Neuroscience and Biobehavioral Reviews 60 (2016) 1225

Contents lists available at ScienceDirect

Neuroscience and Biobehavioral Reviews

journal homepage: www.elsevier.com/locate/neubiorev

Cognitive impairment in amyotrophic lateral sclerosis, clues from the

SOD1 mouse
Alida Spalloni, Patrizia Longone
Molecular Neurobiology Unit, Experimental Neurology, Fondazione Santa Lucia, Rome, Italy

a r t i c l e

i n f o

Article history:
Received 23 April 2015
Received in revised form 9 November 2015
Accepted 16 November 2015
Available online 19 November 2015
Keywords:
Amyotrophic lateral sclerosis
Fronto-temporal dementia
Cortex
N-methyl-d-aspartic acid
SOD1

a b s t r a c t
Amyotrophic lateral sclerosis (ALS) is now recognized as a multisystem disorder, in which the primary
pathology is the degeneration of motor neurons, with cognitive and/or behavioral dysfunctions that
constitutes the non-motor manifestations of ALS. The combination of clinical, neuroimaging, and neuropathological data, and detailed genetic studies suggest that ALS and frontotemporal dementia (FTD)
might form part of a disease continuum, with pure ALS and pure FTD at the two extremes.
Mutations in the superoxide dismutase 1 (SOD1) gene were the rst genetic mutations linked to the
insurgence of ALS. Since that discovery numerous animal models carrying SOD1 mutations have been
created. Despite their limitations these animal models, particularly the mice, have broaden our knowledge
on the system alterations occurring in the ALS spectrum of disorders.
The present review aims at providing an overview of the data obtained with the SOD1 animal models
rst and foremost on the cortical and subcortical regions, the cortico-striatal and hippocampal synaptic
plasticity, dendritic branching and glutamate receptors function.
2015 Elsevier Ltd. All rights reserved.

Contents
1.
2.
3.
4.
5.
6.
7.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Genetics of ALS and FTD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Cognitive impairment in the mutantSOD1 mouse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Glutamatergic excitotoxicity and dying forward hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Cortical NMDA receptors in ALS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Cu2+ /Zn2+ dyshomeostasis: effects on toxicity and altered neuronal activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

1. Introduction
The classical neuropathological description of ALS focuses on
the degeneration of both the upper and lower population of motor
neurons (MNs) yielding a disorder largely recognized as selective to
the motor system, however this view is changing (Robberecht and
Philips, 2013). Fronto-temporal dementia (FTD), the most common
form of dementia after Alzheimers disease, is nowadays considered

Corresponding author at: Molecular Neurobiology Unit, Experimental Neurology, Fondazione Santa Lucia, via del Fosso di Fiorano 64, 00179 Rome, Italy.
E-mail address: p.longone@hsantalucia.it (P. Longone).
http://dx.doi.org/10.1016/j.neubiorev.2015.11.006
0149-7634/ 2015 Elsevier Ltd. All rights reserved.

a component of the pathological spectrum of ALS (Wilson et al.,

2001). Cognitive impairment may in fact be evident in up to 60%
of all ALS patients (Witgert et al., 2010). Indeed longstanding clinical evidence and more recent human magnetic resonance imaging
studies have clearly indicated that cortico-spinal motor neurons
(CSMN) in the motor cortex are affected at relatively early stages
of ALS (Graham et al., 2004; Stewart et al., 2006). Typically, ALS
with cognitive impairment presents subtle decits in frontal and
temporal functions (Strong and Yang, 2011). These include mental
exibility, verbal and nonverbal uency, abstract reasoning, and
memory for both verbal and visual materials (Strong et al., 1999;
Raaphorst et al., 2010; Phukan et al., 2012). Individuals with bulbar
onset disease appear to be at greater risk for the development of

A. Spalloni, P. Longone / Neuroscience and Biobehavioral Reviews 60 (2016) 1225

cognitive impairment (Strong et al., 1999). The language characteristics of the ALS-dementia complex include word-nding difculty,
lexical disorganization (as manifested by problems on tests of word
uency), and reliance of stereotypic sentences (McKhann et al.,
2001; Abrahams et al., 2005). Anterior-based language functions
(e.g., uency, syntax, and grammar) are more compromised than
those associated with temporal-parietal lobe regions (e.g., auditory
and reading comprehension and naming) (Neary et al., 2005; Knibb
et al., 2009). Neuropsychological studies associated with imaging
techniques have repeatedly identied defects in executive functions (Frank et al., 1997; Gordon et al., 2010), most likely caused by
a marked frontal lobe atrophy (Kiernan and Hudson, 1994). In particular, executive function decits were represented by decits in
verbal/nonverbal uency, concept formation, working memory and
response inhibition (Schreiber et al., 2005). Interestingly, patients
with unclear speech showed considerable reduction in planning a
movement task suggesting an extended degeneration across wide
areas of the frontal lobe (Santhosh et al., 2004). Thus, cognitive
alterations might reect functional decits outside the primary
motor system and give clues to the aetiopathogenesis of the disease.
This view is supported by several clinical studies. Positron emission tomography (PET) investigations have revealed a signicant
reduction in cerebral glucose metabolism (Ludolph et al., 1992),
particularly in large frontal and parietal regions in the bulbar onset
patients (Cistaro et al., 2012). Kew et al. (1993) showed a decreased
activation of specic areas in the medial prefrontal cortex (Brodmann areas 9 and 10) the anterior cingulate region (Brodmann
areas 9 and 32), the parahippocampal gyrus and the anterior thalamic nuclear complex. Recent resonance magnetic spectroscopy
analyses have also demonstrated that a signicant and bilaterally
asymmetric alteration of metabolites occurs along the length of the
entire intracranial corticospinal tract in ALS patients (Govind et al.,
2012). A neuroimaging study (Bede et al., 2013) performed on a
cohort of 33 cognitively normal patients with ALS and 44 healthy
controls, to investigate focal gray matter loss in the motor cortex,
found a strikingly linear association between gray matter volumes
in the primary motor cortex and well-established clinical measures of ALS. The authors also measured a signicant difference in
the focal gray matter atrophy of the motor homunculus between
patients with bulbar or limb onset. Moreover, they observed that
the ALS pathology goes behind the motor cortex and affects the
frontal, occipital and temporal regions as well. Additionally, consistent evidence obtained with transcranial magnetic stimulation
(TMS) studies, performed on ALS patients, indicate cortical hyperexcitability as an early feature in sporadic and familial ALS. Thus,
while minorities of ALS patients meet criteria for the FTD and/or
primary progressive aphasia (Neary et al., 1990), approximately
one-third show cognitive impairments of a milder nature (Strong
et al., 2009). Indeed, executive dysfunction, a negative prognostic indicator of survival in ALS, has been the most commonly
investigated cognitive domain in non-demented patients with
ALS.
Mouse models of ALS and the studies performed with them have
greatly contributed to expand our knowledge on the disease progression and are a valuable tool to study ALS pathophysiology and
the resulting cognitive decits. In the present review we underline
the experimental evidence obtained with the mutant superoxide
dismutase 1 (mSOD1) mouse on the cortical and subcortical alterations related to the ALS/FTD syndrome. We have focused primarily
on the glutamatergic system, with a section dedicated to the Nmethyl-d-aspartic acid receptor (NMDAR), and to the mechanisms
of altered cortical functions associated with copper (Cu2+ ) and zinc
(Zn2+ ) dyshomeostasis. With the identication of new genes linked
to the ALS/FTD syndrome additional animal models have been
developed that will further expand our knowledge on this spectrum of diseases. The analyses of these models is beyond the scope

13

of this review that is intended to be an appraisal on the evidences

collected with the mSOD1 mice models.

2. Genetics of ALS and FTD

The majority of cases of ALS are sporadic (sALS). While only
a percentage of cases (10%) are considered to be familial (fALS),
the growing number of genes associated with ALS/FTD disorders
is expanding our knowledge on their pathological pathways and
the genotypic and phenotypic overlaps networking these diseases
(Al-Chalabi et al., 2012; Ling et al., 2013; Ng et al., 2014). fALS is
usually inherited in an autosomal dominant manner, though there
exist rare cases of autosomal recessive and X-linked disease. The
ubiquitously expressed enzyme Cu2+ /Zn2+ superoxide dismutase1
(SOD1) was the rst gene to be associated with ALS (Rosen et al.,
1993). SOD1 mutations are common in both fALS and sALS, and
have been studied in the most depth. Over 150 SOD1 mutations
have been linked to fALS, and are typically present in about 20% of
such cases, as well as in up to 7% of sALS cases (Van Es et al., 2010).
In keeping with the cortical involvement, is the now accepted
view that ALS and FTD represent a continuum of the same family
of illnesses, with strong genetic evidences sustaining their clinical
similarities (Guerreiro et al., 2015). In this context, the recent ndings that an increased hexanucleotide repeat expansion in the rst
intron of the C9ORF72 gene on chromosome 9p21 is associated with
both ALS and FTD (DeJesus-Hernandez et al., 2011; Renton et al.,
2011) has further strengthen the notion that ALS is etiologically
associated with cognitive or behavioral impairment and ultimately
with FTD. Indeed, there is now discussion about a possible revision
of the Awaji-El Escorial diagnostic criteria for ALS (de Carvalho and
Wash, 2009) to incorporate cognitive and behavioral tests. Moreover, the denition of fALS should now include the presence of a
family history of other neurodegenerative diseases, including FTD.
Neuropathological investigations have also shown that repeat
expansions in the C9ORF72 gene are characterized by TDP-43
(transactive response DNA-binding protein 43) pathology in various neuroanatomical regions (DeJesus-Hernandez et al., 2011;
Gijselinck et al., 2012). TDP-43, the major disease protein in
ALS with or without dementia (Arai et al., 2006; Mackenzie and
Rademakers, 2008), is a nuclear protein encoded by the TARDBP
gene. It is involved in exon skipping, alternative splicing, mRNA stabilization, and in linking different types of nuclear bodies (Buratti
and Baralle, 2008). Its identication as the pathological signature
protein in FTD with ubiquitin-positive inclusions (FTD-TDP) and in
ALS has further strengthened the notion of a central involvement
in ALS pathophysiology (Geser et al., 2010). Moreover, ndings
of mutations in the TARDBP gene in fALS and rare sALS cases
corroborate the signicance of pathological TDP-43 as being mechanistically implicated in the disease process (Nozaki et al., 2010;
Tamaoka et al., 2010).
Additional ndings at the level of protein recycling and disposal have highlighted the pathological convergence between ALS
and ALS-FTD. For example, ubiquilin 2 (UBQLN2), the optineurin
(OPTN), the SQSTM1/p62, and valosin-containing protein (VCP), all
related to protein degradation pathways, have been linked to both
diseases (Belzil et al., 2011; Fecto and Siddique, 2012; Sieben et al.,
2012). A mutation in the UBQLN2 was reported in a ve-generation
family with ALS that included individuals with and without dementia (Deng et al., 2011). Ubiquilin 2 positive inclusion pathology
was found not only in patients with UBQLN2 mutations, but also
in their sporadic counterparts. Within the hippocampus of sALS
cases with dementia, it was reported that a subset of the inclusion pathology staining for ubiquilin 2, ubiquitin, and p62 was
TDP-43 immunoreactive. VCP is an AAA + protein (ATPase associated with diverse cellular activities) involved in the degradation

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A. Spalloni, P. Longone / Neuroscience and Biobehavioral Reviews 60 (2016) 1225

of abnormal proteins, specically in targeting endoplasmic reticulum proteins for degeneration (endoplasmic reticulum-associated
degeneration) (Weihl et al., 2009). In Johnson et al. (2010) linked a
number of families with typical ALS, to mutations in the VCP gene.
Some individuals in these families had FTD. The vesicle-associated
membrane protein-associated protein B (VAPB), involved in the ERGolgi-mediated vesicle transport (Nishimura et al., 1999), has also
been linked to ALS (Nishimura et al., 2004). Two missense mutations, the proline to serine substitution at residue 56 (P56S) and
the threonine to isoleucine substitution at residue 46 (T46I) in the
VAPB protein have been associated to ALS8, a slowly progressive
and late-onset dominant form of ALS (Marques et al., 2006; Tsuda
et al., 2008; Larroquette et al., 2015). In 2013, Aliaga et al. generated
transgenic mice expressing human wild-type and P56S VAPB under
the control of a pan-neuronal promoter Thy1.2. The mice carrying
the mutation while developing signs of distress in both CSMNs and
spinal MNs (i.e. increase of endoplasmic reticulum stress, unfolded
protein response activation), presented a progressive loss of CSMNs
but not spinal MNs.
Fused-in-sarcoma (FUS) gene mutations have also been
reported in familial and sporadic cases of ALS with FTD (Vance et al.,
2009; Blair et al., 2010; Broustal et al., 2010). FUS is a member of
the hnRNP family, located on chromosome 16p11.2, a chromosomal
region linked to multiple fALS cases (Sapp et al., 2003). Although
FUS represents an ALS gene, an accumulation of FUS protein in
inclusion bodies in neuronal cytoplasm and nucleus was associated
with clinicopathological subtypes of FTD (Mackenzie et al., 2010).
Mutations in other genes involved in the pathogenesis of ALS
also include senataxin (SETX) (Chen et al., 2004), angiogenin (ANG)
(Greenway et al., 2006), and Ataxin-2 (Elden et al., 2010; Van
Damme et al., 2011).

3. Cognitive impairment in the mutantSOD1 mouse

The clinical features of ALS usually include a combination of
upper and lower MN dysfunction. Since the identication of SOD1
as a gene associated with ALS and responsible for one form of fALS,
transgenic mice over-expressing missense mutations in the human
SOD1 gene have been created (Shibata, 2001). Only 20% of the fALS
cases are attributed to SOD1 mutations and although treatment
that benet the mSOD1 have been mostly unsuccessful when tested
in humans (Rothstein, 2009), these animal models have been vital
in identifying several ALS-related pathogenic mechanisms. More
than 10 different mSOD1 murine models have been created (Bruijn
et al., 1997; Jonsson et al., 2006; Nicholson et al., 2000). Within
them the transgenic line harboring the Gly93Ala amino acid substitution (SOD1G93A) has been used most extensively to study
the ALS pathophysiology (Gurney et al., 1994), followed by the
SOD1G37R, SOD1G85R and SOD1G86R models. These transgenes
develop -motoneuron degeneration, alterations in cytoskeletal
components, and reactive astrocytosis, resulting in paresis and
early death (Morrison and Morrison, 1999).
Patients with SOD1 mutations are less likely to have signicant
cognitive alterations (Wicks et al., 2009) compared to non-SOD1
fALS patients, although case reports of families developing ALS and
FTD linked to SOD1 mutations have been reported (Katz et al., 2012;
Nakamura et al., 2015) revealing that, even SOD1, although rarely,
can cause FTD. Similarly the most relevant neuropathological traits
of the mSOD1 mice seem to be restricted to the spinal and bulbar
MN areas, with the cortical areas less affected (Ralph et al., 2005;
Niessen et al., 2006). Nevertheless, the mSOD1 mice, particularly
the SOD1G93A, have provided valuable insights into the degenerative processes happening in the cortical and subcortical brain areas
throughout the course of the disease. Indeed, a progressive decline
in the corticospinal and bulbospinal (including reticulo-, rubro- and

