Neurochem Res
DOI 10.1007/s11064-017-2239-3
ORIGINAL PAPER
A Mesiotemporal Lobe Epilepsy Mouse Model
Duveau Venceslas1 · Roucard Corinne1 
Received: 27 December 2016 / Revised: 16 March 2017 / Accepted: 16 March 2017
© Springer Science+Business Media New York 2017
Abstract  Among the different forms of epilepsies, mesi-
otemporal lobe epilepsy (MTLE) is one of the most com-
mon and represents the main pharmaco-resistant form of
epilepsy. There is therefore an urgent need to better under-
stand this form of epilepsy to develop better anti-epileptic
drugs. Many rodent models are mimicking some aspects of
the human temporal lobe epilepsy but only few are address-
ing most of the human mesiotemporal lobe epilepsy. In this
article, we describe the main characteristics of a mouse of
model of mesial temporal lobe epilepsy. This model is gen-
erated by a single injection of kainic acid into the dorsal
hippocampus which reproduces most of the morphologi-
cal and electrophysiological features of human MTLE in
a mouse. This model may help to better understand mesial
temporal lobe epilepsy and the development of new thera-
peutic drugs.
Keywords  Mouse models · Epileptic discharges · Kainic
acid · Hippocampus
Introduction
Mesiotemporal lobe epilepsy (MTLE) represents one of the
most common form of focal epilepsies [1]. In this type of
focal epilepsy, seizures arise from the temporal lobe and
are accompanied by mild clinical signs [2–4]. This form of
epilepsy represents as well the most common form of phar-
macoresistant epilepsy [2].
* Duveau Venceslas
vduveau@synapcell.fr
1
SynapCell SAS, Bâtiment Biopolis, 5 Avenue du Grand
Sablon, 38700 La Tronche, France
MTLE Semiology
The classical clinical history of MTLE patients is stereo-
typic and can be divided into three main phases [2].
First, an initial precipitating injury occurs in most of the
cases in early childhood within the first 2 or 3 years of life
[5] but also in some cases in adulthood. These injuries are
often prolonged convulsive febrile seizures or status epi-
lepticus (SE) happening during the early childhood, but as
well head trauma, intracerebral infection, or ischemia epi-
sodes [2, 6] in adulthood.
Second, this initial event is then followed by a latent
phase lasting several years. This period is also known as
the epileptogenesis phase, i.e. the process by which the
brain becomes epileptic. During this phase, a sequence of
events occur leading to the appearance of the first sponta-
neous seizures.
Third, the appearance of spontaneous recurrent seizures
is the indicator of the chronic phase of the disease, which
starts usually in adolescence or early adulthood. Mesio-
temporal recurrent seizures remain stereotyped along the
patients’ life with no aggravation with age [2, 4].
Histological Alterations
Histological analysis of the resected tissue from MTLE
patients shows a typical pathophysiology. The most well-
known is the cell death of pyramidal cells of the Cornu
ammoni (CA) CA1, CA3 and hilus also known as hip-
pocampal sclerosis (HS) [7] (Fig.  1a, b) as well as a loss
of a subpopulation of GABAergic interneurons (those
containing somatostatin and neuropeptide Y) [8]. This HS
is recognized as the most commonly encountered patho-
logical substrate of refractory temporal lobe seizures [2, 9].
13
Vol.:(0123456789)

Fig. 1  Histopathological alterations observed in the hippocampus
of MTLE patients and MTLE mouse. a Control hippocampus where
all the different fields of the hippocampus can be seen. b Epileptic
hippocampus, cell loss in the CA1 and CA3 is observed as well as a
dispersion of the granule cell layer (adapted from Houser C. 1990
Other discrete lesions can also be observed in the amygdala
and parahippocampal gyrus. Associated to this cell death
an astrogliosis is observed in the epileptic focus [10]. In
addition to the HS, another specific histological feature is
observed in 45–75% of MTLE patients: the dispersion of
the granule cells of the dentate gyrus also named the gran-
ule cell dispersion (GCD) [11, 12]. The dentate gyrus in
normal condition is composed of two well defined layers
of granule cells tightly packed together. In the epileptic
hippocampus, the boundaries of the dentate gyrus’s layers
are more difficult to define and the overall dentate gyrus is
enlarged. The shape of the granule cells changes as well,
they increase in size and display an elongated, bipolar shape
with processes extending vertically within the molecular
layer [11, 12]. Along with the HS and GCD a remodeling
of the hippocampus is observed. In a normal hippocam-
pus, mossy cells provide glutamatergic inputs to the inner
molecular layer of the DG. In the epileptic hippocampus
with HS, the loss of hilar neurons leads to a deafferentation
of the granule cell dendrites in the inner molecular layer.
