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ABSTRACT: The dentate gyrus (DG) is thought to enable efficient hippocampal memory acquisition via pattern separation. With patterns
defined as spatiotemporally distributed action potential sequences, the
principal DG output neurons (granule cells, GCs), presumably sparsen
and separate similar input patterns from the perforant path (PP). In
electrophysiological experiments, we have demonstrated that during
temporal lobe epilepsy (TLE), GCs downscale their excitability by transcriptional upregulation of leak channels. Here we studied whether
this cell type-specific intrinsic plasticity is in a position to homeostatically adjust DG network function. We modified an established
conductance-based computer model of the DG network such that it
realizes a spatiotemporal pattern separation task, and quantified its performance with and without the experimentally constrained leaky GC
phenotype. Two proposed TLE seizure mechanisms were implemented
in various degrees and combinations: recurrent GC excitation via mossy
fiber sprouting and increased PP input. While increasing PP strength
degraded pattern separation only gradually, already the slight elevation
of sprouting drastically (non-linearly) impaired pattern separation. In
most tested hyperexcitable networks, leaky GCs ameliorated pattern
separation. However, in some sprouting situations with all-or-none seizure behavior, pattern separation was disabled with and without leaky
GCs. In the mild sprouting (and PP increase) region of non-linear
impairment, leaky GCs were particularly effective in restoring pattern
separation performance. These results are compatible with the hypothesis that the experimentally observed intrinsic rescaling of GCs serves to
C 2014 Wiley
maintain the physiological function of the DG network. V
Periodicals, Inc.
KEY WORDS:
hippocampus; computational model; epilepsy; ion
channel homeostasis; electrophysiology
INTRODUCTION
The dentate gyrus (DG) is involved in hippocampal memory acquisition and is important for the discrimination of similar sensory input
patterns (Gilbert et al., 2001; Leutgeb et al., 2007; McHugh et al.,
2007; Moser et al., 2008). This behavioral discrimination is consistent with theoretical models predicting a
role of the DG in computational orthogonalization of
overlapping activated neuronal assemblies, an operation termed pattern separation (Treves and Rolls,
1992; OReilly and McClelland, 1994; Santoro,
2013). The principal neurons of the DG, the granule
cells (GCs), are thought to contribute to DG function
via their low firing probability and connectivity (Jung
and McNaughton, 1993; Chawla et al., 2005; Leutgeb
et al., 2007; Moser et al., 2008). While connectivity
has received a lot of attention in DG network modeling (Santhakumar et al., 2005; Dyhrfjeld-Johnsen
et al., 2007; Morgan and Soltesz, 2008; de Almeida
et al., 2009; Myers and Scharfman, 2009, 2011;
Schneider et al., 2012), the impact of cell typespecific, intrinsic properties (such as membrane conductivity) on network performance has generally
received less attention. There are however two studies
on the influence of mossy cells (MCs) and interneurons on seizure spread in the DG (Howard et al.,
2007; Yu et al., 2013). The pattern separation ability
of previous DG computer models has been investigated via spatial binary patterns (Myers and Scharfman, 2009, 2011) but not via spatiotemporal spike
coding. Yet, spike timing is an important aspect of
the GC pattern transformation and neuronal information encoding in general (Lisman et al., 2005; Leutgeb et al., 2007; de Almeida et al., 2009; Buzsaki,
2010; Panzeri et al., 2010; Eichenbaum, 2013; Rangel
et al., 2013; Yim et al., 2014).
Temporal lobe epilepsy (TLE) is a common form
of epilepsy characterized by focal seizures in the
entorhinal-hippocampal loop and partial memory
impairments (Spencer, 2002; Bonilha et al., 2007).
Discussed seizure mechanisms include elevated output
from the entorhinal cortex to the DG via perforant
path (PP) axons (Spencer and Spencer, 1994; Kobayashi et al., 2003) and the backsprouting of mossy fiber
(MF) axons of GCs resulting in recurrent excitation
of GCs (Tauck and Nadler, 1985; Buckmaster, 2012).
