫽180°) and reflects a strong correlation between position
and phase. The second component, which is in the middle of
the late part of the place field, shows no or less correlation
between phase and position (475).
Furthermore, Skaggs et al. (402) extended their experi-
ments to two-dimensional environments, where the rat is
freely exploring in a rectangular box. Phase precession is
also present there but less obvious. It is an interesting
notion that two-dimensional environments contain the
possibility of partial place field crossings (402). Due to its
dependence on the place fields, one would expect a
smaller amount of phase precession. This might explain
the reduced distinctiveness. Skaggs et al. (402) addition-
ally reported examples of phase precession in DG granule
cells, but the total phase shift was only about half a theta
cycle and less obvious in general compared with the hip-
pocampal pyramidal cells. Furthermore, only very few
examples were reported. Thus whether phase precession
is already present in earlier levels of processing of the
hippocampus than CA3 is less clear.
675
 BIOLOGY OF MEMORY EVENTS
In contrast to O’Keefe and Recce (328), Skaggs et al. (402)
specify absolute measured phase not in correlation to the
EEG theta rhythm, but instead to the CA1 population ac-
tivity peak, which they previously found to occur at a par-
ticular phase of the EEG theta. They did not report the
phase lag between the CA1 population peak and the EEG
theta explicitly. The CA1 population peak, however, seems
to precede the maximum of the EEG theta rhythm in the
figures found in their publication by at least 45° (see Figures
2 and 3 in Ref. 402). If a large number of the principal
neurons are silent during recordings, the population activity
will largely be shaped by the activity of a limited number of
cells. Spikes of active cells may precede in the phase at the
moment of recording, resulting in a nonstationary reference
point. Nevertheless, the first spikes emitted by a CA1 pyra-
midal cells, when the animal enters the place field, were
determined to be at 90 –120° after the phase corresponding
to the peak CA1 theta activity. The onset of firing of DG
units was 90° earlier than that of CA1 cells, and the peak of
the DG population theta activity preceded the CA1 peak by
about 90°. Meanwhile, further studies have been published,
which investigated different aspects of phase precession,
e.g., on phase precession inheritance from the hippocampal
region CA3 to area CA1 (185). The point of zero phase is
defined in different ways among these studies; therefore, the
comparability of absolute phase specifications remains un-
certain. Most focus has been given to CA1 pyramidal neu-
rons, but some studies present data on CA3 (e.g., Ref. 162).
The latter investigated the relationship between pyramidal
cell firing rate and phase, finding a correlation between
both. The phase of firing is observed to be high and constant
during low spiking activity and phase advance occurs at
times of intense activity. This result even holds true during
nonspatial learning behaviors like wheel running and sleep.
The observed correlation supports the idea that phase pre-
cession depends on the strength of dendritic depolarization
of the pyramidal cell, as discussed above. On the other
hand, it could be shown that the observed correlation be-
tween the rate of action potential firing and phase might
result from a combination of position-phase and rate-phase
relationships (180). They support the idea that phase and
rate encode different parameters, e.g., phase for the ani-
mal’s position in the place field and the firing rate for the
in-field velocity. Thus the absolute place cell activity during
various place field traverses does not have to be the same.
Further experiments indicated that a connection between
firing rate and phase (293) exists, similar to findings in
Reference 162. Furthermore, according to their model hy-
pothesis, they found phase precession only within nega-
tively skewed place fields, which in their opinion emerge
due to NMDA receptor mediated LTP, as described below.
In contrast, Huxter et al. (180) observed that all possible
kinds of place field skewness (negative, positive, symmetric)
exhibit phase precession (see also Figure 2. 1B in Ref. 180).
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Additionally, phase precession has been shown to be unaf-
fected by aging (391) and NMDA receptor blockade (100).
On the one hand, both studies reported a very similar loss of
experience-dependent expansion of place fields, as men-
tioned above, suggesting some possible connection between
aging and deficits in NMDA receptor dependent LTP. On
the other hand, the overall amount of phase precession as
well as the initial firing phase and the firing phase at place
field exit remained unaffected. Due to the smaller field size,
however, the rate of phase precession, i.e., the change of
phase with position, was higher in both studies. Moreover,
both Shen et al. (391) and Ekstrom et al. (100) observed
phase precession throughout the first laps of a specific re-
cording session in a familiar environment, contrary to the
findings of Mehta et al. (293) (see also Ref. 75).
Taken together, theta-oscillations of the hippocampal EEG
rhythm and place cell activity are correlated with each other
with a specific spiking-phase relationship. Is phase-preces-
sion an epiphenomenon or of functional relevance? Within
the next section, we are going to lay down a hypothetical
function for phase precession.
E. Temporal Compression as a Hypothetical
Function of Phase Precession
Due to its relation to the theta rhythm, which depends on
the rat’s location inside the place field, the phase apparently
encodes the precise position in the place field (186). Tem-
poral compression is considered to be a function of phase
precession, and it is presented here as a link between the
cellular and network mechanisms for the encoding of new
information. This is an example for temporal coding, i.e.,
the precise timing of the spike(s) in the theta rhythm pos-
sesses spatial information. Another way to represent infor-
mation is firing rate coding where the number of spikes
determines the information coded, as in the case of the rate
of action potential firing of a place cell. If phase precession
is only a product of learning, then its function would be
restricted to the coding or additional coding of position.
However, it is unclear whether phase precession truly is a
product of learning; for instance, phase precession is pres-
ent already during the first exposure to an environment
(358, 368), suggesting another functional role. Skaggs et al.
(402) proposed an alternative view, how phase precession
might facilitate the learning of sequences. In principle, a
discrepancy exists between the time scales of synaptic plas-
ticity, such as NMDA receptor-dependent LTP, and the
behaviorally driven changes in neural firing patterns. This
discrepancy could be removed by means of phase precession
that provides a temporal code, e.g., for the position, so that
information of different traversed locations can be tempo-
rally related to each other. Within this framework, a se-
quence of overlapping, successively traversed place fields of
neurons would be reactivated or “replayed” in a com-
pressed form during each theta cycle. This arises due to the
 MARTIN KORTE AND DIETMAR SCHMITZ