The surviving neurons (granule cells and some inhibitory
neurons) sprout axon collaterals and re-innervate empty
synaptic sites, with functional connections, giving rise to
abnormal hippocampal circuitry. Excitatory granule cell
13
Neurochem Res
[11]). c and d Contralateral and ipsilateral hippocampi in the MTLE
mouse model. Similarly, to the human sample a cell death is observed
in the CA3 and CA1 along with a dispersion of the granule cell layer.
DG dentate gyrus, CA1 Cornu Ammonis 1, CA3 Cornu Ammonis 3.
adapted from [24]
mossy fibers are found to sprout into the inner molecular
layer (supragranular zone of the DG) of epileptic patients
with HS [11, 13–15]. Mossy fibers establish new synaptic
connections with granule cell bodies and dendrites, which
forms recurrent excitatory circuits. The amount of mossy
fiber sprouting appears to correlate with histories of initial
events [13], seizure frequency [15], and with severity of
neuronal loss in the hilus [11].
Electroencephalographic (EEG) Data
On scalp EEG, the interictal EEG hallmark of MTLE is
typically the occurrence of unilateral spikes and spike-
and-waves over the anterior-mesial-temporal region.
These EEG abnormalities can occur in isolation or
grouped in short interictal epileptiform discharges [2]
(Fig. 2). Interictal EEG abnormalities usually occur ipsi-
laterally to the side of spontaneous seizure onset and HS
[4]. However, similar abnormalities can also be recorded
independently from both mesial temporal areas, even
though spontaneous seizures usually are generated from
only one side [2, 4]. Intracerebral electrodes and ste-
reoEEG (SEEG) recordings reveal numerous interictal
Neurochem Res
Fig. 2  Hippocampal epileptic
discharges recorded in human
(a) and in the MTLE mouse
model (b) # Courtesy of O.
David (Grenoble Institut des
Neurosciences), L. Minotti and
P. Kahane (CHU Grenoble)
spikes that are predominantly recorded in mesial struc-
tures, mainly in the hippocampus [16]. Spikes sometimes
group to give rise to long pseudo-rhythmic discharges.
Depth EEG recordings or stereo-EEG (SEEG) reveal
that the scalp EEG changes are preceded by long peri-
ods of ictal discharges in the mesial temporal structures,
often associated with the aura. Ictal changes on the scalp
EEG are usually not observed until after there is sufficient
propagation to produce impairment of consciousness and
other observable clinical features of the complex partial
seizure. Globally, two different patterns of temporal lobe
seizure onset are frequently recorded in SEEG: one con-
sists of focal “hypersynchronous” and slow discharge of
rhythmic spikes whereas the other pattern begins with
regional low-voltage fast activity [2, 8]. The “hyper-
synchronous” discharge arises in the hippocampus and
is subsequently followed by the development of a high-
frequency low-amplitude discharge [3]. This discharge is
followed by rhythmic spikes or slow waves, which pro-
gressively give rise to an activity of increasing amplitude,
and decreasing frequency. The initial “hypersynchronous”
discharges are usually restricted to the hippocampus and
adjacent structures, and either have no clinical correlate
or correspond to auras. Transition to the high-frequency
low-voltage ictal discharge appears concomitantly with
the spread of the seizure, which subsequently results in
clinical manifestations. Ictal electrical discharges com-
monly spread to the ipsilateral neocortical region and can
propagate to the contralateral mesio-temporal lobe, con-
comitantly with impairment of consciousness [2]. On the
contrary, the low-voltage fast activity onset is more com-
monly seen from the neocortex [2, 3, 17].