The latter inspired modeling studies to demonstrate
that MF sprouting indeed produces seizure-like runaway excitation in DG networks (Santhakumar et al.,
2005; Morgan and Soltesz, 2008; Schneider et al.,
2012).
In surgically resected hippocampi of patients with
TLE, we discovered that GCs of the sclerotic focus
YIM ET AL
FIGURE 1.
DG network model performing pattern separation. A:
Control connectivity (CTRL DG) with PP input, output via 500 GCs
(control properties, CTRL GCs), BCs, HIPP cells (HCs), and MCs.
Vertical tick lines represent APs. B: Summation of active inputs to
GC8 (upper panel) during input pattern 1 (IP1) evoked one AP in
GC8 (lower panel). Inset: voltage responses to 2 pA steps (scale bars:
1 mV, 100 ms). C,D: The IP3 (C) led to a sparse output pattern (OP)
30 (D, all GCs and BCs are displayed; HCs and MCs were inactive).
E: Four of 13 IPs with increasing spatiotemporal difference and
respective OPs (y-scales contain all PPs and GCs). Right panel, similarity scores between IPs vs. those of OPs, fitted by a shifted power
law. Data below the dashed line signify pattern separation, e.g. at 0.60
input similarity, the CTRL DG achieved an output similarity of 0.29.
RESULTS
A Dentate Gyrus Network Model Performing a
Temporal Pattern Separation Task
First, we presented the temporally distributed patterns via
PP inputs to a DG network with control connectivity and control GC properties (Fig. 1A, CTRL DG/CTRL GCs, see
Methods). In Figure 1B, the signal integration is displayed
from the perspective of one representative GC (GC8). This
GC received inputs from various sources (Fig. 1B, upper panel)
during input pattern 1 (IP1). The GC8 summated the excitatory inputs and eventually fired an AP (Fig. 1B, lower panel);
some inhibitory inputs from BCs followed. The necessity of
EPSP summation for AP generation is consistent with the
Hippocampus
YIM ET AL
With Leaky Granule Cells and SproutingRelated All-or-None Seizures, Pattern Separation
Cannot be Computed
Electrophysiological experiments have revealed that during
chronic TLE, GCs display a permanent upregulation of leak
channels and specifically, increased Kir and tonic GABAA conductances were found responsible for a reduction of Rin and
Hippocampus
FIGURE 2.
MF sprouting leads to breakdown of DG pattern
separation ability. A: The DG model of Figure 1 was rendered epileptic by 30% GCGC backsprouting (Spr30 DG, see inset).
Intrinsic GC properties were unchanged (CTRL GCs). During
IP1, GC8 experienced massive excitatory input from other GCs
(upper panel) and was forced to burst (lower panel). B: The IP3
(see Fig. 1C) now led to repeated excitation of all GCs (OP30 ).
Panel B contains all cells, active and inactive (HC, HIPP cells 22
27, light gray; MC, mossy cells 721, dark gray; BC, basket cells
16, medium gray). C: Quantification of pattern separation with
IPs as in Figure 1E (y-scales in left panels correspond to y-axis in
D). The right graph shows the devastating effect of 30% sprouting: the DG was unable to perform pattern separation: at 0.60
input similarity, the output similarity was now 0.91.
excitability (Young et al., 2009). Are these changes in the position to affect the pattern separation ability of the DG? Constrained by our experimental results, we implemented these
leak mechanisms in the epileptic DG model described above
(Figs. 3A,B, Spr30 DG/Leak GCs). Consistent with the respective experiments (Young et al., 2009; Kirchheim et al., 2013),
FIGURE 3.
In some conditions, leaky GCs did not prevent
sprouting-related all-or-none seizures and failure of pattern separation.