phase precession of the neuronal spikes, while the animal
moves through a certain sequence of place fields. As illus-
trated in FIGURE 9, along the path of a running rat neurons
with overlapping place fields successively start to fire and
process in the phase thereafter, which means their firing
advances to the succeeding phase. With the two assump-
tions that 1) firing starts at a fixed phase of the “back-
ground” theta rhythm as a common temporal reference,
and that 2) the phase change with position or time (i.e.,
phase precession) is the same for all cells, the temporal
order of traversed place fields is conserved in the temporal
order of the place cell firing during a theta cycle. That is the
case, because the firing of a cell, whose place field has been
entered before that of a second cell, already occurs at an
earlier phase inside the theta cycle than the firing of the
second cell. Thus a sequence of overlapping place fields is
represented in each theta cycle. The sequence, however, is
temporally compressed, because the time scale of the replay
is in the order of 10 ms.
The compressed time scale of sequence replay meets the
criteria necessary for NMDA receptor-dependent synaptic
plasticity. Additionally, synaptic modifications depend on
the timing of pre- and postsynaptic spikes (STDP), i.e., the
preference of presynaptic activity preceding the postsynap-
tic one, results in an asymmetric reinforcement of the syn-
aptic connections according to the sequence, the more so,
since a portion of the whole sequence is replayed in several
theta cycles. This redundancy supports a reliable associa-
tion of the parts of the sequence. As a high degree of con-
nectivity in a network is necessary to perform this kind of
associations, the CA3 region is the prior candidate for the
described mechanism to occur. As a consequence, apart
from the supporting experimental findings (328, 402, 162),
phase precession should be expected to emerge already in
the CA3 region (185, 302). In sum, temporal compression
of behavioral time scales could be a function of phase pre-
cession: it might link synaptic, cellular, and network mech-
anisms for the encoding of new memories.
F. Sleep: a Long-Lasting Timing Rhythm of
Memory Consolidation
Memory consolidations on a system level refer to the pos-
tencoding reorganization of long-term memory over dis-
tributed neuronal circuits within different brain areas. Sev-
eral models of system consolidation have been established,
from the standard consolidation theory, to the multiple
trace theory, up to the schema assimilation model. The

location

a b c d

a b c d
event
FIGURE 9. Encoding of spatial trajectories
within the hippocampus via temporal com-
pression. Place cells exhibit place cell over-
lap, while at the same time the hippocampal
neuronal network shows robust theta oscilla-
cell a
tions. Overlapping place cell activity and sub-
b sequent temporal compression establish the
time windows for spike-timing dependent syn-
c aptic plasticity (STDP).