Despite the development of many antiepileptic drugs
(AEDs) over the last decades, still 30% of the epileptic
patients does not respond to AEDs. Among these pharma-
coresistant patients a large majority suffers from tempo-
ral lobe epilepsy. One alternative to the pharmacological
treatment is the surgery. Indeed, MTLE is a so-called
“surgical remediable syndrome” however candidates for
such a surgery are few and this technique remains inva-
sive and with risks.
Modelling MTLE in Animals: What is Critical?
In a recent survey performed by the team of Antoine
Depaulis, the opinion of 83 neurologists, with clinical
expertise in epilepsy, from 33 different European coun-
tries about the features of MTLE that are critical to be
seen in an animal model was collected [18]. The most rel-
evant features in a MTLE model for clinicians are:
• The recurrence of focal seizures with mild behav-
ioural manifestations
• The same brain structures involved
• The same histopathology
It is also important to note that the EEG pattern, the
existence of a latent period and a similar pharmacology
were as well mentioned as critical.
The MTLE Mouse Model
The MTLE mouse model is generated by the unilateral
injection of a single low dose (1 nmole) of kainic acid
(KA) into the dorsal hippocampus of adult mice [19]. In
the MTLE syndrome, depth EEG recording is mandatory
to record focal seizures; mice are also implanted with a
bipolar electrode into the ipsilateral hippocampus at the
proximity of the injection site [20, 21].
Similarly, to the human condition, the intrahippocam-
pal injection of KA leads to three consecutives phases:
13

The Status Epilepticus (The Initial Event)
The intrahippocampal injection of 1 nmole of KA leads
to a focal SE that starts upon awakening from anesthesia
and lasts for up to 20–22 h [20, 22]. Animals display dur-
ing this phase asymmetric mild chronic movements of the
forelimbs, clonic deviations of the head, rotations, and/or
immobilization [20, 21]. EEG recording of the SE shows
seizure activity consisting of regular, continuous or sub
continuous spikes, polyspikes and spike-and-wave con-
comitant to this characteristic behavior in both the ipsi and
contralateral hippocampi [22]. Generalized discharges of
spikes and polyspikes associated with generalized clonic
seizures of the forelimbs can be observed in some cases
[20].
The Latent Period or Epileptogenesis Phase
The SE is followed by a 2–3 week period during which the
activity of the injected hippocampus changes with time
[20].
Daily EEG recordings during this period revealed EEG
patterns evolving rapidly in the ipsilateral hippocampus.
Fig. 3  Electroencephalographic recordings from NaCl injected—
(left) and kainate—(KA, right) injected hippocampi in freely mov-
ing C57Bl6/j mice. 28 days after NaCl injection, hippocampal LFP
recording did not show any epileptic activities whereas in the KA
Table 1  Evolution of the W3 W4
number of HPD in the MTLE
mouse model from 3 to 10 Nb of 39.3 ± 3.3 37.1 ± 3.4 37.8 ± 2.8 37.6 ± 1.3 40.7 ± 2.3 37 ± 3.9 40.3 ± 2.5 34.7 ± 4.8
weeks post-KA injection, the HPDs
number of HPD remains stable /h ± SEM
over the 8 weeks post-KA
N 9 14
injection
13
Neurochem Res
First, the hippocampal theta oscillation is replaced by a low-
voltage background during the first days after KA injection.
Second, sporadic hippocampal spikes are observed which
progressively become organized in short hippocampal dis-
charges. These hippocampal discharges increased in spikes
and in duration to finally formed hippocampal paroxysmal
discharge (HPD). These discharges remain localized to the
epileptic (ipsilateral) hippocampus, no paroxystic activity
is observed in the cerebral cortex [20, 21, 23].
The Recurrent Phase and EEG Characteristics
By the end of the epileptogenesis phase, animals dis-
play spontaneous recurrent seizures and enter the chronic
phase of the epilepsy. Hippocampal paroxysmal discharges
(HPD) consist of slow rhythmic high-voltage sharp waves,
followed by a higher frequency and lower-amplitude dis-
charge of spikes and poly-spikes without any paroxysmal
activity on the cortical derivation (Fig. 3). In rare cases sec-
ondarily generalized seizures occur [20, 23, 24] (Fig. 2).