vestibulo-spinal) projections has been described in these mice prior

to the onset of clinical signs (Zang and Cheema, 2002; Leichsenring
et al., 2006; Spalloni et al., 2006). Filali et al. (2011) have described
in transgenic mice carrying the G37R mutation of human SOD1,
early signs of dysfunction in terms of movement and strength,
raised somatosensory thresholds, but also decits in the passive
avoidance learning. The decits in passive avoidance learning are
generally linked to brain dysfunction affecting the prefrontal cortex, known to cause perseverative responding and impaired in the
FTD/ALS syndrome. In this context, ALS patients have a lower glucose uptake in the prefrontal cortex (Ludolph et al., 1992) and
exhibit anomalies in neuropsychological decits in tests sensitive
to defects in this region (Strong et al., 1999; Abrahams et al., 2000).
In 2011, Ozdinler et al. used a combination of techniques and neuronal subtype-specic molecular analyses to demonstrate an early
and neuron specic CSMN degeneration in the SOD1G93A mice that
mirrors the cortical pathology found in human ALS. Moreover, the
neuron type-specic degeneration, occurring via apoptosis, begins
exceptionally early, in the presymptomatic stage (around post natal
day 30), coincident with the earliest degeneration of spinal MNs
(Gurney et al., 1994; Hall et al., 1998; Cleveland and Rothstein,
2001; Bruijn et al., 2004; Wengenack et al., 2004; Hegedus et al.,
2007). More recently, the same group (Yasvoina et al., 2013)
did genetically labeled CSMN and a subset of spinal motor neurons by crossbreeding an ubiquitin carboxy-terminal hydrolase
L1 (UCHL1)-eGFP mouse with the SOD1G93A mouse. Using this
double transgene they conrmed ALS-like phenotypes previously
reported (Gurney et al., 1994; Ozdinler et al., 2011), vacuolated
CSMN apical dendrites (Jara et al., 2012), and the contribution of
autophagy in CSMN degeneration in ALS (Li et al., 2008; Otomo
et al., 2012; Xie et al., 2015). They also observed the accumulation
of autophagosomes within the CSMN apical dendrites, suggesting
that, also for CSMN, autophagy is an intrinsic pathological mechanism certainly for the apical dendrite degeneration (Yasvoina
et al., 2013). Pre-symptomatic and symptomatic SOD1G93A mouse
shows an evident astrogliosis in both the brain and spinal cord,
and by end-stage when MNs are lost (Dal Canto and Gurney, 1994;
Gurney et al., 1994), the number of activated astrocytes are significantly increased in the spinal cord, the motor trigeminal nucleus
of the brainstem, and the primary motor cortex (Yang et al., 2011).
These alterations are clearly indicative of an astrogliosis, a characteristic hallmark of ALS, occurring together with the neuronal
degeneration, not just in the spinal cord but in the motor cortex as
well. Kassa et al. (2009), presented evidence of an up regulation of
mRNAs encoding for proinammatory mediators in the deep layers of the sensorimotor cortex, of corticospinal neuron damage,
and activation of surrounding glia in the SOD1G93A mice. They
investigated proinammatory mediators that are key molecules in
neurodegenerative conditions. In particular, they found a marked
and progressive increase in IL-1 and IL-1, as well as iNOS and NFB transcripts in the cortical area of SOD1G93A mice, comparable
to the values in the spinal cord. These ndings, suggest that similar pathogenic mechanisms may operate in the cortex and in the
spinal cord of the fALS mice. Moreover, an early subtle change in the
walking gait of SOD1G93A mice (8-weeks old) has been detected in
a treadmill assay and according to the authors even gait abnormalities could be observed prior to 8 weeks of age (Wooley et al., 2005).
A delay in the maturation of the descending pathways controlling
the spinal networks may explain the early motor decits observed
in the mutant mice. This could have important consequences for the
development of MNs. We have demonstrated (Ferrucci et al., 2010)
that in the SOD1G93A mouse all branchial motor nuclei (motor,
trigeminal, facial, ambiguous) and the hypoglossal nucleus were
signicantly degenerated, while the oculomotor nuclei (III, IV, and
VI) were spared. For instance, Lever et al. (2009, 2010) have shown a
correlation between neurodegeneration of the trigeminal and

A. Spalloni, P. Longone / Neuroscience and Biobehavioral Reviews 60 (2016) 1225

hypoglossal nuclei and the development of dysphagia and oral dysfunction in the SOD1G93A mouse. They found that oral dysfunction
(i.e. lick and mastication rates) could be detected as early as 60 days
of age. They infer that oral dysphagia could be one of the earliest
clinical symptoms in this fALS mouse model, as it is in about 30% of
patients (bulbar onset) (Khnlein et al., 2008).
Similarly to the neurodegenerative traits, cognitive changes
occur in the mSOD1 mice before clinical symptoms become evident.
These changes are associated with anatomically specic neural
modications in brain regions beyond the classical motor areas.
Indeed, ALS is not anymore regarded as a neurodegenerative disorder primarily involving the pyramidal motor system and the
spinal cord MNs, but there are growing indications that degenerative changes can occur in nonmotor neocortical areas (Toyoshima
et al., 2003), or areas such as the substantia nigra and the basal
ganglia generally neglected in ALS (Borasio et al., 1998; Sudo et al.,
2002; Mackenzie and Feldman, 2004; Sharma et al., 2011). Interestingly, Przedborski and co-workers described a degeneration of
the dopaminergic system in the early years of the SOD1G93A studies (Kostic et al., 1997). In Geracitano et al. (2003) the authors
described for the rst time functional striatal alterations specically associated with a dopaminergic dysfunction. The study shows
that repetitive stimulation of the corticostriatal pathway generates
an N-methyl-d-aspartic acid (NMDAR) receptor-dependent longterm potentiation (LTP) in the SOD1G93A mouse, while the same
stimulation generates a long-term depression (LTD) response in
the control mice. The LTD in the fALS mouse was restored by bath
perfusion of dopamine or quinpirole, a dopamine D(2) receptor
agonist. Consistent with these observations, habituation of locomotor activity and striatal-dependent active avoidance learning were
impaired. These data support the observation that a degeneration of
the dopaminergic neurons occurs in the SOD1G93A mouse affecting the striatal-related synaptic plasticity and behavior, and give a
cellular substrate to the extrapyramidal motor and cognitive disorders observed in familial and sporadic ALS. We went on to explore
a cognitive behavioral phenotype of the fALS models in view of the
frontal lobe dysfunction described in patients. Thus we extended
the description of the cognitive characteristics of this mutant
by investigating various indexes of their hippocampal and prefrontal cortex functions. In the hippocampus, of pre-symptomatic
SOD1G93A mice we observed, an enhanced reactivity to spatial
novelty associated with a higher expression of the hippocampal
-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)
GluR1 subunit (mRNA and protein), and with an increased induction and maintenance of CA3-CA1 LTP (Spalloni et al., 2006). These
ndings are further supported by molecular evidence showing
increased levels of phosphorylated Erk, an extracellular signalregulated kinase involved in neural plasticity and memory in
symptomatic SOD1G93A mice (Chung et al., 2005). In a paper just
published Quarta et al. (2015) described hippocampal alterations
in the SOD1G93A mouse, prior to the onset of motor symptoms,
affecting GABAergic interneurons (parvalbumine-positive). They
linked these damages to the GABAergic system to an increased
anxiety-like behavior in the open-eld test and a delay in learning and impaired long-term memory in the Barnes maze test.
The loss of parvalbumin-positive inhibitory interneurons has been
also described in the motor cortex of ALS patients and linked to
the development of cortical hyperexcitability (Nihei et al., 1993).
Hyperexcitability, probably arising from a combination of glutamate excitotoxicity processes and degeneration of inhibitory
cortical neurons circuitry has also been associated to a characteristic feature of ALS, the split-hand phenomenon (Menon et al.,
2014)
In the prefrontal cortex we described a dramatic reduction
of the dendritic arbor accompanied by a mild decrease in spine
density of basal dendrites on pyramidal neurons lying in the

15

prelimbic/infralimbic regions, while apical dendrites were not

affected (Sgobio et al., 2008). Since basal dendrites receive the
majority of synapses innervating neocortical pyramidal neurons
(Gordon et al., 2006), the pattern of the medialPreFrontalCortex
(mPFC) dendritic reorganization appears to be consistent with
a robust decrease in neuronal connectivity adversely affecting
intracortical excitatory inputs. In line with the cortical alterations the fALS model shows defective fear extinction consistent
with a mutation-related executive function decit reminiscent
of the human ALS prefrontal syndrome (Sgobio et al., 2008).
Thus, the mutant human SOD1overexpression decreases the
mPFC networks connectivity and alters mPFC-related cognitive
operations in presymptomatic fALS mice compared with the agematched control mice. We hypothesize that the early unbalance
between excitatory and inhibitory synaptic inputs observed in the
SOD1G93A MN (Schtz, 2005), could be the consequence of abnormal neural networks properties as our data suggest as well as
the work of others (Durand et al., 2006). Indeed, Foerster et al.
(2013) observed reduced levels of GABA in the motor cortex of
patients with ALS pointing to an imbalance between excitatory
and inhibitory neurotransmitters as an important factor in the
pathogenesis of ALS. This hypothesis has been proposed as an etiological feature that could explain cortical hyperexcitability and
provide support for the dying-forward hypothesis in ALS (see
chapter below) (Vucic et al., 2009a). Interestingly, cortical and
hippocampal hyperexcitability, linked to a GABAergic inhibition
(Nieto-Gonzales et al., 2011; Thielsen et al., 2013), have been
described in the wobbler mouse, a spontaneous mutation leading to spinal cord degeneration and considered a model of ALS
(Moser et al., 2013).

4. Glutamatergic excitotoxicity and dying forward

hypothesis
A central issue in the ALS pathophysiology still remains unresolved: the triggering site. ALS is a disease that causes the
progressive loss of the upper and lower MNs followed by axonal
degeneration and muscle atrophy, resulting in the death of spinal
and cortical MNs (Strong and Rosenfeld, 2003). This is central in the
ongoing debates among neurologists, which MN subtype (cortical
or spinal) is affected rst (Chou and Norris, 1993; Eisen et al., 1996;
Eisen, 2009; Van der Graaff et al., 2009). This review is centered
on the cognitive alterations observed in ALS. In this context we
focus on the degenerative processes occurring in the cortical areas
described as one of the focal sites from where ALS could begin. We
do not favor one hypothesis over the other. Rather, we believe ALS
to be a complex pathology affecting central and peripheral nervous system areas with different degrees of penetration. Upper
and lower MNs could very well degenerate independently of each
other (Terao et al., 1999; Attarian et al., 2008; Agosta et al., 2009),
although the reports that have especially looked at the cortical area,
the minority in the ALS eld, suggest the they have an unquestionable role in the disease path (Fig. 1). In 2006, Browne et al. reported
that in the SOD1G93A mouse model the degeneration of spinal
cord MNs is secondary to the appearance of bioenergetics abnormalities (glucose utilization and cortical ATP depletion) within the
CNS motor pathways (the primary motor cortex, corticospinal tract
and bulbospinal pathways). The elegant work of Thomsen et al.
(2014) further uncovers the critical role played by the cortical
MNs in the development of ALS. Following the silencing of mutant
SOD1G93A, selectively in the motor cortex, these authors observed
an expansion of lifespan and a signicant delay of disease onset,
along with enhanced survival of MNs, and maintenance of neuromuscular junctions (NMJs) in SOD1G93A rats. Moreover ALS shows
a great variability in its morphological traits raising the question

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A. Spalloni, P. Longone / Neuroscience and Biobehavioral Reviews 60 (2016) 1225

Fig. 1. Schematic and simplied representation of the alterations, linked to hyperexcitability and the glutamatergic system, affecting the motor cortex and the spinal cord
in ALS. Motor cortex: At early (2130 days) and later at pre-symptomatic stages (8085 days) the M1 region of the fALS mouse cerebral cortex show an increased vGlut2
expression in the area surrounding the layer V CMN, and a decreased expression of the NMDA receptor subunit GluN2B in the synaptic compartment, respectively. The rst
observation reveals how, already at early stages, the glutamatergic releasing machinery is over-functioning leading to an increased release of glutamate that, associated
with the decrease/malfunction of the glial glutamate transporter EAAT2/GLT1, affects cortical glutamatergic homeostasis. The latter indicate that not only the releasing
machinery but the glutamatergic receptor system (specically the NMDA receptor) is altered leading to a malfunctioning glutamatergic excitatory system. These alterations
together with a decrease of the inhibitory drive lead to a widespread cortical hyperexcitability affecting not just the cortical areas but the descending motor pathways up
until the spinal cord. Spinal cord: Spinal cord hyperexcitability is a well-established characteristic of mutant-SOD1 MNs in cultures and slice preparations. They indicate that
electrophysiological abnormalities in MNs are a very early event in ALS, probably determined by disturbances of the voltage-gated Na+ channels expression and activity
causing an increment in the persistent Na+ currents. This sodium current increased activity may thus lead to excessive inuxes of sodium and calcium ions in the MNs, cells
known to have a limited cytosolic calcium-buffering capacity. The increased cytosolic calcium could lead to an excessive uptake of calcium by mitochondria setting off of
a series of events that ultimately might favor MN degeneration and death. A reduction in the slow K+ channels currents has also been considered as a contributor to the
hyperexcitable MN. Additionally, glutamatergic excitotoxicity promotes MN hyperactivity, intracellular Ca2+ increase, nurturing in the end MN death. The gure summarizes
the ndings presented within this review paper and is not intended to be comprehensive. In the gure is also represented the functional cross-talk between the lower and
upper MNs through the descending and ascending motor pathways.

of a relationship between ALS and extrapyramidal disorders such

as Parkinsons disease. There are now considerable data supporting the concept of a widespread extra-motor involvement in ALS
(Elamin. et al., 2011). The SOD1G93A mouse, for example, shows
evidence of a concurrent reduction of midbrain dopaminergic neurons in the substantia nigra (26%) and in the ventral tegmental area
(16%), when up to 50% of MNs of the spinal cord are lost (Kostic
et al., 1997).
Thus, despite the considerable progress in disclosing the multiple molecular processes involved in the ALS pathology, relatively
little is known about when and how the disease spreads throughout
the motor network (Armon, 2008). In this context cortical hyperexcitability seems to be a phenomenon specic to ALS rather than
a general feature of degenerative MN disorders (Vucic, 2009a).
Numerous TMS studies have demonstrated that it is an early feature in sALS and fALS (Eisen et al., 1993; Desiato et al., 2002; Vucic
and Kiernan, 2009b) and, in asymptomatic SOD1 mutation carriers,
develops prior to the clinical onset of the disease (Zanette et al.,
2002; Vucic et al., 2008). The relationship between cortical hyperexcitability and ALS is also reected by the use of riluzole, the main
approved treatment for ALS (Bensimon et al., 1994). Riluzole has a
therapeutic that still remains elusive, but a variety of effects, mainly
on features like glutamatergic synaptic transmission (Centonze

et al., 1998; Zona et al., 1998; Prakriya and Mennerick, 2000; He

et al., 2002), inhibition of persistent Na+ current and reduction
of action potential ring (Urbani and Belluzzi, 2000; Kuo et al.,
2006; Van Zundert et al., 2008), all affecting neuronal excitability
(Bellingham, 2011), are its pharmacological traits. These observations thus strengthen the belief that cortical hyperexciatability
contributes to the ALS pathophysiology and most likely plays an
important role in the appearance of the cognitive impairments
described in the ALS/FTD syndrome. SOD1G93A hyperexcitability
has also been reported in cultured cortical neurons (Pieri et al.,
2009) and cortical slices (Carunchio et al., 2010), and in spinal
(Kuo et al., 2005; Tamura et al., 2006) and brainstem MNs (Van
Zundert et al., 2008). Using motor unit number estimation (MUNE)
and motor evoked potentials (MEP), to evaluate motor central
pathways, Mancuso et al. (2011) demonstrated, in the SOD1G93A
mouse, that dysfunctions of central motor pathways coexists with
peripheral motor decits. Their study showed that a decit in motor
nerve conduction begins at about 8 weeks of age and that, in parallel, a dysfunction in central motor conduction starts around the
same time. Hence, their ndings, of a concomitant dysfunction of
upper and lower MN, further contributes to the validation of the
SOD1G93A mouse as a useful model of ALS to study pathological
alterations in both cortical and spinal MNs.