c
a

d
b

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 BIOLOGY OF MEMORY EVENTS
different hypotheses underlying these models have been
nicely reviewed (for example, see Ref. 94). In our review we
would like to concentrate on the role of sleep, with a par-
ticular focus on high-frequency oscillations, and its func-
tion in memory consolidation.
Sleep has long been thought to be a rather passive and
recreational event. In recent years this view has been chal-
lenged and very recent studies could even link structural
plasticity with sleep (476). In mammals as well as in birds,
the sleep behavior is generally divided into two phases:
rapid eye movement (REM sleep) and non-rapid eye move-
ment (NREM, non-REM sleep). Each phase of sleep has a
rather distinct set of neurophysiological features associated
with it. REM sleep is linked to dreaming. NREM is divided
into three distinct stages: N1, N2, and N3. N3 is commonly
also called delta sleep or slow-wave sleep (SWS).
Among the different sleep stages, especially the SWS seems
to be important with respect to the consolidation of mem-
ory. During SWS, memory sequences are repeatedly re-
played, which has a pivotal role in transferring labile mem-
ory into stable engrams (for reviews, see Refs. 41, 357). At
the same time, episodic and decontextualized content is
separated and processed in the appropriate networks, the
hippocampus being mainly responsible for orchestrating
the storage of episodic memory and extrahippocampal re-
gions such as the neocortex and the striatum being respon-
sible for semantic and procedural aspects of memory (357).
1. Function of distinct stages of sleep
Several hypotheses seek to explain the function of distinct
sleep states for memory consolidation (for more details, see
Ref. 357). An earlier hypothesis proposed that sleep evolved
to maintain homeostasis (77, 198, 40). In this context, it is
thought that plasticity processes during the awake state
result in a net widespread enhancement in the efficacy of
synapses; sleep is then to downscale synaptic strength to
baseline that is energetically sustainable and potentially
also more useful for the acquisition of new memories the
next day (198). The “active system consolidation” theory
(41, 91) is a modification of the standard consolidation
theory and incorporates an active and integral role of sleep
in long-term memory consolidation. At the heart of this
theory lies the observation that hippocampal place cell as-
semblies (compare sect. IIIB) are replayed in the same order
during SWS as experienced during the initial exploration
and encoding (247, 401, 464). More specifically, Lee and
Wilson (247) report on CA1 pyramidal neurons in rats that
are sequentially activated during spatial behavior, repeat
the same order of firing during sleep, which indicates the
replay of memories during sleep and emphasizes the impor-
tance of the hippocampus in sequence learning. The replay
during SWS occurs 20 times faster compared with the
awake exploration. As a result, sequences are compressed
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to the order of 100 ms, which is strong evidence for the
existence of a temporal compression mechanism.
Different from the standard consolidation theory is that
both hippocampus and extrahippocampal regions store rel-
evant information. The orchestrating central role of the
hippocampus is the integration of different information as-
pects into one spatiotemporal context, thus binding the dif-
ferent components together to form an episodic memory.
Replay of this information in each SWS cycle and informa-
tion transmitted from the hippocampus to extrahippocam-
pal regions might induce plasticity changes in these regions,
representing the transformation steps necessary to extract
the semantic content of the episodic memory and store them
as semantic engrams (41).
2. Information processing during SWS
A key electrophysiological feature enabling this informa-
tion processing during SWS is the interaction of neocortical
slow oscillations (SO) with hippocampal sharp wave ripples
(SWR) and thalamic spindles. SO are characterized by a
highly excitable “up” state, setting the framework for exci-
tation-mediated Ca2⫹ influx, which might lead to appropri-
ate synaptic changes (389). The cyclic change between the
low-frequency and high-amplitude EEG in SWS and the
low-amplitude EEG in the theta range as it occurs during
REM sleep might be a complementary mechanism to enable
memory consolidation. Consistent with this theory, sleep
primarily seems to be beneficial for hippocampus-depen-
dent memories (101, 448). Animal studies support this hy-
pothesis. Although lesions to the hippocampus did not im-
pair the recall of “what,” “when,” or “where” as separated
information, the recall of contextual memory, which char-
acterizes the relation between these aspects, was severely
impaired (254). Additionally, sleep was a prerequisite for
the integration of these aspects into a contextual memory
(182). Interestingly, these observations are also linked to
the occurrence of SWR and spindles during sleep intervals
(33). Moreover, blocking CA3 output by a genetic ap-
proach and thus eliminating the SWR drive to extrahip-
pocampal regions resulted in a reduced retrieval perfor-
mance (316). The importance of sleep in hippocampus-de-
pendent memory consolidation is further supported by
several behavioral observations. In earlier studies, sleep de-
privation only affects the hidden platform version of the
Morris watermaze, which depends on hippocampal func-
tion (404). Furthermore, it induces a shift from hippocam-
pus-dependent navigation strategies towards striatum-de-
pendent ones (153–155). Similarly, context-dependent fear
conditioning is reduced by sleep deprivation, whereas cued
