Review | Disorders of the Nervous System The Kainic acid models of Temporal Lobe Epilepsy https://doi.org/10.1523/ENEURO.0337-20.2021
Cite as: eNeuro 2021; 10.1523/ENEURO.0337-20.2021 Received: 3 August 2020 Revised: 14 January 2021 Accepted: 24 January 2021
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1
2 Manuscript Title Page
3 1. Manuscript title: The Kainic acid models of Temporal Lobe Epilepsy
4 2. Abbreviated title: Kainic Acid Review in Epilepsy: Perspective
5 3. Author list:
6 • Evgeniia Rusina*1
7 • Christophe Bernard*1
8 • AdamWilliamson1,2
9 1Institute de Neurosciences des Systèmes (INS), INSERM, UMR_1106, Aix-Marseille Uni
10 versité, 27 Bd Jean Moulin 13005, Marseille, France
11 2Laboratory of Organic Electronics, Campus Norrköping, Linköping University, 581 83,
12 Norrköping, Sweden
13 4. Author contribution: AW conceived the idea; ER and CB wrote the paper; ER* and CB* are
14 equally first contributing authors.
15 5. Correspondence should be addressed to [email protected]
16 Faculté de Médecine, 27 Boulevard Jean Moulin, 13005, Marseille, France
17 6. Number of figures: 5
18 7. Number of tables: 6
19 8. Number of multimedia: 0
20 9. Number of words for abstract: 86
21 10. Number of words for significance statement: 90
22 11. Number of words for introduction: 377
23 12. Number of words for discussion: -
24 13. Acknowledgements: AW acknowledges funding from the European Research Council (ERC)
25 under the European Union’s Horizon 2020 research and innovation program (grant agreement No
26 716867). AW and ER acknowledge funding from the Excellence Initiative of Aix- Marseille Universi-
27 ty— A*MIDEX, a French “Investissements d’Avenir” program. AW acknowledges support from the
28 Knut and Alice Wallenberg Foundation.
29 14. Authors report no conflict of interests
30 15. Funding sources:
31 • Excellence Initiative of Aix- Marseille University—A*MIDEX
1
32 • European Research Council (ERC) under the European Union’s Horizon 2020 research and in-
33 novation program (grant agreement No 716867)
34 The Kainic Acid Models of Temporal Lobe Epilepsy
35
36 Evgeniia Rusina*, Christophe Bernard*, Adam Williamson
37
38
39 Institute de Neurosciences des Systèmes (INS), INSERM, UMR_1106, Aix-Marseille Université
40 Marseille, France
41 * equally contributing first authors
42 correspondance: [email protected]
43 Abstract
44
45 Experimental models of epilepsy are useful to identify potential mechanisms of epileptogenesis,
46 seizure genesis, comorbidities, and treatment efficacy. The kainic acid (KA) model is one of the
47 most commonly used. Several modes of administration of KA exist, each producing different ef-
48 fects in a strain, species, gender, and age-dependent manner. In this review, we discuss the ad-
49 vantages and limitations of the various forms of KA administration (systemic, intrahippocampal,
50 and intranasal), as well as the histological, electrophysiological, and behavioral outcomes in differ-
51 ent strains and species. We attempt a personal perspective and discuss areas where work is
52 needed. The diversity of KA models and their outcomes offers researchers a rich palette of pheno-
53 types, which may be relevant to specific traits found in patients with temporal lobe epilepsy.
54
55 Keywords: Kainic acid, Hippocampus, Mice models of temporal lobe epilepsy, EEG
56 2
57
58
59
60 Significance statement
61
62 This review aims to help researchers use a knowledge-based approach to study specific aspects
63 of human epilepsy phenotypes. We focus on the Kainic Acid model of temporal lobe epilepsy in
64 rodents, presenting it as a set of sub-models, describing the various administration routes, and the
65 differences in outcome between species, strain, age, and sex. We have reviewed more than 200
66 research articles, summarizing the data with a ready-to-use structure.
67
68 Introduction
69
70 Mesial temporal lobe epilepsy (MTLE) is the most common type of partial epilepsy in adults
71 (J.Engel, 2001). It is characterized by recurrent spontaneous seizures, often resistant to drug treat-
72 ments (Engel et al., 2012). Numerous alterations have been reported in patients with MTLE, includ-
73 ing hippocampal sclerosis (HS) and cell death (Berkovic et al., 1991), mossy fiber sprouting (Sutula
74 et al., 1989), reorganization of hippocampal interneuronal networks (Muñoz et al., 2004; Tóth et al.,
75 2010; Sloviter et al.,1991), alterations in neuropeptide signaling (Vezzani et al., 2004; Kharlamov et
76 al., 2007) and synaptic transmission regulation (Casillas-Espinosa et al., 2012), granular cell disper-
77 sion and gliosis (Blümcke et al., 2006), blood-brain-barrier dysfunction and angiogenesis (Crespel et
78 al., 2007).