Once the HPD are established, HPD remain similar
during the rest of the life of the animals (up to 6 months)
(Table  1) with a similar pattern as seen at the end of the
injected mice, the signal displays a series of spontaneous hippocam-
pal paroxysmal discharges (HPDs) 28 days after the surgery. Adapted
from [24]
W5 W6 W7 W8 W9 W10
9 8 8 8 8 6
Neurochem Res
epileptogenesis phase. HPD occur during the state of quiet
wakefulness with an average frequency of 40 HPD per hour
[24–26].
During the recurrent phase, animals show mild behav-
ioural changes, such as behavioural arrest with mild head
nodding concomitantly with HPD in compliance with the
clinicians’ requirement to model MTLE. Because these
behaviour changes are difficult to discriminate, hippocam-
pal EEG recording is mandatory in this model [20]. A
similar observation has been made for MTLE patients
where behavioural changes are mild and EEG recording is
required to observed epileptic discharges [2].
Histopathological Features
Histological analysis of the epileptic hippocampus of the
MTLE mouse model shows a typical cell loss in the CA1
and CA3 pyramidal cell layer as well as in the hilus and
GABAergic interneurons. The rest of the hippocampus,
i.e. CA2, granule cells of the dentate gyrus do not appear
affected. Similarly the contralateral side remains intact in
this model [19, 21]. Along with the cell death a strong reac-
tive astrogliosis is observed mostly in the lesioned areas
[10, 27] (Fig. 1c, d).
The death of these cells occurs rapidly after the KA
injection and remains localized to the dorsal hippocampus
(1.5  mm from the injection site). In contrast, granule cell
dispersion is a slow and dynamic process. An enlargement
of the GCL is only seen in the ipsilateral hippocampus as
soon as 4 days post-KA injection and up to 23 weeks post-
KA injection the GCL has completely filled the space left
by the pyramidal cells of the Ammon’s horn [19, 21]. Dis-
persed granule cells display a fusiform shape with a hyper-
trophy of the somata, nucleus and proximal dendrites [23,
28, 29]. Another neuroplasticity alteration is observed, the
mossy fiber sprouting. As observed in MTLE patients, a
remodeling of the hippocampal circuits is also observed
in the MTLE mouse. In the KA-injected animals, mossy
fibers form connexions with the GCL, in the supragranu-
lar layer of the DG and also in the infrapyramidal stratum
oriens [21, 30].
Impact of Strain and Gender
The MTLE mouse model has been established in several
mouse strains. Originally, established in the C57Bl/6 mice
by Suzuki, the intrahippocampal injection of kainic acid
has been in several other strains [19]. Following this prin-
ceps article about the model, several following studies have
used the Swiss mice with a similar success in obtaining the
main characteristics of the model [20, 27]. Over the last
2 decades, several other stains have been used. In all the
strains studied, the three phases have been observed as well
as the occurrence of HPD and morphological alterations
[10]. Differences have however been observed regarding
the gender of the mice used. Twele and et al. recently com-
pared the impact of the gender in different strains on the
development of the MTLE model. They found a clear dif-
ference between males and females. In fact, in all the three
strains females did not show neither a latent period nor hip-
pocampal paroxysmal discharges, suggesting a sex differ-
ence in generating the MTLE mouse model [31].
Pharmacology of HPD in the MTLE Mouse Model
In a recent study, we investigated the effect of acute injec-
tion of nine antiepileptic drugs on the occurrence of HPD.
In line with previous studies [20, 26], we identified three
categories of AEDs [24]:
1. AEDs showing effects at high doses but associated
with gross motor impairments and/or effects on fre-
quency bands. We indeed found that acute injection
of valproate, carbamazepine and lamotrigine can sig-
nificantly decrease the occurrence of HPD in a dose-
dependent manner; however, we use higher doses than
the ones used in other animal models of epilepsy. At
these doses animals displayed behavioural alteration
such as drowsiness and reduced locomotion. A quanti-
tative EEG analysis shows as well a modification of the
interictal EEG power.