fear conditioning is not (56). Memories not involving the
hippocampus seem to profit less well from sleep (55). Thus
the hippocampal system seems to provide a temporary
memory buffer, in which labile (explicit) information is
stored and transferred to other brain regions later on, where
the memory becomes more stable. In accordance with this,
 MARTIN KORTE AND DIETMAR SCHMITZ
hippocampal lesions conducted 3 h after a learning para-
digm interfered with the establishment of stable memory,
whereas lesions conducted after 48 h had no effect (442).
Expanding these findings to a more global level leads to the
viewpoint that sleep is the state of the brain optimized for
memory consolidation, whereas vigilance is the brain state
optimized for memory encoding (FIGURE 10). Sleep en-
dorses the branch-specific formation of dendritic spines af-
ter learning (6, 476). Indeed, the need for sleep as a state of
diminished sensory awareness, immobility, and loss of con-
sciousness might explain that encoding of information and
consolidation are mutually exclusive events, since they re-
cruit overlapping neuronal resources and physiological pro-
cesses (357). Bridging this further to the cellular level, it also
means that the cortex might have a different synaptic plas-
ticity machinery than the hippocampus, e.g., it could indeed
be shown that the crucial function of the kinase alpha-
CaMKII during induction of LTP is a different one in the
cortex compared with its role in the hippocampus (125,
256). Elegant experiments proved this point in alpha-CaM-
KII heterozygous mice, which have only half the normal
amount of alpha-CaMKII and these mice showed normal
LTP in the hippocampus, but only short lasting LTP in the
cortex (125). And indeed mice learned normally a new task,
but because LTP in the cortex is only short-lasting in these
mice, long-term memory could not be stabilized (consolida-
tion was impaired). Also, on the behavioral level, these mice
could perform well initially in “hippocampus-dependent”
learning tasks, but these memories could not be maintained.
According to Lisman and Morris (256), the cortex can be
viewed to be a slow learner, capable of consolidation only
consolidation
experience stable memories
FIGURE 10. Neuronal network oscillations in memory consolida-
tion. Memory consolidation critically depends on high-frequency net-
work oscillations named ripples. Ripples enable the strengthening of
newly acquired information on episodic events into stable memories.
The two types of pyramidal neurons within the subicular area at the
hippocampal output (B, burst firing pyramidal cell; R, regular firing
pyramidal neuron) might be differentially embedded during ripple
activity and thereby separate information flow into the cortex.
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as a result of the repeated replaying of information by the
hippocampus, probably during sleep, as suggested here.
Notably, SWS sleep decreases naturally with age, which is
correlated with a reduction in declarative memory consoli-
dation in humans and rodents (159, 278). Furthermore,
when sleep was possible after implicit training on a motor
sequence, children showed bigger improvements in explicit
sequence knowledge after sleep than grownups did. This
superior explicit knowledge in children was connected to
their higher amount of SWS activity as well as to stronger
activation of the hippocampus during explicit knowledge
retrieval (352).
G. Neuronal Network Oscillations in
Memory Consolidation
Within the two-stage model of memory consolidation, theta
oscillations and high-frequency oscillations (ripples) fulfill
complementary functions: theta during encoding and rip-
ples during consolidation. A prerequisite of the aforemen-
tioned memory consolidation during sleep is that hip-
pocampal and extrahippocampal regions need to commu-
nicate in a carefully orchestrated manner. Prominent
electrophysiological hallmark of this orchestration are the
up and down states of the SWS phases (0.75–5 Hz), sleep
spindles (12–15 Hz), and hippocampal SWR complexes
(100 –200 Hz for ripples). SWS might represent the sleep
state most important for the consolidation of declarative
memory. Memory consolidation is thought to be the result
of repeated reactivation of the neuronal representation of a
memory. Alongside consolidation, transformation of mem-
ory takes place at several levels: transformation of labile to
stable memory, but also transformation of abstract content
into semantic or procedural memory (466).
Slow and fast oscillation phenomena seem to set the overall
“time reference” for the information processing during
sleep in a “top-down” manner. The information carrying
“bottom-up” events like SWR and spindles (see below) are
inhibited during the down state of the slow oscillations (20,
72, 73). Interestingly, slow spindles are delayed by ⬃200 –
500 ms with respect to fast spindles, thus occurring during
the transition from up to down states. SWR and spindles
appear to be driven by the depolarizing transition of down
to up states (20, 183, 246). Successful learning is paralleled
by an increase in density of ripples and spindles (73, 107,
135) and facilitates SO (304). In turn, the boosting of SO in
humans and animals has been shown to improve learning
(282).
1. Spindles
Spindles are oscillations in the range of 7–15 Hz, with a
duration of 0.5–3 s generated in the thalamus and spreading
into many cortical areas. They are often further subdivided
679
 BIOLOGY OF MEMORY EVENTS
into fast (12–15 Hz) and slow (10 –12 Hz) spindles, the
latter occurring prominently during SWS (9, 80, 303, 430).
GABAergic neurons of the nucleus reticularis are the prime
pacemaker in spindle generation, which depend to a large
extent on the activation of T-type Ca2⫹ channels (11, 21).
In cortical pyramidal cells, spindle occurrence might lead to