79
80 A striking feature of MTLE in humans is its heterogeneity. There are various forms of HS in pa-
81 tients, which led to a consensus classification based on histopathological differences (Blümcke et
82 al., 2013). Likewise, there is a large diversity in terms of semiologic and electrophysiologic features
83 in temporal lobe seizures, including regional epileptogenicity and whether or not seizures second-
84 arily generalize (Maillard et al., 2004, Barba et al., 2007, Bartolomei et al., 2008). A large variability
85 also exists in hypometabolism in patients with TLE (Guedj et al., 2015). Finally, the diversity be- 3
86 tween patients is even more important when considering comorbidities (i.e. conditions co-occurring
87 with seizures), such as cognitive deficits, anxiety, and depression (Holmes, 2015, Krishnan, 2020,
88 de Barros Lourenço et al., 2020).
89
90 These considerations provide the context of this review: we need a wide array of phenotypes in
91 experimental models to ask specific questions that may be relevant to subsets of patients. It is rea-
92 sonable to propose that genetic and epigenetic differences strongly contribute to phenotypic diver-
93 sity in patients. In contrast, basic research uses inbred rodents living in a "stable" environment in
94 animal facilities. This facilitates the task of researchers, increasing the reproducibility of the results.
95 However, a given model may only be relevant to a specific phenotype in patients. Fortunately,
96 several experimental models of epilepsy have been developed, originally to mimic MTLE, including
97 the pilocarpine models, the electrode-based kindling models, and the kainic acid (KA) models. Alt-
98 hough homology between a rodent model and human epilepsy cannot be claimed, experimental
99 models must reproduce the main symptom: spontaneous recurrent seizures (SRSs). If other patho-
100 logical traits (e.g., mossy fiber sprouting or HS) or comorbidities (e.g., cognitive deficits and de-
101 pression) exist, it may be possible to achieve a degree of granularity compatible with the diversity
102 of phenotypes found in patients. This review will focus on the KA rodent model, its advantages and
103 limitations, methods of administration, histological, electrophysiological, and behavioral outcomes.
104 As we will see, this model alone is characterized by a wide range of phenotypes.
105
106 The ideal situation would be to map the diversity of KA phenotypes with that of MTLE phenotypes.
107 Unfortunately, most of the time, the existing literature does not provide enough information. For
108 example, the part of the hippocampus that is resected in patients corresponds to the ventral hippo-
109 campus in rodents. A minority of experimental studies (apart from intra/supra hippocampal injec-
110 tions) distinguish the ventral from the dorsal hippocampus, despite the fact that clear differences
111 appear in experimental epilepsy when specifically studied (do Canto et al., 2020, Canto et al.,
112 2020, Arnold et al., 2019, Evans & Dougherty, 2018, Isaeva et al., 2015, Ekstrand et al., 2011,
113 Bernard et al., 2007, Brancarti et al., 2020). Most electrophysiological recordings in rodent models
114 are performed in the dorsal hippocampus, or supradurally, essentially capturing the activity of the 4
115 dorsal hippocampus via volume conduction, not what happens in the ventral hippocampus. Like-
116 wise, morphological studies rarely distinguish the ventral and dorsal hippocampi in terms of cell
117 death, sprouting etc. The use of common data elements in future studies will be particularly useful
118 to try correlate experimental models and patient data.
119
120 The last cautionary note relates to the way rodent data are analyzed: results are averaged, which
121 assumes that the model will produce similar results with some variation. The clinic teaches us oth-
122 erwise. If we just consider the electrophysiological signature of seizures, patients with mesial tem-
123 poral atrophy/sclerosis can display low-voltage fast or hypersynchronous seizures (e.g. Table 1 in
124 Perucca et al., 2014). Individual patients can display several types of seizures (Saggio et al.,
125 2020). Rodents, even from the same litter, are not clones. They are also individuals(Gomez-Marin
126 & Ghazanfar, 2019). They can react very differently to a given insult, including epileptogenesis,
127 and produce different phenotypes (Medel-Matus et al., 2017, Becker et al., 2019, Becker et al.,
128 2015). Most studies presented hereafter did not report major differences within experimental
129 groups, but the data may be there. Looking for differences within a given batch of experimental an-
130 imals may constitute a very promising line of research, in keeping with a highly clinically relevant
131 question: the development of personalized medicine.