A. Spalloni, P. Longone / Neuroscience and Biobehavioral Reviews 60 (2016) 1225

Thus in our work we have found an increased expression of the

beta3 subunit of the voltage-gated Na+ channel in the spinal cord of
the pre-symptomatic SOD1G93A mouse (Nutini et al., 2011a). The
beta 3 subunit has been the most consistently related to persistent
sodium currents, which play an important role in the control of
neuronal excitability near ring threshold (Nutini et al., 2011a and
references therein). Likewise, the pathogenic expansions of a noncoding hexanucleotide repeat sequence (GGGGCC) in the C9ORF72
gene, recently linked to familial and sporadic forms of ALS (Vance
et al., 2006; DeJesus-Hernandez et al., 2011; Renton et al., 2011;
Majounie et al., 2012), characterized by an earlier age of onset,
shorter survival and greater incidence of dementia and psychosis
(Byrne et al., 2012), show features of cortical hyperexcitability
(Williams et al., 2013). The authors uncovered a signicant reduction in short interval intracortical inhibition and cortical silent
period duration along with an increase in intracortical facilitation and motor evoked potential amplitude in the C9ORF72-linked
familial ALS, indicative of an increased cortical excitability. They
suggest that glutamate excitotoxicity could contribute to the pathophysiological process that they observed. Two recent studies by
Vucic et al. (Geevasinga et al., 2015a,b) have further established that
ion channel dysfunction and cortical hyperexcitability are associated with upper and lower MNs degeneration. In the rst study
(Geevasinga et al., 2015a) they looked at abnormalities in the axonal
excitability mostly linked to the development of features like fasciculation and neurodegeneration. They found in patients with
c9orf72 fALS and in sALS patients signicant changes in axonal
excitability, compared to asymptomatic C9 carriers and healthy
controls. They linked these alterations to a reduction of slow nodal
K+ currents and an upregulation of persistent Na+ conductances. In
the second work (Geevasinga et al., 2015b) they looked at cortical
hyperexcitability in a cohort of sALS and C9 fALS patients compared
to C9 asymptomatic carriers and healthy controls. They reasoned
that both the cortical inhibitory -aminobutyric acid pathway as
well as the glutamate-mediated function could trigger the hyperexcitability that they observed. Once more they conrmed cortical
hyperexcitability as an intrinsic feature of the C9 carries and sALS
patients. Hence, this further underscores its importance in ALS, as
a process that, as they discuss it, mediates neuronal degeneration
via a transsynaptic glutamate process (Geevasinga et al., 2015b).
Thus, two forms of familial ALS, with unrelated genetic basis and
different phenotypes, retain a similar feature, cortical hyperexcitability, associated to glutamatergic excitotoxicity. Consistent with
the above-mentioned studies is the work by Wainger et al. (2014)
that found hyperexcitability in MNs derived from iPSCs of a wideranging group of familial ALS patients, spanning the majority of
familial ALS cases. Interestingly they also propose voltage-activated
potassium channels to be counted as players in the ALS-related MN
death.
Despite the fact that the underlying mechanisms leading
to the cortical hyperexcitability are still unclear, the interplay
between excitatory CSMNs and inhibitory interneurons appears
also strongly associated as described in the previous chapter.
Hyperexcitability shows a pattern of spatiotemporal progression
and may serve as a trigger to induce anterior horn cell degeneration
transsynaptically through a dying forward process (dying forward
hypothesis) (Vucic et al., 2013; Bae et al., 2013) via an anterograde excitotoxic process. The dying forward hypothesis envisions
an active process in which the CSMN impacts negatively on the
anterior horn cell, with a hyperexcitable corticomotoneuron driving the anterior horn cell into a metabolic decit. Some of this
hyperexcitability is probably glutamate-induced (Shaw and Ince,
1997), very likely a secondary event in ALS, but probably a prerequisite for anterograde degeneration (Urushitani et al., 1998). Thus,
it could be hypothesized that hyperexcitability of the descending
motor pathways may contribute to the generation of fasciculation

17

in ALS, an important diagnostic criterion (de Carvalho et al., 2008),

and it may precede the onset of lower MN dysfunction (de Carvalho,
2000; Kleine et al., 2008). Hirota et al. (2000) found abnormal
evoked excitatory postsynaptic potential in ALS patients associated to fasciculations that may arise supraspinally to the anterior
horn cells. Moreover, molecular approaches have provided further
corroborating evidence supporting the contribution of glutamate
excitotoxicity to the ALS-related neurodegeneration. Specically, a
signicant reduction in the expression and function of the astrocytic glutamate transporter, the excitatory amino acid transporter
2 (EAAT2/GLT1), has been reported in the SOD1 mouse models
and in the motor cortex and spinal cord of ALS patients (Rothstein
et al., 1995; Trotti et al., 1999; Boille et al., 2006). In addition,
dysfunction of the EAAT2 transporter appears to be a preclinical
feature in the SOD1G93A mouse model (Gibb et al., 2007). Further
underscoring the importance of astrocytes in ALS pathophysiology
are studies documenting that MN degeneration seems to be initiated by dysfunction of astrocytes (Haidet-Phillips et al., 2011). Of
further relevance is the increased expression of the vesicular glutamate transporter VGluT2 in the synaptic terminals surrounding the
layer V corticomotoneuron of one month old SOD1G93A mice (Saba
et al., 2015). As discussed by the authors, it may favor an increased
glutamate release that, associated with the decreased EAAT2/GLT1
expression, disrupts glutamate homeostasis leading to morphological (spines) and functional (hyperexcitability) alterations ending to
an inevitable cell death.
For the glutamate hypothesis to be a plausible mechanism of MN
degeneration, the issue of the selectivity of the MN involvement
in ALS, together with the sparing of MNs in non-ALS conditions
exhibiting cortical hyperexcitability, must be explained. Along with
their major energy needs, due to the extraordinary size of their
axonal tree and relatively fast ring rate during muscle activation, a
number of molecular features may render the MNs more vulnerable
to glutamate toxicity in ALS. First, MNs preferentially express the
ionotropic glutamate receptors AMPA, NMDA and kainate. AMPA
receptor subunit alteration has been largely demonstrated in ALS
rodent models (Spalloni et al., 2004; Zhao et al., 2008; Kwak et al.,
2010) leading to abnormal Ca2+ inux and neurodegeneration (Van
Den Bosch et al., 2006). In addition, MNs in ALS patients lack the
intracellular expression of Ca2+ binding proteins, parvalbumin and
calbindin D28k, both required to buffer intracellular Ca2+ (Ince
et al., 1993). Abnormal inux of Ca2+ ions through the ionotropic
glutamate receptors NMDA in the MNs, results in an increased
intracellular Ca2+ concentration and activation of Ca2 + -dependent
enzymatic pathways that mediate neuronal death (Sanelli et al.,
2007; Spalloni et al., 2013). Glutamate excitotoxicity may also
result in the production of free radicals that can further damage intracellular organelles and thereby cause cell death. Finally,
mitochondrial dysfunction may in turn enhance glutamate excitotoxicity by disrupting the normal resting membrane potential
(Pambo-Pambo et al., 2009), resulting in the loss of the voltage dependent Mg2+ -mediated block of NMDAR receptors (Kanki
et al., 2004). Hence, glutamate receptor activation leading to Ca2+
increase and free radicals production associated with alterations in
mitochondrial homeostasis could be a co-contributing factor in the
MN demise in ALS.

5. Cortical NMDA receptors in ALS

The NMDARs are centrally involved in cognitive processes and
are becoming a prime target for cognitive enhancement therapies
(Collingridge et al., 2013). Their transient activation is important for
the induction of long-term potentiation (LTP) (Collingridge et al.,
1983) and activity-dependent synapse modications (Furukawa
et al., 2005). Although not all forms of LTP are triggered by NMDARs

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A. Spalloni, P. Longone / Neuroscience and Biobehavioral Reviews 60 (2016) 1225

activation (Volianskis et al., 2015). Moreover, they have a high Ca2+

permeability and slow activation/deactivation kinetics, thereby
playing an important role in excitotoxicity (Cull-Candy et al., 2001;
Spalloni et al., 2013).
In ALS, although less analyzed than the AMPARs, NMDARs
contribute to the excitotoxic-mediated MN death. Sera from sporadic ALS patients are able to induce transient oscillatory currents
in oocytes expressing NMDARs with a signicantly higher total
electrical charge than that induced by sera from healthy subjects or patients with other neuromuscular diseases (Texid et al.,
2011). These currents were inhibited by MK-801, a noncompetitive
blocker of NMDARs (Texid et al., 2011). Esquerda and co-workers
(Tarabal et al., 2005) have established how, after chronic treatment
with NMDA, chick embryo MNs fail to respond to a subsequent excitotoxic stimulus. They show prominent cytoplasmic alterations,
following the NMDA-mediated insult, probably affecting, as a main
target of this toxicity, the endoplasmic reticulum. Thus in the
ALS/FTD pathology, the NMDAR involvement could be associated
with the excitotoxic-mediated death, having a more subtle role
linked to its undertaking in synaptic communication/plasticity.
NMDARs are composed of the structural GluN1 subunit and 4
isoforms of the GluN2 subunits (GluN2A-D). In the adult rat brain,
GluN2A is widespread, GluN2B is mainly detected in forebrain,
GluN2C is concentrated in the cerebellum and GluN2D is primarily
found in midbrain structures and brainstem (Laurie et al., 1997).
There is evidence that the forebrain and cortical GluN2A/GluN2B
ratio is developmentally regulated, with GluN2A partly replacing
GluN2B during ontogenesis (Flint et al., 1997; Mierau et al., 2004).
In adult rat brains, GluN2A and GluN2B control different aspects of
cortical synaptic plasticity. It is well accepted that LTP and LTD, as
regarded by their threshold of induction and saturation, are inuenced by the GluN2A/GluN2B expression and ratio, with a stronger
contribution of GluN2B to LTD induction, as opposed to GluN2A,
which is more involved in LTP (Massey et al., 2004; Miwa et al.,
2008; Yashiro and Philpot, 2008; Brigman et al., 2010) although the
actual role of each subunit in mediating the two forms of synaptic plasticity is still controversial (Barria and Malinow, 2005; de
Marchena et al., 2008).
NMDAR composition also plays a crucial role in neuronal
structural development. For example, the prominent role of the
GluN2A subunit in branch clustering has been also conrmed
by experiments in which both exogenous subunit expression
and endogenous subunit knockdown were used to shift synaptic NMDARs composition (Ewald et al., 2008). In particular, these
authors showed that the knocking down of any one of the subunits
produce a retraction of dendritic arbor development, whereas the
selective knocking down of GluN2A specically disrupted branch
clustering. These observations therefore support the view that the
signal through GluN2A is crucial for the formation of higher dendrite branch orders. Gambrill and Barria (2011) found that the
ratio of synaptic GluN2B over GluN2A controls spine motility and
synaptogenesis. They propose that the intracellular C terminus
of the GluN2 subunits retains a structural role in recruiting the
signaling and scaffolding molecules needed for synapses formation and stabilization. In agreement with this, we (Spalloni et al.,
2011) have observed a strong reduction of dendritic branching in
SOD1G93A motor cortex neurons in which postsynaptic expression
of GluN2A and alphaCaMKII autophosphorylation at threonine286 is decreased. These abnormalities occur prior to the onset
of motor symptoms and are accompanied by robust alterations
in upper MNs synaptic plasticity and morphology. Similarly, in a
previous work we have observed (Sgobio et al., 2008) in the prelimbic/infralimbic medial prefrontal corteces, a decreased dendrites
ramication. The reduction in cortical MN ramications reveals a
progressive loss of cortico-cortical and local connections, which in
turn might affect other cortical regions more directly involved in

cognitive tasks and could contribute to the occurrence of cognitive impairment/dementia in ALS. NMDAR subunit expression is
downregulated in response to its excessive activation in in vitro
and in vivo models of excitotoxicity (Gascn et al., 2005). Thus,
we may infer that the enhancement of extracellular glutamate levels present in presymptomatic SOD1G93A mice (Guo et al., 2000)
could modify the pattern of glutamate receptors subunit expression at upper MNs synapses affecting, in turn, the synaptic plasticity
and neuronal morphology of the motor cortex. In this context two
recent studies (Saba et al., 2015; Fogarty et al., 2015) illustrate how,
as early as postnatal day 21, morphological and electrophysiological changes occur in the cortical area of the SOD1G93A strongly
supporting an early onset of motor cortical dysfunction in this fALS
SOD1 mouse model.

6. Cu2+ /Zn2+ dyshomeostasis: effects on toxicity and altered

neuronal activity
A key characteristic of the SOD1 protein, frequently overlooked
in ALS, is the binding of the two metal cofactors, copper (Cu2+ ) and
zinc (Zn2+ ), which are critical for its proper functioning (Rhoads
et al., 2011).
Cu2+ and Zn2+ play a catalytic and structural role in many
enzymes and regulatory proteins, including various effectors of
synaptic plasticity. Cu2+ electron structure allows its direct interaction with spin-restricted molecular oxygen, thus enabling it to
participate as a protein cofactor in fundamental redox reactions.
Cu2+ action is recognized as an important mechanism to prevent
oxidative damage. However under pro-oxidant conditions, Cu2+
ions may be released from proteins and become redox-active.
Zn2+ has been implicated in the regulation of many channels and
receptors (Frederickson et al., 2005). The cation can also trigger neuronal loss in several neurological conditions promoting
oxidative stress as well as mitochondrial dysfunction (Sensi et al.,
2011 and references therein). Redox changes (i.e. alterations in the
oxidation-reduction status) affect NMDAR synaptic responses and
NMDAR-dependent LTP and cognition (Bodhinathan et al., 2010;
Robillard et al., 2011; Ghosh et al., 2012; Haxaire et al., 2012; Lee
et al., 2012).
SOD1 is a cytosolic enzyme that functions as an antioxidant
and plays an essential role in normal metal homeostasis. For its
activity and proper protein structure the metals Cu2+ and Zn2+
are integral. The redox-active Cu2+ is crucial for protein activity,
while the structural Zn2+ , closely coordinated to the Cu2+ , is essential for the proper folding of the protein (Kayatekin et al., 2008).
Of the more than 170 mutations identied within SOD1 linked to
ALS (http://alsod.iop.kcl.ac.uk/) (Andersen and Al-Chalabi, 2011),
except for the ones that directly interfere with metal coordination, many of them have no effect on SOD1 dismutase activity
(Potter and Valentine, 2003). However, alterations in the protein
ion afnity have been described and metal dyshomeostasis is a
common pathogenic feature of different SOD1 mutants (Tokuda
et al., 2013). Cu2+ ions are signicantly elevated in the spinal cords
of mutant SOD1 mice, regardless of the copper-binding abilities
(Tokuda et al., 2007, 2009, 2013) and accumulate in the ventral
horn of SOD1G93A mice (Lelie et al., 2011). In the aforementioned
study Whitelegge and co-workers (Lelie et al., 2011) observed a
major shift in Cu2+ levels in tissues from mSOD1 spinal cord (G93A
and G37R) and wild-type SOD1 spinal cords. Thus linking this effect
to the SOD1 overexpression and not merely to the disease associated mutations. Nevertheless, their ndings, together with the
work by Tokuda et al. (2007, 2009, 2013), support the notion that
regulated Cu2+ homeostasis has an essential role in maintaining MN
function and viability. In the same study the authors found a significant net increase in Zn2+ associated with the white matter for the