a massive Ca2⫹ influx with consequences for the excitability
of the cell (34, 389). Likely, one of the targets of this activity
on the genetic and molecular level is the protein Arg3.1 (88,
389), which has been introduced in section III. Further-
more, similar to SWR, plasticity inducing protocols also
facilitate spindle occurrence (28). Spindle activity seems to
be positively correlated with successful learning in several
paradigms; noteworthy, in some paradigms spindle activity
increases selectively in the cortical areas associated with
that particular paradigm, e.g., motor cortex (322, 454,
455). Furthermore, fast spindle activity is in synchrony with
hippocampal and extrahippocampal oscillations starting
shortly before the occurrence of SWR and also outlasting
them (422). In the resulting spindle-ripple complex, ripples
are temporally locked to the trough of a spindle and also
synchronize with neocortical gamma activity (73, 397, 461,
422). Slow spindles on the other hand might coincide with
the silencing of hippocampal input to the cortex (73, 347).
2. Hippocampal SWRs
Hippocampal SWRs are 40 –150 ms periods of massive ac-
tivation of the entire hippocampal-subicular network (51,
54, 482), in which characteristically slow sharp waves are
overlaid with 120- to 250-Hz ripple oscillations. SWRs are
observed during awake immobility and SWS (51, 54) and
have been suggested to support the consolidation of re-
cently acquired memories (53, 90, 240, 247, 464). Accord-
ing to a current hypothesis, SWRs represent population
discharges of basically the entire hippocampal network
(53). The basic mechanisms of how SWRs are initiated,
maintained for ⬃50 –100 ms, and finally terminated are
largely unknown.
Recently, different experimental approaches, including jux-
tacellular recordings in vivo and investigations in hip-
pocampal slices, have identified several classes of inhibitory
interneurons that are activated during SWRs (187, 206,
220, 221, 222, 156, 334, 408, 449). With these techniques,
it has been shown that ripple network activity is paralleled
by an increase or decrease in specific classes of interneurons
(for a review, see Ref. 223). Based on these data, it has been
concluded that interneurons induce ripple oscillations, al-
though a direct and causal link has not been established yet.
Alternative mechanisms of ripple generation have been sug-
gested where electrical coupling (93, 381) or combined
mechanisms involving synaptic and electrical coupling
(441) contribute to the oscillogenesis. In these models, the
phasic discharge of assemblies of pyramidal neurons is the
immediate source of ripples. A straightforward prediction
of such a synchronous activation of pyramidal cells would
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be the presence of phasic excitation during ripples that is
coherent across the neuronal network and apparent as ex-
citatory postsynaptic currents and potentials at the single-
cell level (270).
The main output of the hippocampus, the subicular area,
also exhibits SWRs activity (25, 102, 285). Within the
subicular area two types of pyramidal cells have been
described based on their specific firing properties: regular
or burst firing pyramids (for a review, see Ref. 25). In
contrast to CA1 pyramidal cells, subicular pyramidal
cells exhibit a low degree of axonal collateralization and
project mostly to only one target region (313). Interest-
ingly, the two pyramids project to different target areas,
e.g., the lateral and medial entorhinal cortex, but also
other brain areas (313). Recently, Böhm et al. could show
by whole cell patch-clamp recordings in awake mice that
bursting cells are activated during sharp wave-ripples
whereas regular firing cells are inhibited (39a). Similar
observations were made in in vitro models of sharp-wave
ripples (102, 285). Böhm and colleagues also identified
the principles that underlie the differential recruitment
during sharp wave-ripples by using multiple patch clamp
recordings and circuit analysis. Regular firing cells re-
ceive more and stronger inhibition while the pyramidal
cell network favors excitatory input onto burst firing
cells. Thus principal cells that project to the same target
regions are connected among themselves, and in addi-
tion, there is exclusive unidirectional connectivity from
one group of principal cells, regular firing cells, to the
other, burst firing cells, but not vice versa. Considering
the cell-type specific extrahippocampal target areas of
burst and regular firing cells (218), mainly target regions
of the burst firing cells would receive excitatory input
from the subiculum during SWR. Indeed, neuronal activ-
ity that is temporally locked to hippocampal sharp waves
could be shown in both the medial entorhinal cortex (68,
471) and the presubiculum (68), which are target areas of
burst firing cells (218). It is tempting to speculate that
there is no or less SWR-associated input to the lateral
entorhinal cortex, a target area mostly innervated by
regular firing cells. This would imply a pivotal role of the
subiculum in separating information streams and distrib-
uting this information to cortical targets.
In summary, memory consolidation requires not only cel-
lular events at activated synapses, but also fast network
oscillations, and it involves the transfer of information from
the hippocampus to various cortical targets. Experimental-
ists in close interaction with theoreticians will further de-
velop the differing models over the near future. In addition,
modern techniques such as cell-type specific optogenetics
will not only contribute to an improved understanding of
the connectivity of neuronal networks, but will also provide
further insights in memory formation on a system level.
 MARTIN KORTE AND DIETMAR SCHMITZ