2. AEDs with significant effect on HPD at relatively high
doses with minor effect on both the behaviour and
the frequency bands. In this group, we identify leveti-
racetam and pregabalin. Acute injection of high doses
of these two drugs is necessary to significantly reduce
the occurrence of HPD but no obvious modifications
of the animals’ behavior or the interictal EEG power
spectra are observed.
3. AEDs showing a significant suppression of HPDs at
low doses. In this group fall tiagabine, vigabatrin, diaz-
epam and phenobarbital. All these drugs significantly
reduce the occurrence of HPD at similar doses used in
other epilepsy rodent models and do not show behavio-
ral or qEEG alterations.
The suppressive effect of diazepam was somewhat
expected as this compound and benzodiazepines in general
suppress seizures in almost all animal models. For exam-
ple, in amygdala or hippocampal-kindled rats, discharges
were suppressed by similar doses of diazepam used in the
present study, with limited sedative effects [32]. The large-
spectrum efficacy of benzodiazepines is also well known
13

on human practice as these compounds are generally used
to stop status epilepticus [33]. Previous data showed that
pregabalin protects against spontaneous seizures in the
lithium-pilocarpine rat model during epileptogenesis [34].
It also prevented stage 4–5 behavioral seizures in the kin-
dled rat model in a similar dose-range as in the present
study [35]. Finally, the effectiveness of vigabatrin on the
MTLE mouse model, even at low doses, strongly suggests
that this model could be predictive for the efficacy of new
compounds. Indeed, vigabatrin was shown to be effective
in animal models of MTLE [36] and, more importantly to
control patients with refractory epilepsies [37]. Unfortu-
nately, the toxicity of vigabatrin on the visual system has
strongly limited its clinical use [38].
In comparison to other models of partial seizures, higher
doses of drugs acting on voltage gated channels showed an
effect on the MTLE mouse model. In fact, in the lithium-
pilocarpine or the systemic Kainate models of epilepsy,
valproate is effective at a lower dose than in the MTLE
mouse model. Similarly, levetiracetam has shown to be
effective in chronic models of partial epilepsies (kindling
and lithium-pilocarpine models).
In comparison to the 6-Hz model, the pharmacology of
the MTLE mouse model is like the 6-Hz model but with
the highest intensity of stimulation (44 mA). In fact, simi-
lar doses of valproic acid, levetiracetam and lamotrigine are
needed to be effective in this model [39].
The MTLE mouse model shows a specific pharmacol-
ogy with a lower sensitivity to drugs acting on voltage
gated channels and a greater sensitivity to drugs acting on
the GABAergic system.
The MTLE mouse model can be used to identify new
and non-conventional targets. In fact, emerging evidences
have suggested a critical role played by neuroinflamma-
tion during epileptogenesis and possibly the occurrence
of spontaneous recurrent seizures [40]. Recent data have
shown that neuroinflammation played a key role in the
occurrence of SRS in the MTLE mouse model [10]. More-
over, compounds controlling the inflammatory response
such as dexamethasone or the IL-1β cascade (VX765) were
able to significantly reduce the number and cumulated
duration of HPD in the MTLE mouse model [25].
Altogether these data suggest a specific pharmacosensi-
tivity of the MTLE mouse model to AEDs already on the
market.
Conclusion
The MTLE mouse model recapitulates a wide-range of
characteristics observed in human MTLE. Indeed, in this
model we observed similarities in the establishment of
the disease from the initial event to the chronic phase of
13
Neurochem Res
epilepsy. Moreover, this model reproduces the electrophysi-
ological and histological characteristics of human MTLE.
References
1. Wieser HG, Häne A (2004) Antiepileptic drug treatment in sei-
zure-free mesial temporal lobe epilepsy patients with hippocam-
pal sclerosis following selective amygdalohippocampectomy.