A: The epileptic DG network of 30% sprouting as in Figure 2
(Spr30 DG) was used with leaky GCs (Leak GCs, gray). Middle panel:
smaller voltage responses of leaky GCs to 2 pA steps compared to
CTRL GCs (thin black traces; scale bars, 1 mV, 100 ms). Right panel:
the current (I)AP frequency (F) relation of leaky GCs was right
shifted. B: Leaky GC8 received two IPs (upper panel, IP2 and IP4). It
was activated by IP4 (lower panel) which recruited recurrent GC excitation (CCs row). C: The IP4 produced a slowly developing seizure
(panel contains all active and inactive cells). D: Since only few IPs
produced a GC output, no similarity scores could be computed (yscales contain all PPs and GCs). Hence, no meaningful pattern separation abilities remained under these conditions of recurrent excitation.
YIM ET AL
FIGURE 4.
Epileptic hyperexcitation via increased PP activity
gradually reduced the DG pattern separation ability. A,B: With
epilepsy-related increase of the PP input strength to 160% and
additional mild (10%) MF sprouting (PP160Spr10 DG), the network activity was overall enhanced and most GCs were repeatedly
activated (B, the panel contains all active and inactive cells. C:
Under these epileptic conditions, the DG possessed only weak pattern separation abilities (left panel y-scales correspond to y-axis in
B). At 0.60 input similarity, the output similarity was 0.36.
FIGURE 5.
Leaky GCs can restore the pattern separation ability lost due to epileptic hyperexcitation. A,B: This simulation was
performed with the same epileptic DG network and IPs as in Figure 4 (PP160Spr10 DG), except that leaky GCs were implemented
(see Fig. 3A). The same PP inputs evoked only sparse activity in
the GC population (A, B). As in Figure 1D, HCs and MCs
remained silent. C: Left panels show representative patterns (yscales correspond to y-axis in B). The pattern separation abilities
of the DG were restored with leaky GCs (gray line), despite the
epileptic wiring and input (thin black line shows performance
with CTRL GCs as in Fig. 4C). At an input similarity of 0.60,
output similarity was now only 0.16.
FIGURE 6.
The amelioration of the pattern separation via
leaky GCs was robust but heterogeneous under different conditions
of epileptic hyperexcitation. A: With more sprouting (030%,
Spr030), pattern separation deteriorated (black fits, higher output
similarity scores). Leaky GCs reduced output similarity in all cases
(blue fits). B: Comparison of output similarity at 0.6 input similarity (y-axis) with different degrees of sprouting or PP strength
(CTRL GCs, black; leaky GCs, blue). Pattern separation failed
non-linearly with sprouting (left panel). Leaky GCs shifted the
curve, hence the large effect at 20% sprouting (see also A). Right
panel, with increased PP strength, pattern separation deteriorated
only gradually. Similar results were obtained with other network
realizations (error bars are STD, n 5 5). The PP strength of left
panel (and in A) was 140%. C: Comparison of pattern separation
(color-coded, measured as above) in dependence of sprouting and
PP strength. With the combination of leaky GCs and PP80100,
no similarity score could be computed (white). In many conditions
of epileptic hyperexcitation, the DG with CTRL GCs failed to separate patterns (red colors, left panel). In contrast, with leaky GCs
pattern separation was restored under conditions of epileptic
hyperexcitation (right panel). [Color figure can be viewed in the
online issue, which is available at wileyonlinelibrary.com.]