IV. PERSPECTIVE
In this review we covered a huge research field, not only in
terms of papers and results, but also in space: vesicle size in
the nanometer scale, phosphorylation of proteins ever
smaller, up to large centimeter wide neuronal networks,
and the crosstalk of different brain areas during sleep and
memory consolidation. But also the time frame covered
shows the complexity of information storage and retrieval
in the brain: some events are extremely fast, like the phos-
phorylation of glutamate receptors due to changes in syn-
aptic activity, the change in synaptic release machinery and
also Ca2⫹ signals inside neuronal compartment, which hap-
pen in the millisecond to second range. Signaling to the
nucleus, expression of early change and the transport of
their products can happen in 30 min up to a few hours, and
this happens in parallel to structural changes at synaptic
sides. But these activity-dependent changes are also modu-
lated and shaped via rhythmic, sometimes oscillatory, brain
activity, in the time range of seconds and minutes. Long-
lasting changes in gene expression can last hours, days,
weeks, and most likely in concert with epigenetic genes even
for months and years. It will be an exciting question to
explore how prior experience minutes, hours, or days ear-
lier can increase or decrease the gain of synaptic plasticity
and how by what means network activity and synaptic ac-
tivity are timed to store, or encode specific memories. It is
also an open question why certain forms of network activ-
ity, theta (5–7 Hz) during encoding and ripples 100 –300
Hz during consolidation, foster certain components of
memory storage and retrieval.
What became evident in the last decade is that a specific
memory can be encoded by an astonishingly sparse pop-
ulation of principal neurons. These cells can be tagged
during the learning events for the subsequent identifica-
tion and manipulation. Moreover, their destruction or
their inactivation can result in reduced memory expres-
sion, suggesting their necessity in mnemonic processes
(e.g., Ref. 369). Although this convincingly shows the
necessity of these neuronal populations, the equally im-
portant question of sufficiency remains: is it possible to
elicit a specific (learning) behavior by directly stimulating
precisely the specific population of cells that was active
during the learning period? Here an amazing experiment
highlights how future experiments can be conducted to
prove what is necessary and what is sufficient for infor-
mation storage, as was outlined in the review by Morris
and colleagues (284). In mice, it was recently shown that
optogenetic reactivation of hippocampal cells, which
were also active during a learning paradigm which in-
cluded fear conditioning, is enough to induce freezing
behavior (260). During this experiment a certain popu-
lation of granule cells in the hippocampus were labeled
after they have been activated during fear conditioning
with the optogenetic protein channelrhodopsin-2
(ChR2). These neurons have been reactivated optically in
a different context during the latter part of the experi-
ment. And indeed, these animals showed a higher freez-
ing rate only upon optogenetic stimulation. This out-
come indicates a recall of a light-induced fear memory. In
a control situation, no freezing behavior could be de-
tected in mice, which were non-fear-conditioned but ex-
pressed ChR2s (260). All control experiments indicated
that optogenetically induced fear recall is context spe-
cific.
In summary, these experiments show that activating a
sparse but highly specific assembly of hippocampal neu-
rons, which were involved in the initial learning paradigm,
can be adequate for the recall of that specific memory.
Moreover, we think that this experimental paradigm used
by Tonegawa and colleagues offers a general paradigm to
map neuronal populations bearing an engram (memory
trace). It also paves the way for not only clarifying the role
of single neurons in a neuronal network storing a specific
memory content, it also offers the possibility to study the
molecular nature subserving these events.