A. Spalloni, P. Longone / Neuroscience and Biobehavioral Reviews 60 (2016) 1225

mutants SOD1H46R/SOD1H48Q, SOD1G37R, and SOD1G93A mice,

consistent with studies that have shown disturbances of free Zn2+
homeostasis in transgenic mouse spinal cords (Smith and Lee, 2007;
Bertoni-Freddari et al., 2008). Koh and co-workers (Kim et al., 2009)
observed that the accumulation of free Zn2+ occurred in the cells
(MNs and astrocytes) exhibiting increased levels of SOD1 in mutant
SOD1G93A mice. They also described fewer Zn2+ -accumulating
cells and more surviving motorneurons in the spinal cord of the
mutant mice treated with the cell-permeant Zn2+ chelator TPEN
and difference in survival time between treated and untreated
mSOD1 ranging from 5 to 10 days. They also observed signicantly
reduced levels of labile Zn2+ (20%) in the hippocampal mossy ber.
High levels of endogenous Zn2+ may act as a potential neurotoxin
(Choi et al., 1988) triggering oxidative stress which in turn may
release Zn2+ from Zn2+ -binding proteins such as metallothioneins (Hidalgo et al., 2001; Lee et al., 2003), and play a crucial role
in causing neuronal death (Sillevis Smitt et al., 1994; Gong and
Elliott, 2000). Crow et al. (1997) have reported that SOD1 binding afnity to Zn2+ is signicantly decreased in the mutant protein.
In 1999, Beckman and coworkers (Estvez et al., 1999) reported
that the loss of Zn2+ from the wild-type and mSOD1 protein was
sufcient to induce apoptotic cell death in cultured motorneurons. These data led them to conclude that Zn2+ -decient SOD1
is implicated in both sALS and fALS via a NO-dependent oxidative
mechanism of the receptor. Thus mSOD1 can lead to redox changes
and disruption of the normal metal homeostasis, ongoing events
that may facilitate aberrant interactions of SOD1 with itself or
with other cellular constituents and may thereby contribute to the
progression of the neurodegenerative process (Rakhit et al., 2002;
Tiwari et al., 2009).
As we have mentioned earlier Zn2+ and Cu2+ can affect neuronal
excitability and synaptic transmission (Horning and Trombley,
2001; Sensi et al., 2011; Gaier et al., 2013). Cu2+ ions are indispensable for normal brain development and function and modulate a
variety of ion channels, including AMPAR (Weiser and Wienrich,
1996), and are emerging as important modulators of the NMDAR
(Stys et al., 2012). Following neuronal depolarization, Cu2+ is
released at the glutamatergic synapses from synaptic vesicles in
cortical and hippocampal neurons (Kardos et al., 1989; Schlief and
Gitlin, 2006). Cu2+ is able, at low micromolar level, to bind and
modulate the function of the NMDAR. Acting as a high-afnity
NMDAR blocker, in a voltage-dependent manner, Cu2+ alters cortical glutamatergic transmission at the synaptic level (Tamano and
Takeda, 2011). In cultured hippocampal neurons Cu2+ is released in
an NMDAR-dependent manner (Schlief et al., 2005; Dodani et al.,
2011). Stimulation of NMDAR results in the trafcking of the Cu2+ transporting P-type ATPase out of the late Golgi into dendrites
resulting in the rapid release of Cu2+ from hippocampal neurons,
linking Cu2+ homeostasis and neuronal activation within the CNS
(Schlief et al., 2005; Dodani et al., 2011). Since NMDAR activity
is crucial for different forms of synaptic plasticity (Malenka and
Bear, 2004; Yashiro and Philpot, 2008), Cu2+ is very likely to have
a direct role in synaptic transmission, or learning and memory.
Thus in a disease where its homeostasis is greatly altered, like
ALS, redox reactive Cu2+ , besides been a source of reactive oxygen species, it may very well interfere with synaptic plasticity
and cognitive functions. Indeed, its importance in learning and
memory is underscored in other neurological diseases such as
Alzheimers, Menkes, Wilsons, and Prion diseases, in which its
misregulation is strongly associated with learning and memory
decits (Strausak et al., 2001; Barnham and Bush, 2008; Viles et al.,
2008).
A similar neuromodulatory role has been proposed for Zn2+
(Sensi et al., 2011). Free ionic Zn2+ can be coreleased following vesicle fusion at the glutamatercig synapses (Sensi et al., 2011) and
modies synaptic function by altering the activity of ion channels,

19

receptors, and transporters (Frederickson et al., 2005). NMDAR are

among the most studied targets for extracellular Zn2+ actions. Zn2+
can modulate NMDAR activity by binding to its extracellular aminoterminal domain, which inhibits channel gating, and is found at
many excitatory synapses (Spalloni et al., 2013). At low micromolar concentrations Zn2+ selectively inhibits NMDAR-mediated
responses in cultured hippocampal neurons (Frederickson et al.,
2005). At higher concentrations (>20 M) Zn2+ produces a voltagedependent inhibition of NMDAR currents, probably by binding at
the Mg2+ -blocking site inside the pore. Similar to Cu2+ , other than
inducing conformational changes in mutant and wild-type SOD1
(Ip et al., 2011; Homma et al., 2013), Zn2+ dyshomeostasis can
greatly affects synaptic function particularly at the central synapse
where Zn2+ modulation has been fully demonstrated (Sensi et al.,
2011). We have investigated the modulatory effects that a brief
exposure to extracellular Zn2+ has on NMDAR-mediated neurotoxicity in cortical cultures carrying the SOD1G93A mutation (Nutini
et al., 2011b). We found that, in the mutant neurons, Zn2+ pretreatment enhances NMDAR-mediated toxicity through intracellular
Ca2+ overload and increased ROS generation. These ndings further
support the view of a signicant involvement of cortical neurons
in the ALS pathophysiology with a substantial contribution of the
NMDAR in the regulation/control of cortical synaptic functions and
neuronal degeneration.

7. Conclusion
Cognitive impairment is becoming increasingly important in the
ALS pathogenesis. The presence of frontal decits has a negative
inuence on survival. In one study language-dominant impairment
had a larger impact than behavioral impairment (Coon et al., 2011).
To intervene promptly, with an appropriate drug treatment, it is
important to develop practical relevant screening instruments for
behavioral and aphasic decits in ALS patients, independently from
the decline of motor function. Similarly, when testing therapeutic
strategies in experimental models of the ALS/FTD-type of pathologies we should also evaluate the degeneration of the CSMN as to
have a complete picture of any potential compound tested as elegantly highlighted by Hand zdinler in a recent review (Genc and
zdinler, 2014). Although, it is important to keep in mind that these
models are incomplete analogs of human cognition. A key limitation is that many cognitive functions are unique to humans or
cannot be adequately measured in experimental models (i.e. language). Indeed, these differences might explain, at least in part, the
recent high-prole clinical trial failures with drugs that showed
promising efcacy in preclinical behavioral tasks. However, in the
absence of practical alternatives, mouse models will continue to be
essential.
Interest and knowledge regarding the involvement of the cortical and subcortical areas in the ALS spectrum of disorders has grown
rapidly over the past years. In this review we have discussed the
evidences collected with the SOD1 fALS mouse models, particularly
the involvement of the glutamatergic system in the ALS-related cortical decit and the alterations that may occur prior to or coexist
with the lower MN degeneration.

Acknowledgements
We gratefully acknowledge the support of the EU Joint ProgramNeurodegenerative Disease (JPND) project RimoD-FTD to PL. We
also acknowledge the long lasting and fruitful collaboration with
Dr. Martine Ammassari-Teule, with whom a great deal of our work,
discussed in the review, was conducted.

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A. Spalloni, P. Longone / Neuroscience and Biobehavioral Reviews 60 (2016) 1225

References
Abrahams, S., Leigh, P.N., Harvey, A., Vythelingum, G.N., Gris, D., Goldstein, L.H.,
2000. Verbal uency and executive dysfunction in amyotrophic lateral
sclerosis (ALS). Neuropsychologia 38, 734747.
Abrahams, S., Leigh, P.N., Goldstein, L.H., 2005. Cognitive change in ALS: a
prospective study. Neurology 12, 12221226.
Agosta, F., Rocca, M.A., Valsasina, P., Sala, S., Caputo, D., Perini, M., Salvi, F., Prelle,
A., Filippi, M., 2009. A longitudinal diffusion tensor MRI study of the cervical
cord and brain in amyotrophic lateral sclerosis patients. J. Neurol. Neurosurg.
Psychiatry 80, 5355.
Al-Chalabi, A., Jones, A., Troakes, C., King, A., Al-Sarraj, S., van den Berg, L.H., 2012.
The genetics and neuropathology of amyotrophic lateral sclerosis. Acta
Neuropathol. 124, 339352.
Aliaga, L., Lai, C., Yu, J., Chub, N., Shim, H., Sun, L., Xie, C., Yang, W.J., Lin, X.,
ODonovan, M.J., Cai, H., 2013. 2013 Amyotrophic lateral sclerosis-related VAPB
P56S mutation differentially affects the function and survival of corticospinal
and spinal motor neurons. Hum. Mol. Genet. 22, 42934305.
Andersen, P.M., Al-Chalabi, A., 2011. Clinical genetics of amyotrophic lateral
sclerosis. What do we really know? Nat. Rev. Neurol. 7, 603615.
Arai, T., Hasegawa, M., Akiyama, H., Ikeda, K., Nonaka, T., Mori, H., Mann, D.,
Tsuchiya, K., Yoshida, M., Hashizume, Y., Oda, T., 2006. TDP-43 is a component
of ubiquitin-positive tau-negative inclusions in frontotemporal lobar
degeneration and amyotrophic lateral sclerosis. Biochem. Biophys. Res.
Commun. 351, 602611.
Armon, C., 2008. From clues to mechanisms: understanding ALS initiation and
spread. Neurology 71, 872873.
Attarian, S., Vedel, J.P., Pouget, J., Schmied, A., 2008. Progression of cortical and
spinal dysfunctions over time in amyotrophic lateral sclerosis. Muscle Nerve
37, 364375.
Bae, J.S., Simon, N.G., Menon, P., Vucic, S., Kiernan, M.C., 2013. The puzzling case of
hyperexcitability in amyotrophic lateral sclerosis. J. Clin. Neurol. 9,
6574.
Barnham, K.J., Bush, A.I., 2008. Metals in Alzheimers and Parkinsons diseases.
Curr. Opin. Chem. Biol. 2, 222228.
Barria, A., Malinow, R., 2005. NMDA receptor subunit composition controls
synaptic plasticity by regulating binding to CaMKII. Neuron 48, 289301.
Bede, P., Bokde, A., Elamin, M., Byrne, S., McLaughlin, R.L., Jordan, N., Hampel, H.,
Gallagher, L., Lynch, C., Fagan, A.J., Pender, N., Hardiman, O., 2013. Grey matter
correlates of clinical variables in amyotrophic lateral sclerosis (ALS): a
neuroimaging study of ALS motor phenotype heterogeneity and cortical
focality. J. Neurol. Neurosurg. Psychiatry 84, 766773.
Bellingham, M.C., 2011. A review of the neural mechanisms of action and clinical
efciency of riluzole in treating amyotrophic lateral sclerosis: what have we
learned in the last decade? CNS Neurosci. Ther. 17, 431.
Belzil, V.V., Daoud, H., Desjarlais, A., Bouchard, J.P., Dupr, N., Camu, W., Dion, P.A.,
Rouleau, G.A., 2011. Analysis of OPTN as a causative gene for amyotrophic
lateral sclerosis. Neurobiol. Aging 32, 1843.e19-1843.e24.
Bertoni-Freddari, C., Fattoretti, P., Casoli, T., Di Stefano, G., Giorgetti, B., Balietti, M.,
2008. Brain aging: the zinc connection. Exp. Gerontol. 43, 389393.
Bensimon, G., Lacomblez, L., Meininger, V., 1994. A controlled trial of riluzole in
amyotrophic lateral sclerosis. ALS/Riluzole Study Group. N. Engl. J. Med. 30,
585591.
Blair, I.P., Williams, K.L., Warraich, S.T., Durnall, J.C., Thoeng, A.D., Manavis, J.,
Blumbergs, P.C., Vucic, S., Kiernan, M.C., Nicholson, G.A., 2010. FUS mutations
in amyotrophic lateral sclerosis: clinical, pathological, neurophysiological and
genetic analysis. J Neurol. Neurosurg. Psychiatry 81, 639645.
Boille, S., Vande Velde, C., Cleveland, D.W., 2006. ALS: a disease of motor neurons
and their nonneuronal neighbors. Neuron 52, 3959.
Bodhinathan, K., Kumar, A., Foster, T.C., 2010. Intracellular redox state alters NMDA
receptor response during aging through Ca2+ /calmodulin-dependent protein
kinase II. J. Neurosci. 30, 19141924.
Borasio, G.D., Linke, R., Schwarz, J., Schlamp, V., Abel, A., Mozley, P.D., Tatsch, K.,
1998. Dopaminergic decit in amyotrophic lateral sclerosis assessed with
[I-123] IPT single photon emission computed tomography. J. Neurol.
Neurosurg. Psychiatry 65, 263265.
Brigman, J.L., Wright, T., Talani, G., Prasad-Mulcare, S., Jinde, S., Seabold, G.K.,
Mathur, P., Davis, M.I., Bock, R., Gustin, R.M., Colbran, R.J., Alvarez, V.A.,
Nakazawa, K., Delpire, E., Lovinger, D.M., Holmes, A., 2010. Loss of
GluN2B-containing NMDA receptors in CA1 hippocampus and cortex impairs
long-term depression, reduces dendritic spine density, and disrupt learning. J.
Neurosci. 30, 45904600.
Broustal, O., Camuzat, A., Guillot-Noe, L., Guy, N., Millecamps, S., Deffond, D.,
Lacomblez, L., Goler, V., Hannequin, D., Salachas, F., Camu, W., Didic, M.,
Dubois, B., Meininger, V., Le Ber, I., Brice, A., 2010. FUS mutations in
frontotemporal lobar degeneration with amyotrophic lateral sclerosis. J.
Alzheimers Dis. 22, 765769.
Browne, S.E., Yang, L., Di Mauro, J.P., Fuller, S.W., Licata, S.C., Beal, M.F., 2006.
Bioenergetic abnormalities in discrete cerebral motor pathways presage spinal
cord pathology in the G93A SOD1 mouse model of ALS. Neurobiol. Dis. 22,
599610.
Bruijn, L.I., Becher, M.W., Lee, M.K., Anderson, K.L., Jenkins, N.A., Copeland, N.G.,
Sisodia, S.S., Rothstein, J.D., Borchelt, D.R., Price, D.L., Cleveland, D.W., 1997.
ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes
rapidly progressive disease with SOD1-containing inclusions. Neuron 18,
327338.