Hippocampus
YIM ET AL
DISCUSSION
Here, we studied the impact of cell-intrinsic conductance
scaling on the function of a neuronal network, using a modified version of the DG network model from the work by Santhakumar et al. (2005). We demonstrate that pattern
separation capability emerges from our version of the network,
consistent with the proposed function of the DG (Treves and
Rolls, 1992; OReilly and McClelland, 1994; Gilbert et al.,
2001; Leutgeb et al., 2007; McHugh et al., 2007; Moser et al.,
2008; Clelland et al., 2009; Myers and Scharfman, 2009;
Sahay et al., 2011; Yassa et al., 2011; Deng et al., 2013; Santoro, 2013). The pattern separation ability was degraded by
epileptic hyperexcitation and to variable degrees restored by the
epilepsy-related adaptation of intrinsic GC properties, which
we determined experimentally before (Young et al., 2009).
cell type-specific intrinsic (non-synaptic) plasticity was investigated in only few network modeling studies (Howard et al.,
2007; Thomas et al., 2009, 2010). Pattern separation is prominently discussed in the field of dentate neurogenesis because the
addition of immature GCs to the DG affects behavioral discrimination (Aimone et al., 2009, 2011; Clelland et al., 2009; Deng
et al., 2010; Sahay et al., 2011; Nakashiba et al., 2012; Tronel
et al., 2012; Dery et al., 2013; Rangel et al., 2013). Since immature GCs have different intrinsic properties compared to mature
GCs (Haussler et al., 2012), the role of neurogenesis in pattern
separation could be viewed in favor of our hypothesis that intrinsic properties of GCs are important for the task. However, the
polarity of how newborn GCs are involved is not straightforward:
if it is true that specifically the sparse activation of GCs supports
pattern separation (Treves and Rolls, 1992; Jung and McNaughton, 1993; OReilly and McClelland, 1994; Chawla et al., 2005),
then the highly excitable immature GCs would be expected to
degrade pattern separation. Yet, GC neurogenesis appears to support DG-dependent behavioral discrimination (Sahay et al.,
2011; Nakashiba et al., 2012; Tronel et al., 2012; Dery et al.,
2013). Some of the puzzle could be due to mechanistic differences underlying computational and behavioral pattern separation
(Santoro, 2013). Furthermore, it is possible that immature GCs
are involved in tasks slightly different from classic pattern separation, e.g. increasing memory resolution and/or time stamping
on larger time scales (Clelland et al., 2009; Aimone et al., 2009,
2011; Deng et al., 2010; Rangel et al., 2013). It will be interesting to test our hypotheses by selective modification of GCs in
vivo combined with behavioral experiments.
In summary, the present study demonstrates that the intrinsic ion channel adaptations discovered previously (Stegen et al.,
2009; Young et al., 2009) are in a good position to homeostatically assure the sparseness of GC activation and thereby
dynamically maintain DG network function under different
levels of network excitability.
Acknowledgments
Authors thank Catherine E. Myers for providing and discussing her simulation code on the separation of binary patterns.
Part of the analysis was conducted using the high performance
computing facilities offered by the Information Technology
Services, University of Hong Kong.
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APPENDIX
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YIM ET AL
TABLE AI.
Parameters of the Network Model During Control Condition
From (row)/to (column)
PP
Connectivity
Weight (nS)
Delay (ms)
GC
Connectivity
Weight (nS)
Delay (ms)
BC
Connectivity
Weight (nS)
Delay (ms)
MC
Connectivity
Weight (nS)
Delay (ms)
HIPP
Connectivity
Weight (nS)
Delay (ms)
GC
BC
MC
HIPP
(%)
20 (CC)
2.0a
3
20a (CC)
1.0a
3
(%)
(sprouted)
2.0
0.8
16.7
14.1a
0.8
6.7
0.2
1.5
(%)
20
4.8a
0.85
33.3
7.6
0.8
20
1.5
1.5
(%)
40
0.3
3
16.7b
0.3
3
20b
0.5
2
(%)
32
0.5
1.6
66.7
0.5
1.6
26.7
1.5b
1
33.3
0.2
3
CC, convergent connection (each postsynaptic cell receives the same number of
presynaptic afferents); all other connections are divergent (postsynaptic cell can
have different numbers of presynaptic afferents).
a
Values were modified from the original model.
b
Entries differed between Santhakumar et al. (2005) and their ModelDB script.
We used the values and the presynaptic target pool as published in ModelDB.