Seizure 13:534–536
2. Engel J Jr (2001) Mesial temporal lobe epilepsy: what have we
learned? The Neuroscientist 7:340–352
3. Chabardès S, Kahane P, Minotti L et al (2005) The temporopo-
lar cortex plays a pivotal role in temporal lobe seizures. Brain
128:1818–1831
4. Santos NF, Sousa SC, Kobayashi E et  al (2002) Clinical and
genetic heterogeneity in familial temporal lobe epilepsy. Epilep-
sia 43(5):136
5. Mathern GW, Babb TL, Mischel PS et al (1996) Childhood gen-
eralized and mesial temporal epilepsies demonstrate different
amounts and patterns of hippocampal neuron loss and mossy
fibre synaptic reorganization. Brain 119(3):965–987
6. Cendes F, Andermann F, Gloor P et al (1993) Atrophy of mesial
structures in patients with temporal lobe epilepsy: cause or con-
sequence of repeated seizures? Ann Neurol 34:795–801
7. Berg AT, Mathern GW, Bronen RA et  al (2009) Frequency,
prognosis and surgical treatment of structural abnormalities seen
with magnetic resonance imaging in childhood epilepsy. Brain
132:2785–2797
8. de Lanerolle NC, Brines ML, Kim JH, et al (1992) Neurochemi-
cal remodelling of the hippocampus in human temporal lobe epi-
lepsy. Epilepsy Res 9:205–219. Discussion 220
9. Blümcke I (2009) Neuropathology of focal epilepsies: a critical
review. Epilepsy Behav 15:34–39
10. Zattoni M, Mura ML, Deprez F et al (2011) Brain infiltration of
leukocytes contributes to the pathophysiology of temporal lobe
epilepsy. J Neurosci 31:4037–4050
11. Houser CR (1990) Granule cell dispersion in the dentate gyrus
of humans with temporal lobe epilepsy. Brain Res 535:195–204
12. Lurton D, Bahh el B, Sundstrom L, Rougier A (1998) Granule
cell dispersion is correlated with early epileptic events in human
temporal lobe epilepsy. J Neurol Sci 154:133–136
13. Mathern GW, Leite JP, Babb TL et al (1996) Aberrant hippocam-
pal mossy fiber sprouting correlates with greater NMDAR2
receptor staining. Neuroreport 7:1029–1035
14. Represa A, Robain O, Tremblay E, Ben-Ari Y (1989) Hippocam-
pal plasticity in childhood epilepsy. Neurosci Lett 99:351–355
15. Sutula T, Cascino G, Cavazos J et al (1989) Mossy fiber synaptic
reorganization in the epileptic human temporal lobe. Ann Neurol
26:321–330
16. Lim SH, So NK, Lüders H et  al (1991) Etiologic factors for
unitemporal vs bitemporal epileptiform discharges. Arch Neurol
48:1225–1228
17. Velasco F, Velasco M, Jiménez F et al (2000) Predictors in the
treatment of difficult-to-control seizures by electrical stimulation
of the centromedian thalamic nucleus. Neurosurgery 47:295–304
Discussion 304–305
18. Guillemain I, Kahane P, Depaulis A (2012) Animal models
to study aetiopathology of epilepsy: what are the features to
model?. Epileptic Disord 14:217–225
19. Suzuki F, Junier M, Guilhem D, Sørensen J (1995) Morphoge-
netic effect of kainate on adult hippocampal neurons associated
with a prolonged expression of brain-derived neurotrophic factor.
Neuroscience 64(3):665–674
Neurochem Res
20. Riban V, Bouilleret V, Pham-Lê BT et  al (2002) Evolution of
hippocampal epileptic activity during the development of hip-
pocampal sclerosis in a mouse model of temporal lobe epilepsy.