Bruijn, L.I., Miller, T.M., Cleveland, D.W., 2004. Unraveling the mechanisms
involved in motor neuron degeneration in ALS. Annu. Rev. Neurosci. 27,
723749.
Buratti, E., Baralle, F.E., 2008. Multiple roles of TDP-43 in gene expression, splicing
regulation, and human disease. Front. Biosci. 13, 867878.
Byrne, S., Elamin, M., Bede, P., Shatunov, A., Walsh, C., Corr, B., Heverin, M., Jordan,
N., Kenna, K., Lynch, C., McLaughlin, R.L., Iyer, P.M., OBrien, C., Phukan, J.,
Wynne, B., Bokde, A.L., Bradley, D.G., Pender, N., Al-Chalabi, A., Hardiman, O.,
2012. Cognitive and clinical characteristics of patients with amyotrophic
lateral sclerosis carrying a C9orf72 repeat expansion: a population-based
cohort study. Lancet Neurol. 11, 232240.
Carunchio, I., Curcio, L., Pieri, M., Pica, F., Caioli, S., Viscomi, M.T., Molinari, M.,
Canu, N., Bernardi, G., Zona, C., 2010. Increased levels of p70S6
phosphorylation in the G93A mouse model of Amyotrophic Lateral Sclerosis
and in valine-exposed cortical neurons in culture. Exp. Neurol. 226,
218230.
Centonze, D., Calabresi, P., Pisani, A., Marinelli, S., Mara, G.A., Bernardi, G., 1998.
Electrophysiology of the neuroprotective agent riluzole on striatal spiny
neurons. Neuropharmacology 37, 10631070.
Chen, Y.Z., Bennett, C.L., Huynh, H.M., Blair, I.P., Puls, I., Irobi, J., Dierick, I., Abel, A.,
Kennerson, M.L., Rabin, B.A., Nicholson, G.A., Auer-Grumbach, M., Wagner, K.,
De Jonghe, P., Grifn, J.W., Fischbeck, K.H., Timmerman, V., Cornblath, D.R.,
Chance, P.F., 2004. DNA/RNA helicase gene mutations in a form of juvenile
amyotrophic lateral sclerosis (ALS4). Am. J. Hum. Genet. 74, 11281135.
Choi, D.W., Yokoyama, M., Koh, J., 1988. Zinc neurotoxicity in cortical cell culture.
Neuroscience 24, 6779.
Chou, S.M., Norris, F.H., 1993. Amyotrophic lateral sclerosis: lower motor neuron
disease spreading to upper motor neurons. Muscle Nerve 16, 864869.
Chung, Y.H., Joo, K.M., Lim, H.C., Cho, M.H., Kim, D., Lee, W.B., Cha, C.I., 2005.
Immunohistochemical study on the distribution of phosphorylated
extracellular signal-regulated kinase (ERK) in the central nervous system of
SOD1G93A transgenic mice. Brain Res. 1050, 203209.
Cistaro, A., Valentini, M.C., Chi, A., Nobili, F., Calvo, A., Moglia, C., Montuschi, A.,
Morbelli, S., Salmaso, D., Fania, P., Carrara, G., Pagani, M., 2012. Brain
hypermetabolism in amyotrophic lateral sclerosis: a FDG PET study in ALS of
spinal and bulbar onset. Eur. J. Nucl. Med. Mol. Imaging 39, 251259.
Cleveland, D.W., Rothstein, J.D., 2001. From Charcot to Lou Gehrig: deciphering
selective motor neuron death in ALS. Nat. Rev. Neurosci. 2, 806819.
Collingridge, G.L., Kehl, S.J., McLennan, H., 1983. Excitatory amino acids in synaptic
transmission in the Schaffer collateral-commissural pathway of the rat
hippocampus. J. Physiol. 334, 3346.
Collingridge, G.L., Volianskis, A., Bannister, N., France, G., Hanna, L., Mercier, M.,
Tidball, P., Fang, G., Irvine, M.W., Costa, B.M., Monaghan, D.T., Bortolotto, Z.A.,
Molnr, E., Lodge, D., Jane, D.E., 2013. The NMDA receptor as a target for
cognitive enhancement. Neuropharmacology 64, 1326.
Coon, E.A., Sorenson, E.J., Whitwell, J.L., Knopman, D.S., Josephs, K.A., 2011.
Predicting survival in frontotemporal dementia with motor neuron disease.
Neurology 76, 18861893.
Crow, J.P., Sampson, J.B., Zhuang, Y., Thompson, J.A., Beckman, J.S., 1997. Decreased
zinc afnity of amyotrophic lateral sclerosis-associated superoxide dismutase
mutants leads to enhanced catalysis of tyrosine nitration by peroxynitrite. J.
Neurochem., 19361944.
Cull-Candy, S.G., Brickley, S., Farrant, M., 2001. NMDA receptor subunits: diversity,
development and disease. Curr. Opin. Neurobiol. 11, 327335.
Dal Canto, M.C., Gurney, M.E., 1994. Development of central nervous system
pathology in a murine transgenic model of human amyotrophic lateral
sclerosis. Am. J. Pathol. 145, 12711279.
de Carvalho, M., 2000. Pathophysiological signicance of fasciculations in the early
diagnosis of ALS. Amyotroph. Lateral Scler. Other Motor Neuron Disord. 1
(Suppl. 1), S43S46.
de Carvalho, M., Dengler, R., Eisen, A., England, J.D., Kaji, R., Kimura, J., Mills, K.,
Mitsumoto, H., Nodera, H., Shefner, J., Swash, M., 2008. Electrodiagnostic
criteria for diagnosis of ALS. Clin. Neurophysiol. 119, 497503.
de Carvalho, M., Wash, M.S., 2009. Awaji diagnostic algorithm increases sensitivity
of El Escorial criteria for ALS diagnosis. Amyotroph. Lateral Scler. 10,
5357.
Deng, H.X., Chen, W., Hong, S.T., Boycott, K.M., Gorrie, G.H., Siddique, N., Yang, Y.,
Fecto, F., Shi, Y., Zhai, H., Jiang, H., Hirano, M., Rampersaud, E., Jansen, G.H.,
Donkervoort, S., Bigio, E.H., Brooks, B.R., Ajroud, K., Su, R.L., Haines, J.L.,
Mugnaini, E., Pericak-Vance, M.A., Siddique, T., 2011. Mutations in UBQLN2
cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia.
Nature 477, 211215.
DeJesus-Hernandez, M., Mackenzie, I.R., Boeve Boxer, A.L., Baker, M., Rutherford,
N.J., Nicholson, A.M., Finch, N.A., Flynn, H., Adamson, J., Kouri, N., Wojtas, A.,
Sengdy, P., Hsiung, G.Y., Karydas, A., Seeley, W.W., Josephs, K.A., Coppola, G.,
Geschwind, D.H., Wszolek, Z.K., Feldman, H., Knopman, D.S., Petersen, R.C.,
Miller, B.L., Dickson, D.W., Boylan, K.B., Graff-Radford, N.R., Rademakers, R.,
2011. Expanded GGGGCC hexanucleotide repeat in noncoding region of
C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72, 245256.
de Marchena, J., Roberts, A.C., Middlebrooks, P.G., Valakh, V., Yashiro, K., Wiley,
L.R., Philpot, B.D., 2008. NMDA receptor antagonists reveal age-dependent
differences in the properties of visual cortical plasticity. J. Neurophysiol. 100,
19361948.
Desiato, M., Bernardi, G., Hagi, A.H., Boffa, L., Caramia, M.D., 2002. Transcranial
magnetic stimulation of motor pathways directed to muscles supplied by
cranial nerves in ALS. Clin. Neurophysiol. 113, 132140.

A. Spalloni, P. Longone / Neuroscience and Biobehavioral Reviews 60 (2016) 1225

Dodani, S.C., Domaille, D.W., Nam, C.I., Miller, E.W., Finney, L.A., Vogt, S., Chang, C.J.,
2011. Calcium-dependent copper redistributions in neuronal cells revealed by
a uorescent copper sensor and X-ray uorescence microscopy. Proc. Natl.
Acad. Sci. U S A 108, 59805985.
Durand, J., Amendola, J., Bories, C., Lamotte dIncamps, B., 2006. Early abnormalities
in transgenic mouse models of amyotrophic lateral sclerosis. J. Physiol. Paris
99, 211220.
Eisen, A., Pant, B., Stewart, H., 1993. Cortical excitability in amyotrophic lateral
sclerosis: a clue to pathogenesis. Can. J. Neurol. Sci. 20, 1116.
Eisen, A., Entezari-Taher, M., Stewart, H., 1996. Cortical projections to spinal
motoneurons: changes with aging and amyotrophic lateral sclerosis.
Neurology 46, 13961404.
Eisen, A., 2009. Amyotrophic lateral sclerosis evolutionary and other
perspectives. Muscle Nerve 40, 297304.
Elamin, M., Phukan, J., Bede, P., Jordan, N., Byrne, S., Pender, N., Hardiman, O., 2011.
Executive dysfunction is a negative prognostic indicator in patients with ALS
without dementia. Neurology 76, 12631269.
Elden, A.C., Kim, H.J., Hart, M.P., Chen-Plotkin, A.S., Johnson, B.S., Fang, X.,
Armakola, M., Geser, F., Greene, R., Lu, M.M., Padmanabhan, A., Clay-Falcone,
D., McCluskey, L., Elman, L., Juhr, D., Gruber, P.J., Ru, U., Auburger, G.,
Trojanowski, J.Q., Lee, V.M.-Y., Van Deerlin, V.M., Bonini, N.M., Gitler, A.D.,
2010. Ataxin-2 intermediate- length polyglutamine expansions are associated
with increased risk for ALS. Nature 466, 10691075.
Estvez, A.G., Crow, J.P., Sampson, J.B., Reiter, C., Zhuang, Y., Richardson, G.J.,
Tarpey, M.M., Barbeito, L., Beckman, J.S., 1999. Induction of nitric
oxide-dependent apoptosis in motor neurons by zinc-decient superoxide
dismutase. Science 286, 24982500.
Ewald, R.C., Van Keuren-Jensen, K.R., Aizenman, C.D., Cline, H.T., 2008. Roles of
NR2A and NR2B in the development of dendritic arbor morphology in vivo. J.
Neurosci. 28, 850861.
Fecto, F., Siddique, T., 2012. UBQLN2/P62 cellular recycling pathways in
amyotrophic lateral sclerosis and frontotemporal dementia. Muscle Nerve 45,
157162.
Ferrucci, M., Spalloni, A., Bartalucci, A., Cantafora, E., Fulceri, F., Nutini, M., Longone,
P., Paparelli, A., Fornai, F., 2010. A systematic study of brainstem motor nuclei
in a mouse model of ALS, the effects of lithium. Neurobiol. Dis. 37, 370383.
Filali, M., Lalonde, R., Rivest, S., 2011. Sensorimotor and cognitive functions in a
SOD1(G37R) transgenic mouse model of amyotrophic lateral sclerosis. Behav.
Brain Res. 225, 215221.
Flint, A.C., Maisch, U.S., Weishaupt, J.H., Kriegstein, A.R., Monyer, H., 1997. NR2A
subunit expression shortens NMDA receptor synaptic currents in developing
neocortex. J. Neurosci. 17, 24692476.
Foerster, B.R., Pomper, M.G., Callaghan, B.C., Petrou, M., Edden, R.A., Mohamed,
M.A., Welsh, R.C., Carlos, R.C., Barker, P.B., Feldman, E.L., 2013. An imbalance
between excitatory and inhibitory neurotransmitters in amyotrophic lateral
sclerosis revealed by use of 3-T proton magnetic resonance spectroscopy.
JAMA Neurol. 70, 10091016.
Fogarty, M.J., Noakes, P.G., Bellingham, M.C., 2015. Motor cortex layer V pyramidal
neurons exhibit dendritic regression, spine loss, and increased synaptic
excitation in the presymptomatic hSOD1G93A mouse model of amyotrophic
lateral sclerosis. J. Neurosci. 35, 643647.
Frank, B., Haas, J., Heinze, H.J., Stark, E., Mnte, T.F., 1997. Relation of
neuropsychological and magnetic resonance ndings in amyotrophic lateral
sclerosis: evidence for subgroups. Clin. Neurol. Neurosurg. 99, 7986.
Frederickson, C.J., Koh, J.Y., Bush, A.I., 2005. The neurobiology of zinc in health and
disease. Nat. Rev. Neurosci. 6, 449462.
Furukawa, H., Singh, S.K., Mancusso, R., Gouaux, E., 2005. Subunit arrangement and
function in NMDA receptors. Nature 438, 185192.
Gaier, E.D., Miller, M.B., Ralle, M., Aryal, D., Wetsel, W.C., Mains, R.E., Eipper, B.A.,
2013. Peptidylglycine -amidating monooxygenase heterozygosity alters
brain copper handling with region specicity. J. Neurochem. 127, 605619.
Gambrill, A.C., Barria, A., 2011. NMDA receptor subunit composition controls
synaptogenesis and synapse stabilization. Proc. Natl. Acad. Sci. USA 108,
58555860.
A.,
Gascn, S., Deogracias, R., Sobrado, M., Roda, J.M., Renart, J., Rodrguez-Pena,
Daz-Guerra, M., 2005. Transcription of the NR1 subunit of the
N-methyl-d-aspartate receptor is down-regulated by excitotoxic stimulation
and cerebral ischemia. J. Biol. Chem. 280, 3501835027.
Geevasinga, N., Menon, P., Howells, J., Nicholson, G.A., Kiernan, M.C., Vucic, S.,
2015a. Axonal ion channel dysfunction in c9orf72 familial amyotrophic lateral
sclerosis. JAMA Neurol. 72, 4957.
Geevasinga, N., Menon, P., Nicholson, G.A., Ng, K., Howells, J., Kril, J.J., Yiannikas, C.,
Kiernan, M.C., Vucic, S., 2015b. Cortical function in asymptomatic carriers and
patients with C9orf72 amyotrophic lateral sclerosis. JAMA Neurol.
(September), 17, http://dx.doi.org/10.1001/jamaneurol.2015.1872 [Epub
ahead of print] PubMed PMID: 26348842.
Genc, B., zdinler, P.H., 2014. Moving forward in clinical trials for ALS: motor
neurons lead the way please. Drug Discov Today 19, 441449.
Geracitano, R., Paolucci, E., Prisco, S., Guatteo, E., Zona, C., Longone, P.,
Ammassari-Teule, M., Bernardi, G., Berretta, N., Mercuri, N.B., 2003. Altered
long-term corticostriatal synaptic plasticity in transgenic mice overexpressing
human CU/ZN superoxide dismutase (GLY(93)ALA) mutation. Neuroscience
118, 399408.
Geser, F., Lee, V.M., Trojanowski, J.Q., 2010. Amyotrophic lateral sclerosis and
frontotemporal lobar degeneration: a spectrum of TDP-43 proteinopathies.
Neuropathology 30, 103112.

21

Ghosh, D., LeVault, K.R., Barnett, A.J., Brewer, G.J., 2012. A reversible early oxidized
redox state that precedes macromolecular ROS damage in aging nontransgenic
and 3xTg-AD mouse neurons. J Neurosci 32, 58215832.
Gibb, S.L., Boston-Howes, W., Lavina, Z.S., Gustincich, S., Brown Jr., R.H., Pasinelli, P.,
Trotti, D., 2007. A Caspase-3-cleaved fragment of the glial glutamate
transporter EAAT2 is sumoylated and targeted to promyelocytic leukemia
nuclear bodies in mutant SOD1-linked amyotrophic lateral sclerosis. J. Biol.
Chem. 282, 3248032490.
Gijselinck, I., Van Langenhove, T., van der Zee, J., Sleegers, K., Philtjens, S.,
Kleinberger, G., Janssens, J., Bettens, K., Van Cauwenberghe, C., Pereson, S.,
Engelborghs, S., Sieben, A., De Jonghe, P., Vandenberghe, R., Santens, P., De
Bleecker, J., Maes, G., Bumer, V., Dillen, L., Joris, G., Cuijt, I., Corsmit, E., Elinck,
E., Van Dongen, J., Vermeulen, S., Van den Broeck, M., Vaerenberg, C.,
Mattheijssens, M., Peeters, K., Robberecht, W., Cras, P., Martin, J.J., De Deyn,
P.P., Cruts, M., Van Broeckhoven, C., 2012. A C9orf72 promoter repeat
expansion in a Flanders-Belgian cohort with disorders of the frontotemporal
lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene
identication study. Lancet Neurol. 11, 5465.
Gong, Y.H., Elliott, J.L., 2000. Metallothionein expression is altered in a transgenic
murine model of familial amyotrophic lateral sclerosis. Exp. Neurol. 162,
2736.
Gordon, U., Polsky, A., Schiller, J., 2006. Plasticity compartments in basal dendrites
of neocortical pyramidal neurons. J. Neurosci. 26, 1271712726.
Gordon, P.H., Goetz, R.R., Rabkin, J.G., Dalton, K., McElhiney, M., Hays, A.P., Marder,
K., Stern, Y., Mitsumoto, H., 2010. A prospective cohort study of
neuropsychological test performance in ALS. Amyotroph. Lateral Scler. 3,
312320.
Govind, V., Sharma, K.R., Maudsley, A.A., Arheart, K.L., Saigal, G., Sheriff, S., 2012.
Comprehensive evaluation of corticospinal tract metabolites in amyotrophic
lateral sclerosis using whole-brain 1H MR spectroscopy. PLoS ONE 7 (4).
Graham, J.M., Papadakis, N., Evans, J., Widjaja, E., Romanowski, C.A., Paley, M.N.,
Wallis, L.I., Wilkinson, I.D., Shaw, P.J., Grifths, P.D., 2004. Diffusion tensor
imaging for the assessment of upper motor neuron integrity in ALS. Neurology
63, 21112119.
Greenway, M.J., Andersen, P.M., Russ, C., Ennis, S., Cashman, S., Donaghy, C.,
Patterson, V., Swingler, R., Kieran, D., Prehn, J., Morrison, K.E., Green, A.,
Acharya, K.R., Brown Jr., R.H., Hardiman, O., 2006. ANG mutations segregate
with familial and sporadic amyotrophic lateral sclerosis. Nat. Genet. 38,
411413.
Guo, Z., Kindy, M.S., Kruman, I., Mattson, M.P., 2000. ALS-linked Cu/Zn-SOD
mutation impairs cerebral synaptic glucose and glutamate transport and
exacerbates ischemic brain injury. J. Cereb. Blood. Flow. Metab. 20, 463468.
Guerreiro, R., Bras, J., Hardy, J., 2015. SnapShot: genetics of ALS and FTD. Cell 160,
798-798.e1.
Gurney, M.E., Pu, H., Chiu, A.Y., Dal Canto, M.C., Polchow, C.Y., Alexander, D.D.,
Caliendo, J., Hentati, A., Kwon, Y.W., Deng, H.X., Chen, W., Zhai, P., Sut, R.L.,
Siddique, T., 1994. Motor neuron degeneration in mice that express a human
Cu, Zn superoxide dismutase mutation. Science 264, 17721775.
Haidet-Phillips, A.M., Hester, M.E., Miranda, C.J., Meyer, K., Braun, L., Frakes, A.,
Song, S., Likhite, S., Murtha, M.J., Foust, K.D., Rao, M., Eagle, A., Kammesheidt,
A., Christensen, A., Mendell, J.R., Burghes, A.H., Kaspar, B.K., 2011. Astrocytes
from familial and sporadic ALS patients are toxic to motor neurons. Nat.
Biotech. 29, 824828.
Hall, E.D., Andrus, P.K., Oostveen, J.A., Fleck, T.J., Gurney, M.E., 1998. Relationship of
oxygen radical-induced lipid peroxidative damage to disease onset and
progression in a transgenic model of familial ALS. J. Neurosci. Res. 53, 6677.
Haxaire, C., Turpin, F.R., Potier, B., Kervern, M., Sinet, P.M., Barbanel, G., Mothet, J.P.,
Dutar, P., Billard, J.M., 2012. Reversal of age-related oxidative stress prevents
hippocampal synaptic plasticity decits by protecting d-serine-dependent
NMDA receptor activation. Aging Cell 11, 336344.
He, Y., Benz, A., Fu, T., Wang, M., Covey, D.F., Zorumski, C.F., Mennerick, S., 2002.
Neuroprotective agent riluzole potentiates postsynaptic GABA(A) receptor
function. Neuropharmacology 42, 199209.
Hegedus, J., Putman, C.T., Gordon, T., 2007. Time course of preferential motor unit
loss in the SOD1 G93A mouse model of amyotrophic lateral sclerosis.
Neurobiol. Dis. 28, 154164.
Hidalgo, J., Aschner, M., Zatta, P., Vask, M., 2001. Roles of the metallothionein
family of proteins in the central nervous system. Brain Res. Bull. 55, 133145.
Hirota, N., Eisen, A., Weber, M., 2000. Complex fasciculations and their origin in
amyotrophic lateral sclerosis and Kennedys disease. Muscle Nerve 23,
18721875.
Homma, K., Fujisawa, T., Tsuburaya, N., Yamaguchi, N., Kadowaki, H., Takeda, K.,
Nishitoh, H., Matsuzawa, A., Naguro, I., Ichijo, H., 2013. SOD1 as a molecular
switch for initiating the homeostatic ER stress response under zinc deciency.
Mol. Cell 52, 7586.
Horning, M.S., Trombley, P.Q., 2001. Zinc and copper inuence excitability of rat
olfactory bulb neurons by multiple mechanisms. J. Neurophysiol. 86,
16521660.
Ince, P., Stout, N., Shaw, P., Slade, J., Hunziker, W., Heizmann, C.W., Baimbridge,
K.G., 1993. Parvalbumin and calbindin D-28k in the human motor system and
in motor neuron disease. Neuropathol. Appl. Neurobiol. 19, 291299.
Ip, P., Mulligan, V.K., Chakrabartty, A., 2011. ALS-causing SOD1 mutations promote
production of copper-decient misfolded species. J. Mol. Biol. 409, 839852.
Jara, J.H., Villa, S.R., Khan, N.A., Bohn, M.C., zdinler, P.H., 2012. AAV2 mediated
retrograde transduction of corticospinal motor neurons reveals initial and
selective apical dendrite degeneration in ALS. Neurobiol. Dis. 47, 174183.