TIMING OF EVENTS

Waves and STDP: Implementation Consolidation Epigenetic:

rhythms: Timing on of change at when we sleep the “before”
coupling the network the synapse and the “after”
level of learning

FIGURE 11. Timing of events in the biology of memory formation and consolidation. There is mutual
interdependence at every process for events of memory storage that need precise timing and might influence
current events (like the implementation of changes at the synapse) or future events (like epigenetic factors).

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 BIOLOGY OF MEMORY EVENTS
Consolidation is a continuous and long-lasting process on
several molecular, network and systems levels, as Dudai
phrased it, “Taken together, the picture that emerges is of
dynamic engrams that are formed, modified, and re-modi-
fied over time at the systems level by using synaptic consol-
idation mechanisms as subroutines. This implies that, con-
trary to interpretations that have dominated neuroscience
for a while, but similar to long-standing cognitive concepts,
consolidation of at least some items in long-term memory
may never really come to an end” (94). In recent years, it
became clear that synaptic plasticity, in particular LTP, is of
crucial importance for memory processes in vivo, and it
became also evident how neuronal assemblies can store in-
formation and represent a memory (see, e.g., Refs. 137,
260, 312, 355).
For the past 40 years, the expedition into the neural basis of
learning, memory, and retrieval focused mainly on the mo-
lecular and cellular basis of activity-dependent plasticity.
This approach has brought tremendous insight into the mo-
lecular machinery and the timing events of learning and
memory so far (FIGURE 11). Nevertheless, here we provide
evidence that a full understanding of the different processes
leading to complex learning and memory behavior will re-
quire incorporating the properties of individual cells and
the functional dynamics of large-scale networks. Further
progress in examining the conceptional foundation of mem-
ory will require an approach that takes into consideration
the importance of timing events in the CNS on every level of
complexity.
Therefore, we would like to conclude: “If any one faculty
of our nature may be called more wonderful than the rest,
I do think it is memory. There seems something more
speakingly incomprehensible in the powers, the failures,
the inequalities of memory, than in any other of our
intelligences. The memory is sometimes so retentive, so
serviceable, so obedient–at others, so bewildered and so
weak– but at others again, so tyrannic, so beyond con-
trol! We are to be sure a miracle every way– but our
powers of recollecting and of forgetting, do seem pecu-
liarly past finding out” (Jane Austen in Mansfield Park).
ACKNOWLEDGMENTS
We thank Wiebke Arendt, Anita Remus, Marta Zagreb-
elsky, and Benedikt Salmen for critical comments to an
earlier version of the manuscript. We are especially
thankful to Claudia Brose for the excellent help with the
figures.
Address for reprint requests and other correspondence: M.
Korte, TU Braunschweig, Zoological Institute, Div. Cellu-
lar Neurobiology, Spielmannstr. 7, 38106 Braunschweig,
Germany (e-mail: m.korte@tu-bs.de).
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GRANTS
We are grateful to the DFG (to M. Korte and D. S. Schmitz)
and N-RENNT, Ministry of Science and Culture of Lower
Saxony (to M. Korte), for funding our work.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared
by the authors.
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