Neuroscience 112:101–111
21. Bouilleret V, Loup F, Kiener T et  al (2000) Early loss of
interneurons and delayed subunit-specific changes in GABA(A)-
receptor expression in a mouse model of mesial temporal lobe
epilepsy. Hippocampus 10:305–324
22. Pernot F, Heinrich C, Barbier L et  al (2011) Inflammatory
changes during epileptogenesis and spontaneous seizures in
a mouse model of mesiotemporal lobe epilepsy. Epilepsia
52:2315–2325
23. Heinrich C, Lähteinen S, Suzuki F, et  al (2011) Increase in
BDNF-mediated TrkB signaling promotes epileptogenesis in a
mouse model of mesial temporal lobe epilepsy. Neurobiol Dis
42:35–47
24. Duveau V, Pouyatos B, Bress K, et al (2016) Differential effects
of antiepileptic drugs on focal seizures in the intrahippocampal
kainate mouse model of mesial temporal lobe epilepsy. CNS
Neurosci Ther 22:497–506
25. Maroso M, Balosso S, Ravizza T et  al (2011) Interleukin-1β
biosynthesis inhibition reduces acute seizures and drug resistant
chronic epileptic activity in mice. Neurotherapeutics 8:304–315
26. Klein S, Bankstahl M, Löscher W (2015) Inter-individual vari-
ation in the effect of antiepileptic drugs in the intrahippocampal
kainate model of mesial temporal lobe epilepsy in mice. Neurop-
harmacology 90:53–62
27. Duveau V, Fritschy J (2010) PSA-NCAM-dependent GDNF
signaling limits neurodegeneration and epileptogenesis in tempo-
ral lobe epilepsy. Eur J Neurosci 32:89–98
28. Nitta N, Heinrich C, Hirai H, Suzuki F (2008) Granule cell dis-
persion develops without neurogenesis and does not fully depend
on astroglial cell generation in a mouse model of temporal lobe
epilepsy. Epilepsia 49:1711–1722
29. Kralic JE, Ledergerber DA, Fritschy J (2005) Disruption of the
neurogenic potential of the dentate gyrus in a mouse model
of temporal lobe epilepsy with focal seizures. Eur J Neurosci
22:1916–1927
30. Twele F, Töllner K, Br C, et  al (2016) Significant effects of
sex, strain, and anesthesia in the intrahippocampal kainate
mouse model of mesial temporal lobe epilepsy. Epilepsy Behav
55:47–56
31. Otsuki K, Morimoto K, Sato K et  al (1998) Effects of lamo-
trigine and conventional antiepileptic drugs on amygdala- and
hippocampal-kindled seizures in rats. Epilepsy Res 31:101–112
32. Riss J, Cloyd J, Gates J, Collins S (2008) Benzodiazepines in
epilepsy: pharmacology and pharmacokinetics. Acta Neurol
Scand 118:69–86
33. André V, Rigoulot M, Koning E et al (2003) Long-term pregaba-
lin treatment protects basal cortices and delays the occurrence of
spontaneous seizures in the lithium-pilocarpine model in the rat.
Epilepsia 44:893–903
34. Vartanian MG, Radulovic LL, Kinsora JJ et  al (2006) Activity
profile of pregabalin in rodent models of epilepsy and ataxia.
Epilepsy Res 68:189–205
35. Nissinen J, Pitkänen A (2007) Effect of antiepileptic drugs on
spontaneous seizures in epileptic rats. Epilepsy Res 73:181–191
36. Hemming K, Maguire MJ, Hutton JL, Marson AG (2008)
Vigabatrin for refractory partial epilepsy. Cochrane Database of
Syst Rev 1:CD007302
37. Wild JM, Chiron C, Ahn H, et  al (2009) Visual field loss in
patients with refractory partial epilepsy treated with vigabatrin:
final results from an open-label, observational, multicentre study.
CNS Drugs 23:965–982
38. Leclercq K, Matagne A, Kaminski RM (2014) Low potency and
limited efficacy of antiepileptic drugs in the mouse 6 Hz corneal
kindling model. Epilepsy Res 108:675–683
39. Maroso M, Balosso S, Ravizza T et al (2010) Toll-like receptor
4 and high-mobility group box-1 are involved in ictogenesis and
can be targeted to reduce seizures. Nat Med 16:413–419
40. Stables JP, Bertram E, Dudek FE et al (2003) Therapy discovery
for pharmacoresistant epilepsy and for disease-modifying thera-
peutics: summary of the NIH/NINDS/AES models II workshop.
Epilepsia 44:1472–1478
13