22

A. Spalloni, P. Longone / Neuroscience and Biobehavioral Reviews 60 (2016) 1225

Johnson, J.O., Mandrioli, J., Benatar, M., Abramzon, Y., Van Deerlin, V.M.,
Trojanowski, J.Q., Gibbs, J.R., Brunetti, M., Gronka, S., Wuu, J., Ding, J.,
McCluskey, L., Martinez-Lage, M., Falcone, D., Hernandez, D.G., Arepalli, S.,
Chong, S., Schymick, J.C., Rothstein, J., Landi, F., Wang, Y.D., Calvo, A., Mora, G.,
Sabatelli, M., Monsurr, M.R., Battistini, S., Salvi, F., Spataro, R., Sola, P.,
Borghero, G., ITALSGEN Consortium, Galassi, G., Scholz, S.W., Taylor, J.P.,
Restagno, G., Chi, A., Traynor, B.J., 2010. Exome sequencing reveals VCP
mutations as a cause of familial ALS. Neuron 68, 857864.
Jonsson, P.A., Graffmo, K.S., Andersen, P.M., Brnnstrm, T., Lindberg, M., Oliveberg,
M., Marklund, S.L., 2006. Disulphide-reduced superoxide dismutase-1 in CNS
of transgenic amyotrophic lateral sclerosis models. Brain 29, 451464.
Kayatekin, C., Zitzewitz, J.A., Matthews, C.R., 2008. Zinc binding modulates the
entire folding free energy surface of human Cu, Zn superoxide dismutase. J.
Mol. Biol. 384, 540555.
Kanki, R., Nakamizo, T., Yamashita, H., Kihara, T., Sawada, H., Uemura, K.,
Kawamata, J., Shibasaki, H., Akaike, A., Shimohama, S., 2004. Effects of
mitochondrial dysfunction on glutamate receptor-mediated neurotoxicity in
cultured rat spinal motor neurons. Brain Res. 1015, 7381.
Kardos, J., Kovcs, I., Hajs, F., Klmn, M., Simonyi, M., 1989. 1989 Nerve endings
from rat brain tissue release copper upon depolarization. A possible role in
regulating neuronal excitability. Neurosci. Lett. 103, 139144.
Kassa, R.M., Mariotti, R., Bonaconsa, M., Bertini, G., Bentivoglio, M., 2009. Gene, cell,
and axon changes in the familial amyotrophic lateral sclerosis mouse
sensorimotor cortex. J. Neuropathol. Exp. Neurol. 68, 5972.
Katz, J.S., Katzberg, H.D., Woolley, S.C., Marklund, S.L., Andersen, P.M., 2012.
Combined fulminant frontotemporal dementia and amyotrophic lateral
sclerosis associated with an I113 T SOD1 mutation. Amyotroph. Lateral Scler.
13, 567569.
Kew, J.J., Goldstein, L.H., Leigh, P.N., Abrahams, S., Cosgrave, N., Passingham, R.E.,
Frackowiak, R.S., Brooks, D.J., 1993. The relationship between abnormalities of
cognitive function and cerebral activation in amyotrophic lateral sclerosis. A
neuropsychological and positron emission tomography study. Brain 116,
13991423.
Kiernan, J.A., Hudson, A.J., 1994. Frontal lobe atrophy in motor neuron diseases.
Brain 117, 747757.
Kim, J., Kim, T.Y., Hwang, J.J., Lee, J.Y., Shin, J.H., Gwag, B.J., Koh, J.Y., 2009.
Accumulation of labile zinc in neurons and astrocytes in the spinal cords of
G93A SOD-1 transgenic mice. Neurobiol. Dis. 34, 221229.
Kleine, B.U., Stegeman, D.F., Schelhaas, H.J., Zwarts, M.J., 2008. Firing pattern of
fasciculations in ALS: evidence for axonal and neuronal origin. Neurology 70,
353359.
Knibb, J.A., Woollams, A.M., Hodges, J.R., Patterson, K., 2009. Making sense of
progressive non-uent aphasia: an analysis of conversational speech. Brain
132, 27342746.
Kostic, V., Gurney, M.E., Deng, H.X., Siddique, T., Epstein, C.J., Przedborski, S., 1997.
Midbrain dopaminergic neuronal degeneration in a transgenic mouse model of
familial amyotrophic lateral sclerosis. Ann. Neurol. 41, 497504.
Khnlein, P., Gdynia, H.J., Sperfeld, A.D., Lindner-Peghar, B., Ludolph, A.C.,
Prosiegel, M., Riecker, A., 2008. Diagnosis and treatment of bulbar symptoms in
amyotrophic lateral sclerosis. Nat. Clin. Pract. Neurol. 4, 366374.
Kuo, J.J., Siddique, T., Fu, R., Heckman, C.J., 2005. Increased persistent Na(+) current
and its effect on excitability in motoneurones cultured from mutant SOD1
mice. J. Physiol. 563, 843854.
Kuo, J.J., Lee, R.H., Zhang, L., Heckman, C., 2006. Essential role of the persistent
sodium current in spike initiation during slowly rising inputs in mouse spinal
neurones. J. Physiol. 574, 819834.
Kwak, S., Hideyama, T., Yamashita, T., Aizawa, H., 2010. AMPA receptor-mediated
neuronal death in sporadic ALS. Neuropathology 30, 182188.
Larroquette, F., Seto, L., Gaub, P.L., Kamal, B., Wallis, D., Larivire, R., Valle, J.,
Robitaille, R., Tsuda, H., 2015. Vapb/Amyotrophic lateral sclerosis 8 knock-in
mice display slowly progressive motor behavior defects accompanying ER
stress and autophagic response. Hum. Mol. Genet. 24, 65156529.
Laurie, D.J., Bartke, I., Schoepfer, R., Naujoks, K., Seeburg, P.H., 1997. Regional,
developmental and interspecies expression of the four NMDAR2 subunits,
examined using monoclonal antibodies. Brain Res. Mol. Brain Res. 51, 2332.
Lee, J.Y., Kim, J.H., Palmiter, R.D., Koh, J.Y., 2003. Zinc released from
metallothionein-iii may contribute to hippocampal CA1 and thalamic neuronal
death following acute brain injury. Exp. Neurol. 184, 337347.
Lee, W.H., Kumar, A., Rani, A., Herrera, J., Xu, J., Someya, S., Foster, T.C., 2012.
Inuence of viral vector-mediated delivery of superoxide dismutase and
catalase to the hippocampus on spatial learning and memory during aging.
Antioxid. Redox Signal 16, 339350.
Leichsenring, A., Linnartz, B., Zhu, X.R., Lbbert, H., Stichel, C.C., 2006. Ascending
neuropathology in the CNS of a mutant SOD1 mouse model of amyotrophic
lateral sclerosis. Brain. Res. 1096, 180195.
Lelie, H.L., Liba, A., Bourassa, M.W., Chattopadhyay, M., Chan, P.K., Gralla, E.B.,
Miller, L.M., Borchelt, D.R., Valentine, J.S., Whitelegge, J.P., 2011. Copper and
zinc metallation status of copperzinc superoxide dismutase from
amyotrophic lateral sclerosis transgenic mice. J. Biol. Chem. 286, 27952806.
Lever, T.E., Gorsek, A., Cox, K.T., OBrien, K.F., Capra, N.F., Hough, M.S., Murashov,
A.K., 2009. An animal model of oral dysphagia in amyotrophic lateral sclerosis.
Dysphagia 24, 180195.
Lever, T.E., Simon, E., Cox, K.T., Capra, N.F., OBrien, K.F., Hough, M.S., Murashov,
A.K., 2010. A mouse model of pharyngeal dysphagia in amyotrophic lateral
sclerosis. Dysphagia 25, 112126.

Li, L., Zhang, X., Le, W., 2008. Altered macroautophagy in the spinal cord of SOD1
mutant mice. Autophagy 4, 290293.
Ling, S.C., Polymenidou, M., Cleveland, D.W., 2013. Converging mechanisms in ALS
and FTD: disrupted RNA and protein homeostasis. Neuron 79,
416438.
Ludolph, A.C., Langen, K.J., Regard, M., Herzog, H., Kemper, B., Kuwert, T., Bttger,
I.G., Feinendegen, L., 1992. Frontal lobe function in amyotrophic lateral
sclerosis: a neuropsychologic and positron emission tomography study. Acta
Neurol. Scand. 85, 8189.
Mackenzie, I.R., Feldman, H., 2004. Extrapyramidal features in patients with motor
neuron disease and dementia: a clinicopathological correlative study. Acta
Neuropathol. 107, 336340.
Mackenzie, I.R., Rademakers, R., 2008. The role of transactive response DNAbinding
protein-43 in amyotrophic lateral sclerosis and frontotemporal dementia. Curr.
Opin. Neurol. 21, 693700.
Mackenzie, I.R., Rademakers, R., Neumann, M., 2010. TDP-43 and FUS in
amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol. 9,
9951007.
Majounie, E., Renton, A.E., Mok, K., Dopper, E.G., Waite, A., Rollinson, S., Chi, A.,
Restagno, G., Nicolaou, N., Simon-Sanchez, J., van Swieten, J.C., Abramzon, Y.,
Johnson, J.O., Sendtner, M., Pamphlett, R., Orrell, R.W., Mead, S., Sidle, K.C.,
Houlden, H., Rohrer, J.D., Morrison, K.E., Pall, H., Talbot, K., Ansorge, O.,
Chromosome 9-ALS/FTD Consortium, French research network on
FTLD/FTLD/ALS, ITALSGEN Consortium, Hernandez, D.G., Arepalli, S., Sabatelli,
M., Mora, G., Corbo, M., Giannini, F., Calvo, A., Englund, E., Borghero, G., Floris,
G.L., Remes, A.M., Laaksovirta, H., McCluskey, L., Trojanowski, J.Q., Van Deerlin,
V.M., Schellenberg, G.D., Nalls, M.A., Drory, V.E., Lu, C.S., Yeh, T.H., Ishiura, H.,
Takahashi, Y., Tsuji, S., Le Ber, I., Brice, A., Drepper, C., Williams, N., Kirby, J.,
Shaw, P., Hardy, J., Tienari, P.J., Heutink, P., Morris, H.R., Pickering-Brown, S.,
Traynor, B.J., 2012. Frequency of the C9orf72 hexanucleotide repeat expansion
in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a
cross-sectional study. Lancet Neurol. 11, 323330.
Malenka, R.C., Bear, M.F., 2004. LTP and LTD: an embarrassment of riches. Neuron
44, 521.
Mancuso, R., Santos-Nogueira, E., Osta, R., Navarro, X., 2011. Electrophysiological
analysis of a murine model of motoneuron disease. Clin. Neurophysiol. 122,
16601670.
Marques, V.D., Barreira, A.A., Davis, M.B., Abou-Sleiman, P.M., Silva Jr., W.A., Zago,
M.A., Sobreira, C., Fazan, V., Marques Jr., W., 2006. Expanding the phenotypes
of the Pro56Ser VAPB mutation: proximal SMA with dysautonomia. Muscle
Nerve 34, 731739.
Massey, P.V., Johnson, B.E., Moult, P.R., Auberson, Y.P., Brown, M.W., Molnar, E.,
Collingridge, G.L., Bashir, Z.I., 2004. Differential roles of NR2A and
NR2B-containing NMDA receptors in cortical long-term potentiation and
long-term depression. J. Neurosci. 24, 78217828.
McKhann, G.M., Albert, M.S., Grossman, M., Miller, B., Dickson, D., Trojanowski, J.Q.,
2001. Clinical and pathological diagnosis of frontotemporal dementia. Arch.
Neurol. 58, 18031809.
Menon, P., Kiernan, M.C., Vucic, S., 2014. 2014 Cortical dysfunction underlies the
development of the split-hand in amyotrophic lateral sclerosis. PLoS ONE 9,
e87124, http://dx.doi.org/10.1371/journal.pone.0087124.
Mierau, S.B., Meredith, R.M., Upton, A.L., Paulsen, O., 2004. Dissociation of
experience-dependent and -independent changes in excitatory synaptic
transmission during development of barrel cortex. Proc. Natl. Acad. Sci. USA
101, 1551815523.
Miwa, H., Fukaya, M., Watabe, A.M., Watanabe, M., Manabe, T., 2008. Functional
contributions of synaptically localized NR2B subunits of the NMDA receptor to
synaptic transmission and long-term potentiation in the adult mouse. CNS J.
Physiol. 586, 25392550.
Morrison, B.M., Morrison, J.H., 1999. Amyotrophic lateral sclerosis associated with
mutations in superoxide dismutase: a putative mechanisms of degeneration.
Brain Res. Rev. 29, 121135.
Moser, J.M., Bigini, P., Schmitt-John, T., 2013. The wobbler mouse, an ALS animal
model. Mol. Genet. Genom. 288, 207229.
Nakamura, M., Bieniek, K.F., Lin, W.-L., Graff-Radford, N.R., Murray, M.R.,
Castanedes-Casey, M., Desaro, P., Baker, M.C., Rutherford, N.J., Robertson, J.,
Rademakers, R., Dickson, D.W., Boylan, K.B., 2015. A truncating SOD1 mutation,
p.Gly141X, is associated with clinical and pathologic heterogeneity, including
frontotemporal lobar degeneration. Acta Neuropathol. 130, 145157.
Neary, D., Snowden, J.S., Mann, D.M., Northen, B., Goulding, P.J., Macdermott, N.,
1990. Frontal lobe dementia and motor neuron disease. J. Neurol. Neurosurg.
Psychiatry 53, 2332.
Neary, D., Snowden, J., Mann, D., 2005. Frontotemporal dementia. Lancet Neurol. 4,
771780.
Ng, A.S., Rademakers, R., Miller, B.L., 2014. Frontotemporal dementia: a bridge
between dementia and neuromuscular disease. Ann. N. Y. Acad. Sci. 1338,
7193.
Nicholson, S.J., Witherden, A.S., Hafezparast, M., Martin, J.E., Fisher, E.M., 2000.
Mice, the motor system, and human motor neuron pathology. Mamm. Genome
11, 10411052.
Niessen, H.G., Angenstein, F., Sander, K., Kunz, W.S., Teuchert, M., Ludolph, A.C.,
Heinze, H.J., Scheich, H., Vielhaber, S., 2006. In vivo quantication of spinal and
bulbar motor neuron degeneration in the G93A-SOD1 transgenic mouse model
of ALS by T2 relaxation time and apparent diffusion coefcient. Exp. Neurol.
201, 293300.

A. Spalloni, P. Longone / Neuroscience and Biobehavioral Reviews 60 (2016) 1225

Nieto-Gonzales, J.L., Moser, J., Lauritzen, M., Schmitt-John, T., Jensen, K., 2011.
Reduced GABAergic inhibition explains cortical hyperexciatbility in the
wobbler mouse model of ALS. Cereb. Cortex 21, 625635.
Nihei, K., McKee, A.C., Kowall, N.W., 1993. Patterns of neuronal degeneration in the
motor cortex of amyotrophic lateral sclerosis patients. Acta Neuropathol. 86,
5564.
Nishimura, Y., Hayashi, M., Inada, H., Tanaka, T., 1999. Molecular cloning and
characterization of mammalian homologues of vesicle-associated membrane
protein-associated (VAMP-associated) proteins. Biochem. Biophys. Res.
Commun. 254, 2126.
Nishimura, A.L., Mitne-Neto, M., Silva, H.C., Richieri-Costa, A., Middleton, S., Cascio,
D., Kok, F., Oliveira, J.R., Gillingwater, T., Webb, J., Skehel, P., Zatz, M., 2004. A
mutation in the vesicle-trafcking protein VAPB causes late-onset spinal
muscular atrophy and amyotrophic lateral sclerosis. Am. J. Hum. Genet. 75,
822831.
Nozaki, I., Arai, M., Takahashi, K., Hamaguchi, T., Yoshikawa, H., Muroishi, T.,
Noguchi-Shinohara, M., Ito, H., Itokawa, M., Akiyama, H., Kawata, A., Yamada,
M., 2010. Familial ALS with G298S mutation in TARDBP: a comparison of CSF
tau protein levels with those in sporadic ALS. Intern. Med. 49, 12091212.
Nutini, M., Spalloni, A., Florenzano, F., Westenbroek, R.E., Marini, C., Catterall, W.A.,
Bernardi, G., Longone, P., 2011a. Increased expression of the beta3 subunit of
voltage-gated Na+ channels in the spinal cord of the SOD1G93A mouse. Mol.
Cell. Neurosci. 47, 108118.
Nutini, M., Frazzini, V., Marini, C., Spalloni, A., Sensi, S.L., Longone, P., 2011b. Zinc
pre-treatment enhances NMDAR-mediated excitotoxicity in cultured cortical
neurons from SOD1(G93A) mouse, a model of amyotrophic lateral sclerosis.
Neuropharmacology 60, 12001208.
Otomo, A., Pan, L., Hadano, S., 2012. 2012 Dysregulation of the
autophagy-endolysosomal system in amyotrophic lateral sclerosis and related
motor neuron diseases. Neurol. Res. Int., 498428.
Ozdinler, P.H., Benn, S., Yamamoto, T.H., Gzel, M., Brown, R.H., Macklis, J.D., 2011.
Corticospinal motor neurons and related subcerebral projection neurons
undergo early and specic neurodegeneration in hSOD1G93A transgenic ALS
mice. J. Neurosci. 31, 41664177.
Pambo-Pambo, A., Durand, J., Gueritaud, J.P., 2009. Early excitability changes in
lumbar motoneurons of transgenic SOD1G85R and SOD1G(93A-Low) mice. J.
Neurophysiol. 102, 36273642.
Phukan, J., Elamin, M., Bede, P., Jordan, N., Gallagher, L., Byrne, S., Lynch, C., Pender,
N., Hardiman, O., 2012. The syndrome of cognitive impairment in amyotrophic
lateral sclerosis: a population-based study. Neurol. Neurosurg. Psychiatry 83,
102108.
Pieri, M., Carunchio, I., Curcio, L., Mercuri, N.B., Zona, C., 2009. Increased persistent
sodium current determines cortical hyperexcitability in a genetic model of
amyotrophic lateral sclerosis. Exp. Neurol. 215, 368379.
Potter, S.Z., Valentine, J.S., 2003. The perplexing role of copper-zinc superoxide
dismutase in amyotrophic lateral sclerosis (Lou Gehrigs disease). J. Biol. Inorg.
Chem. 4, 373380.
Prakriya, M., Mennerick, S., 2000. Selective depression of low-release probability
excitatory synapses by sodium channel blockers. Neuron 26, 671682.
Quarta, E., Bravi, R., Scambi, I., Mariotti, R., Minciacchi, D., 2015. Increased
anxiety-like behavior and selective learning impairments are concomitant to
loss of hippocampal interneurons in the presymptomatic SOD1(G93A) ALS
mouse model. J. Comp. Neurol., http://dx.doi.org/10.1002/cne.23759.
Raaphorst, J., de Visser, M., Linssen, W.H., de Haan, R.J., Schmand, B., 2010. The
cognitive prole of amyotrophic lateral sclerosis: a meta-analysis. Amyotroph.
Lateral Scler. 11, 2737.
Rakhit, R., Cunningham, P., Furtos-Matei, A., Dahan, S., Qi, X.-F., Crow, J.P.,
Cashman, N.R., Kondejewski, L.H., Chakrabartty, A., 2002. Oxidation-induced
misfolding and aggregation of superoxide dismutase and its implications for
amyotrophic lateral sclerosis. J. Biol. Chem. 277, 4755147556.
Ralph, G.S., Radcliffe, P.A., Day, D.M., Carthy, J.M., Leroux, M.A., Lee, D.C., Wong, L.F.,
Bilsland, L.G., Greensmith, L., Kingsman, S.M., Mitrophanous, K.A., Mazarakis,
N.D., Azzouz, M., 2005. Silencing mutant SOD1 using RNAi protects against
neurodegeneration and extends survival in an ALS model. Nat. Med. 11,
429433.
Renton, A.E., Majounie, E., Waite, A., Simn-Snchez, J., Rollinson, S., Gibbs, J.R.,
Schymick, J.C., Laaksovirta, H., van Swieten, J.C., Myllykangas, L., Kalimo, H.,
Paetau, A., Abramzon, Y., Remes, A.M., Kaganovich, A., Scholz, S.W., Duckworth,
J., Ding, J., Harmer, D.W., Hernandez, D.G., Johnson, J.O., Mok, K., Ryten, M.,
Trabzuni, D., Guerreiro, R.J., Orrell, R.W., Neal, J., Murray, A., Pearson, J., Jansen,
I.E., Sondervan, D., Seelaar, H., Blake, D., Young, K., Halliwell, N., Callister, J.B.,
Toulson, G., Richardson, A., Gerhard, A., Snowden, J., Mann, D., Neary, D., Nalls,
M.A., Peuralinna, T., Jansson, L., Isoviita, V.M., Kaivorinne, A.L., Hltt-Vuori, M.,
Ikonen, E., Sulkava, R., Benatar, M., Wuu, J., Chi, A., Restagno, G., Borghero, G.,
Sabatelli, M., ITALSGEN Consortium, Heckerman, D., Rogaeva, E., Zinman, L.,
Rothstein, J.D., Sendtner, M., Drepper, C., Eichler, E.E., Alkan, C., Abdullaev, Z.,
Pack, S.D., Dutra, A., Pak, E., Hardy, J., Singleton, A., Williams, N.M., Heutink, P.,
Pickering-Brown, S., Morris, H.R., Tienari, P.J., Traynor, B.J., 2011. A
hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome
9p21-linked ALS-FTD. Neuron 72, 257268.
Rhoads, T.W., Lopez, N.I., Zollinger, D.R., Morr, J.T., Arbogast, B.L., Maier, C.S.,
DeNoyer, L., Beckman, J.S., 2011. Measuring copper and zinc superoxide
dismutase from spinal cord tissue using electrospray mass spectrometry. Anal.
Biochem. 415, 5258.
Robberecht, W., Philips, T., 2013. The changing scene of amyotrophic lateral
sclerosis. Nat. Rev. Neurosci. 14, 248264.

23

Robillard, J.M., Gordon, G.R., Choi, H.B., Christie, B.R., MacVicar, B.A., 2011.
Glutathione restores the mechanism of synaptic plasticity in aged mice to that
of the adult. PLoS ONE 6, pe20676.
Rosen, D.R., Siddique, T., Patterson, D., Figlewicz, D.A., Sapp, P., Hentati, A.,
Donaldson, D., Goto, J., ORegan, J.P., Deng, H.X., Rahmani, Z., Krizus, A.,
McKenna-Yasek, D., Cayabyab, A., Gaston, S.M., Berger, R., Tanzi, R.E., Halperin,
J.J., Herzfeldt, B., Van Den Bergh, R., Hung, W.Y., Bird, T., Deng, G., Mulder, D.W.,
Smyth, C., Laing, N.G., Soriano, E., Pericak-Vance, M.A., Haines, J., Rouleau, G.A.,
Gusella, J.S., Horvitz, H.R., Brown Jr., R.H., 1993. Mutations in Cu/Zn superoxide
dismutase gene are associated with familial amyotrophic lateral sclerosis.
Nature 362, 5962.
Rothstein, J.D., Van Kammen, M., Levey, A.I., Martin, L.J., Kuncl, R.W., 1995.
Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral
sclerosis. Ann. Neurol. 38, 7384.
Rothstein, J.D., 2009. Current hypotheses for the underlying biology of
amyotrophic lateral sclerosis. Ann. Neurol. 65 (Suppl, 1), S3S9.
Saba, L., Viscomi, M.T., Caioli, S., Pignataro, A., Bisicchia, E., Pieri, M., Molinari, M.,
Ammassari-Teule, M., Zona, C., 2015. Altered functionality, morphology, and
vesicular glutamate transporter expression of cortical motor neurons from a
presymptomatic mouse model of amyotrophic lateral sclerosis. Cereb. Cortex.,
pii: bhu317. [Epub ahead of print].
Sanelli, T., Ge, W., Leystra-Lantz, C., Strong, M.J., 2007. Calcium mediated
excitotoxicity in neurolament aggregate-bearing neurons in vitro is NMDA
receptor dependant. J. Neurol. Sci. 256, 3951.
Santhosh, J., Bhatia, M., Sahu, S., Anand, S., 2004. Quantitative EEG analysis for
assessment to plan a task in amyotrophic lateral sclerosis patients: a study of
executive functions (planning) in ALS patients. Brain. Res. Cogn. Brain. Res. 22,
5966.
Sapp, P.C., Hosler, B.A., McKenna-Yasek, D., Chin, W., Gann, A., Genise, H.,
Gorenstein, J., Huang, M., Sailer, W., Schefer, M., Valesky, M., Haines, J.L.,
Pericak-Vance, M., Siddique, T., Horvitz, H.R., Brown Jr., R.H., 2003.
Identication of two novel loci for dominantly inherited familial amyotrophic
lateral sclerosis. Am. J. Hum. Genet. 73, 397403.
Schlief, M.L., Craig, A.M., Gitlin, J.D., 2005. NMDA receptor activation mediates
copper homeostasis in hippocampal neurons. J. Neurosci. 25, 239246.
Schlief, M.L., Gitlin, J.D., 2006. Copper homeostasis in the CNS: a novel link
between the NMDA receptor and copper homeostasis in the hippocampus.
Mol. Neurobiol. 33, 8190.
Schreiber, H., Gaigalat, T., Wiedemuth-Catrinescu, U., Graf, M., Uttner, I., Muche, R.,
Ludolph, A.C., 2005. Cognitive function in bulbar- and spinal-onset
amyotrophic lateral sclerosis. A longitudinal study in 52 patients. J. Neurol.
252, 772781.
Schtz, B., 2005. Imbalanced excitatory to inhibitory synaptic input precedes
motor neuron degeneration in an animal model of amyotrophic lateral
sclerosis. Neurobiol. Dis. 20, 131140.
Sensi, S.L., Paoletti, P., Koh, J.Y., Aizenman, E., Bush, A.I., Hershnkel, M., 2011. The
neurophysiology and pathology of brain zinc. J. Neurosci. 31, 1607616085.
Sgobio, C., Trabalza, A., Spalloni, A., Zona, C., Carunchio, I., Longone, P.,
Ammassari-Teule, M., 2008. Abnormal medial prefrontal cortex connectivity
and defective fear extinction in the presymptomatic G93A SOD1 mouse model
of ALS. Genes Brain Behav. 7, 427434.
Sharma, K.R., Saigal, G., Maudsley, A.A., Govind, V., 2011. 1HMRS of basal ganglia
and thalamus in amyotrophic lateral sclerosis. NMR Biomed. 24,
12701276.
Shaw, P.J., Ince, P.G., 1997. Glutamate, excitotoxicity and amyotrophic lateral
sclerosis. J. Neurol. 244, S3S14.
Shibata, N., 2001. Transgenic mouse model for familial amyotrophic lateral
sclerosis with superoxide dismutase-1 mutation. Neuropathology 21,
8292.
Sieben, A., Van Langenhove, T., Engelborghs, S., Martin, J.J., Boon, P., Cras, P., De
Deyn, P.P., Santens, P., Van Broeckhoven, C., Cruts, M., 2012. The genetics and
neuropathology of frontotemporal lobar degeneration. Acta Neuropathol. 124,
353372.
Sillevis Smitt, P.A., Mulder, T.P., Verspaget, H.W., Blaauwgeers, H.G., Troost, D., de
Jong, J.M., 1994. Metallothionein in amyotrophic lateral sclerosis. Biol. Signals
3, 193197.
Smith, A.P., Lee, N.M., 2007. Role of zinc in ALS. Amyotroph. Lateral Scler. 3,
131143.
Spalloni, A., Albo, F., Ferrari, F., Mercuri, N., Bernardi, G., Zona, C., Longone, P., 2004.
Cu/Zn-superoxide dismutase (GLY93ALA) mutation alters AMPA receptor
subunit expression and function and potentiates kainate-mediated toxicity in
motor neurons in culture. Neurobiol. Dis. 15, 340350.
Spalloni, A., Geracitano, R., Berretta, N., Sgobio, C., Bernardi, G., Mercuri, N.B.,
Longone, P., Ammassari-Teule, M., 2006. Molecular and synaptic changes in the
hippocampus underlying superior spatial abilities in pre-symptomatic
G93A+/+ mice overexpressing the human Cu/Zn superoxide dismutase
(Gly93ALA) mutation. Exp. Neurol. 197, 505514.
Spalloni, A., Origlia, N., Sgobio, C., Trabalza, A., Nutini, M., Berretta, N., Bernardi, G.,
Domenici, L., Ammassari-Teule, M., Longone, P., 2011. Postsynaptic alteration
of NR2A subunit and defective autophosphorylation of alphaCaMKII at
threonine-286 contribute to abnormal plasticity and morphology of upper
motor neurons in presymptomatic SOD1G93A mice, a murine model for
amyotrophic lateral sclerosis. Cereb. Cortex 21, 796805.
Spalloni, A., Nutini, M., Longone, P., 2013. Role of the N-methyl-d-aspartate
receptors complex in amyotrophic lateral sclerosis. Biochim. Biophys. Acta
1832, 312322.

24

A. Spalloni, P. Longone / Neuroscience and Biobehavioral Reviews 60 (2016) 1225

Strausak, D., Mercer, J.F., Dieter, H.H., Stremmel, W., Multhaup, G., 2001. Copper in
disorders with neurological symptoms: Alzheimers, Menkes, and Wilson
diseases. Brain Res. Bull. 55, 175185.
Stewart, H.G., Andersen, P.M., Eisen, A., Weber, M., 2006. Corticomotoneuronal
dysfunction in ALS patients with different SOD1 mutations. Clin. Neurophysiol.
117, 18501861.
Strong, M.J., Grace, G.M., Orange, J.B., Leeper, H.A., Menon, R., Aere, C., 1999. A
prospective study of cognitive impairment in ALS. Neurology 53, 16651670.
Strong, M., Rosenfeld, J., 2003. Amyotrophic lateral sclerosis: a review of current
concepts. Amyotroph. Lateral Scler. Other Motor Neuron Disord. 4,
136143.
Strong, M.J., Grace, G.M., Freedman, M., Lomen-Hoerth, C., Woolley, S., Goldstein,
L.H., Murphy, J., Shoesmith, C., Rosenfeld, J., Leigh, P.N., Bruijn, L., Ince, P.,
Figlewicz, D., 2009. Consensus criteria for the diagnosis of frontotemporal
cognitive and behavioural syndromes in amyotrophic lateral sclerosis.
Amyotroph. Lateral Scler. 10, 131146.
Strong, M.J., Yang, W., 2011. The frontotemporal syndromes of ALS,
clinicopathological correlates. J. Mol. Neurosci. 45, 648655.
Stys, P.K., You, H., Zamponi, G.W., 2012. Copper-dependent regulation of NMDA
receptors by cellular prion protein: implications for neurodegenerative
disorders. J. Physiol. 590, 13571368.
Sudo, S., Fukutani, Y., Matsubara, R., Sasaki, K., Shiozawa, M., Wada, Y., Naiki, H.,
Isaki, K., 2002. Motor neuron disease with dementia combined with
degeneration of striatonigral and pallidoluysian systems. Acta Neuropathol.
103, 521525.
Tamaoka, A., Arai, M., Itokawa, M., Arai, T., Hasegawa, M., Tsuchiya, K., Takuma, H.,
Tsuji, H., Ishii, A., Watanabe, M., Takahashi, Y., Goto, J., Tsuji, S., Akiyama, H.,
2010. TDP-43 M337 V mutation in familial amyotrophic lateral sclerosis in
Japan. Intern. Med. 49, 331334.
Tamano, H., Takeda, A., 2011. Dynamic action of neurometals at the synapse.
Metallomics 3, 656661.
Tamura, N., Kuwabara, S., Misawa, S., Kanai, K., Nakata, M., Sawai, S., Hattori, T.,
2006. Increased nodal persistent Na+ currents in human neuropathy and motor
neuron disease estimated by latent addition. Clin. Neurophysiol. 117,
24512458.
Tarabal, O., Calder, J., Casas, C., Oppenheim, R.W., Esquerda, J.E., 2005. Protein
retention in the endoplasmic reticulum, blockade of programmed cell death
and autophagy selectively occur in spinal cord motoneurons after glutamate
receptor-mediated injury. Mol. Cell. Neurosci. 29, 283298.
Terao, S., Li, M., Hashizume, Y., Mitsuma, T., Sobue, G., 1999. No transneuronal
degeneration between human cortical motor neurons and spinal motor
neurons. J. Neurol. 246, 6162.
Texid, L., Hernndez, S., Martn-Satu, M., Povedano, M., Casanovas, A., Esquerda,
J., Marsal, J., Solsona, C., 2011. Sera from amyotrophic lateral sclerosis patients
induce the non-canonical activation of NMDA receptors in vitro. Neurochem.
Int. 59, 954964.
Thielsen, K.D., Moser, J.M., Schmitt-John, T., Jensen, M.S., Jensen, K., Holm, M.M.,
2013. The wobbler mouse model of amyotrophic lateral sclerosis (ALS)
displays hippocampal hyperexcitability, and reduced number of interneurons,
but not presynaptic vesicle release impairments. PLOS ONE 8, e82767.
Thomsen, G.M., Gowing, G., Latter, J., Chen, M., Vit, J.P., Staggenborg, K., Avalos, P.,
Alkaslasi, M., Ferraiuolo, L., Likhite, S., Kaspar, B.K., Svendsen, C.N., 2014.
Delayed disease onset and extended survival in the SOD1G93A rat model of
amyotrophic lateral sclerosis after suppression of mutant SOD1 in the motor
cortex. J. Neurosci. 34, 1558715600.
Tiwari, A., Liba, A., Sohn, S.H., Seetharaman, S.V., Bilsel, O., Matthews, C.R., Hart, P.J.,
Selverstone Valentine, J., Hayward, L.J., 2009. Metal deciency increases
aberrant hydrophobicity of mutant superoxide dismutases that cause
amyotrophic lateral sclerosis. J. Biol. Chem. 284, 2774627758.
Toyoshima, Y., Piao, Y.S., Tan, C.F., Morita, M., Tanaka, M., Oyanagi, K., Okamoto, K.,
Takahashi, H., 2003. Pathological involvement of the motor neuron system and
hippocampal formation in motor neuron disease-inclusion dementia. Acta
Neuropathol. 106, 5056.
Tokuda, E., Ono, S., Ishige, K., Naganuma, A., Ito, Y., Suzuki, T., 2007.
Metallothionein proteins expression, copper and zinc concentrations, and lipid
peroxidation level in a rodent model for amyotrophic lateral sclerosis.
Toxicology 229, 3341.
Tokuda, E., Okawa, E., Ono, S., 2009. Dysregulation of intracellular copper
trafcking pathway in a mouse model of mutant copper/zinc superoxide
dismutase-linked familial amyotrophic lateral sclerosis. J. Neurochem. 111,
181191.
Tokuda, E., Okawa, E., Watanabe, S., Ono, S., Marklund, S.L., 2013. Dysregulation of
intracellular copper homeostasis is common to transgenic mice expressing
human mutant superoxide dismutase-1s regardless of their copper-binding
abilities. Neurobiol. Dis. 54, 308319.
Trotti, D., Rolfs, A., Danbolt, N.C., Brown Jr., R.H., Hediger, M.A., 1999. SOD1
mutants linked to amyotrophic lateral sclerosis selectively inactivate a glial
glutamate transporter. Nat. Neurosci. 2, 427433.
Tsuda, H., Han, S.M., Yang, Y., Tong, C., Lin, Y.Q., Mohan, K., Haueterm, C., Zoghbim,
A., Haratim, Y., Kwan, J., Miller, M.A., Bellen, H.J., 2008. The amyotrophic lateral
sclerosis 8 protein VAPB is cleaved, secreted, and acts as a ligand for Eph
receptors. Cell 133, 963977.
Urbani, A., Belluzzi, O., 2000. Riluzole inhibits the persistent sodium current in
mammalian CNS neurons. Eur. J. Neurosci. 12, 35673574.
Urushitani, M., Shimohama, S., Kihara, T., Sawada, H., 1998. Mechanism of selective
motor neuronal death after exposure of spinal cord to glutamate: involvement

of glutamate-induced nitric oxide in motor neuron toxicity and nonmotor

neuron protection. Ann. Neurol. 4, 796807.
Vance, C., Al-Chalabi, A., Ruddy, D., Smith, B.N., Hu, X., Sreedharan, J., Siddique, T.,
Schelhaas, H.J., Kusters, B., Troost, D., Baas, F., de Jong, V., Shaw, C.E., 2006.
Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked
to a locus on chromosome 9p13.2-21.3. Brain 129, 868876.
Vance, C., Rogelj, B., Hortobgyi, T., De Vos, K.J., Nishimura, A.L., Sreedharan, J., Hu,
X., Smith, B., Ruddy, D., Wright, P., Ganesalingam, J., Williams, K.L., Tripathi, V.,
Al-Saraj, S., Al-Chalabi, A., Leigh, P.N., Blair, I.P., Nicholson, G., de Belleroche, J.,
Gallo, J.M., Miller, C.C., Shaw, C.E., 2009. Mutations in FUS, an RNA processing
protein, cause familial amyotrophic lateral sclerosis type 6. Science 323,
12081211.
Van Damme, P., Veldink, J.H., van Blitterswijk, M., Corveleyn, A., van Vught, P.W.J.,
Thijs, V., Dubois, B., Matthijs, G., van den Berg, L.H., Robberecht, W., 2011.
Expanded ATXN2 CAG repeat size in ALS identies genetic overlap between
ALS and SCA2. Neurology 76, 20662072.
Van Den Bosch, L., Van Damme, P., Bogaert, E., Robberecht, W., 2006. The role of
excitotoxicity in the pathogenesis of amyotrophic lateral sclerosis. Biochim.
Biophys. Acta 1762, 10681082.
Van der Graaff, M.M., de Jong, J.M., Baas, F., de Visser, M., 2009. Upper motor
neuron and extra-motor neuron involvement in amyotrophic lateral sclerosis:
a clinical and brain imaging review. Neuromuscul. Disord. 19, 5358.
Van Es, M.A., Dahlberg, C., Birve, A., Veldink, J.H., van den Berg, L.H., Andersen, P.M.,
2010. Large-scale SOD1 mutation screening provides evidence for genetic
heterogeneity in amyotrophic lateral sclerosis. J. Neurol. Neurosurg. Psychiatry
81, 562566.
Van Zundert, B., Peuscher, M.H., Hynynen, M., Chen, A., Neve, R.L., Brown Jr., R.H.,
Constantine-Paton, M., Bellingham, M.C., 2008. Neonatal neuronal circuitry
shows hyperexcitable disturbance in a mouse model of the adult-onset
neurodegenerative disease amyotrophic lateral sclerosis. J. Neurosci. 28,
1086410874.
Viles, J.H., Klewpatinond, M., Nadal, R.C., 2008. Copper and the structural biology of
the prion protein. Biochem. Soc. Trans. 36 (Pt 6), 12881292.
Volianskis, A., France, G., Jensen, M.S., Bortolotto, Z.A., Jane, D.E., Collingridge, G.L.,
2015. Long-term potentiation and the role of N-methyl-d-aspartate receptors.
Brain Res., http://dx.doi.org/10.1016/j.brainres.2015.01.016.
Vucic, S., Nicholson, G.A., Kiernan, M.C., 2008. Cortical hyperexcitability may
precede the onset of familial amyotrophic lateral sclerosis. Brain 131,
15401550.
Vucic, S., 2009a. Corticomotoneuronal dysfunction: a process specic to
amyotrophic lateral sclerosis? Clin. Neurophysiol. 120, 18811882.
Vucic, S., Kiernan, M., 2009b. Pathophysiology of degeneration in familial
amyotrophic lateral sclerosis. Curr. Mol. Med. 9, 255272.
Vucic, S., Cheah, B.C., Kiernan, M.C., 2009a. Dening the mechanisms that underlie
cortical hyperexcitability in amyotrophic lateral sclerosis. Exp. Neurol. 220,
177182.
Vucic, S., Ziemann, U., Eisen, A., Hallett, M., Kiernan, M.C., 2013. Transcranial
magnetic stimulation and amyotrophic lateral sclerosis: pathophysiological
insights. J. Neurol. Neurosurg. Psychiatry 84, 11611170.
Wainger, B.J., Kiskinis, E., Mellin, C., Wiskow, O., Han, S.S., Sandoe, J., Perez, N.P.,
Williams, L.A., Lee, S., Boulting, G., Berry, J.D., Brown Jr., R.H., Cudkowicz, M.E.,
Bean, B.P., Eggan, K., Woolf, C.J., 2014. Intrinsic membrane hyperexcitability of
amyotrophic lateral sclerosis patient-derived motor neurons. Cell Rep. 7, 111.
Weihl, C.C., Pestronk, A., Kimonis, V.E., 2009. Valosin-containing protein disease:
inclusion body myopathy with Pagets disease of the bone and fronto-temporal
dementia. Neuromuscul. Disord. 19, 308315.
Weiser, T., Wienrich, M., 1996. The effects of copper ions on glutamate receptors in
cultured rat cortical neurons. Brain Res. 742, 211218.
Wengenack, T.M., Holasek, S.S., Montano, C.M., Gregor, D., Curran, G.L., Poduslo, J.F.,
2004. Activation of programmed cell death markers in ventral horn motor
neurons during early presymptomatic stages of amyotrophic lateral sclerosis
in a transgenic mouse model. Brain Res. 1027, 7386.
Wicks, P., Abrahams, S., Papps, B., Al-Chalabi, A., Shaw, C.E., Leigh, P.N., Goldstein,
L.H., 2009. SOD1 and cognitive dysfunction in familial amyotrophic lateral
sclerosis. J. Neurol. 256, 234241.
Williams, K.L., Fita, J.A., Vucic, S., Durnall, J.C., Kiernan, M.C., Blair, I.P., Nicholson,
G.A., 2013. Pathophysiological insights into ALS with C9ORF72 expansions. J.
Neurol. Neurosurg. Psychiatry 84, 931935.
Wilson, C.M., Grace, G.M., Munoz, D.G., He, B.P., Strong, M.J., 2001. Cognitive
impairment in sporadic ALS: a pathologic continuum underlying a
multisystem disorder. Neurology 57, 651657.
Witgert, M., Salamone, A.R., Strutt, A.M., Jawaid, A., Massman, P.J., Bradshaw, M.,
Mosnik, D., Appel, S.H., Schulz, P.E., 2010. Frontal-lobe mediated behavioral
dysfunction in amyotrophic lateral sclerosis. Eur. J. Neurol. 17, 103110.
Wooley, C.M., Sher, R.B., Kale, A., Frankel, W.N., Cox, G.A., Seburn, K.L., 2005. Gait
analysis detects early changes in transgenic SOD1(G93A) mice. Muscle Nerve
32, 4350.
Xie, Y., Zhou, B., Lin, M.Y., Wang, S., Foust, K.D., Sheng, Z.H., 2015. Endolysosomal
decits augment mitochondria pathology in spinal motor neurons of
asymptomatic fALS mice. Neuron 87, 355370.
Yang, W.W., Sidman, R.L., Taksir, T.V., Treleaven, C.M., Fidler, J.A., Cheng, S.H.,
Dodge, J.C., Shihabuddin, L.S., 2011. Relationship between neuropathology and
disease progression in the SOD1(G93A) ALS mouse. Exp. Neurol. 227, 287295.
Yashiro, K., Philpot, B.D., 2008. Regulation of NMDA receptor subunit expression
and its implications for LTD, LTP, and metaplasticity. Neuropharmacology 55,
10811094.

A. Spalloni, P. Longone / Neuroscience and Biobehavioral Reviews 60 (2016) 1225

Yasvoina, M.V., Genc, B., Jara, J.H., Sheets, P.L., Quinlan, K.A., Milosevic, A.,
Shepherd, G.M.G., Heckman, C.J.P., Hande zdinler, P.A., 2013. eGFP expression
under UCHL1 promoter genetically labels corticospinal motor neurons and a
subpopulation of degeneration-resistant spinal motor neurons in an ALS
mouse model. J. Neurosci. 33, 78907904.
Zanette, G., Tamburin, S., Manganotti, P., Refatti, N., Forgione, A., Rizzuto, N., 2002.
Different mechanisms contribute to motor cortex hyperexcitability in
amyotrophic lateral sclerosis. Clin. Neurophysiol. 113,
16881697.

25

Zang, D.W., Cheema, S.S., 2002. Degeneration of corticospinal and bulbospinal

systems in the superoxide dismutase1(G93A G1H) transgenic mouse model of
familial amyotrophic lateral sclerosis. Neurosci. Lett. 332, 99102.
Zhao, P., Ignacio, S., Beattie, E.C., Abood, M.E., 2008. Altered presymptomatic AMPA
and cannabinoid receptor trafcking in motor neurons of ALS model mice:
implications for excitotoxicity. Eur. J. Neurosci. 27, 572579.
Zona, C., Siniscalchi, A., Mercuri, N.B., Bernardi, G., 1998. Riluzole interacts with
voltage-activated sodium and potassium currents in cultured rat cortical
neurons. Neuroscience 85, 931938.