132
133 Summarizing the data over the past decades is not an easy task. There was no standardized way
134 to report experimental protocol and analysis methods, which prevents a real comparison between
135 labs. Although 24h video/EEG-recordings are now routinely used in experimental rodent models,
136 there were not as widespread in the past. Notwithstanding their importance, some studies used
137 short recording sessions (a few hours per day, during working days) and could potentially have
138 missed some epileptic activity. Some studies only used visual observation.
139 As mentioned previously, there is still no agreement between scientists on how to define a seizure
140 in a rodent. While the Racine scale provides an attempt to organize and quantify behavioral sei-
141 zures, subclinical seizures, frequent spikes, and bursts may be present on the EEG without overt
142 behavioral correlates. Considering the differences in seizure profile between rats and mice and the
5
143 variability between labs, it is really hard to draw clear conclusions from the huge pool of data col-
144 lected through so many years.
145
146 The problems of standardization also apply to neuroanatomical and functional morphological stud-
147 ies. Many confounding factors can affect the interpretation of the observations. The counting
148 method is important. Stereological techniques were not available in the past. Hence it is difficult to
149 compare studies even when the same experimental model of epilepsy is used. Furthermore, the
150 hippocampus is heterogeneous in terms of structure, cell distribution, and properties along both
151 septo-temporal and longitudinal axes, and even within the pyramidal cell layer (Malik et al., 2016,
152 Sotiriou et al., 2005, Pandis et al., 2006, Thompson et al., 2008, Dong et al., 2009, Mizuseki et al., 2011,
153 Sharif et al., 2021).
154 It is not always clear which regions/subfields are being investigated, e.g., to assess cell death.
155 Morphological alterations may be regionalized. Human data demonstrates even more complex
156 changes as basket innervation is patchy from one subfield to the next in a given patient (Arellano
157 et al., 2004). Such heterogeneity is also found in multidrug transporters' expression, which can be
158 very different from one slice to the next obtained after neurosurgery (Sandow et al., 2015). In animal
159 models, we tend to assume that neuroanatomical changes are homogeneous, i.e., that the meas-
160 urements performed in a few sections can be generalized to the structure. Many other brain re-
161 gions are also characterized by spatial gradients, which should be considered when assessing cir-
162 cuit alterations. Likewise, since it is cumbersome to do, few studies engage in a global assessment
163 of anatomical alterations in different regions in experimental models. Much work is needed to ad-
164 dress. It would be helpful to use common data elements to standardize protocols and facilitate
165 comparisons between studies (Lapinlampi et al., 2017).
166
167 We have attempted to be as neutral as possible in our evaluation, relying on the interpretation pro-
168 vided in each study and, whenever relevant, providing our own experience. In the following, we
169 describe the different phenotypes found in various KA models. Given the wide heterogeneity found
170 in patients, all models described hereafter reproduce some features found in some patients. Most
171 experimental models share similarities with properties found in a majority of MTLE patients, includ- 6
172 ing electrophysiological (seizures, interictal spikes, high frequency oscillations) and morphological
173 (granule cell dispersion, mossy fiber sprouting) signatures. We will not take a position regarding a
174 possible relevance to features found in patients, because there is no prototypical signature of
175 MTLE at the morpho-functional level. For example, hippocampal sclerosis is found in only 60% of
176 MTLE cases (Thom, 2014), and patients with MTLE can have low-voltage fast or hypersynchro-
177 nous seizures (Perucca et al., 2014). The choice of the model should be tailored to the scientific
178 question, which is laboratory-specific. We describe and provide tables listing the various observa-
179 tions made in different models. These tables can be used for knowledge-based approaches. For
180 example, if one is interested in the mechanisms of low-voltage fast seizures in patients with end
181 folium sclerosis, identify an experimental model reproducing such features (if available) and study
182 it. We also highlight issues that need to be investigated, which could constitute interesting oppor-
183 tunities for young investigators.
184
185 1. Models of TLE: a brief overview
186
187 The main goal of creating a reliable animal model of epilepsy is to develop a chronic condition,
188 which is consistent and efficient in generating SRSs. Several methods have been developed, all of
189 them are based on different approaches, but they generally use an initial brain insult. It is worth
190 noting that despite the fact that all these methods produce reliable epilepsy models, they do not
191 always show the same phenotypes, such as neuronal cell death, neuropathological alterations and
192 epileptogenesis. The reasons behind such heterogeneity are not clear. Every single model has its
193 nuances, which should be seen as a strength. We provide a brief information about other TLE
194 models to stress further the diversity that can be achieved in terms of phenotypes. We did not at-
195 tempt to compare them to the kainate models, which was beyond this review's scope. We are also
196 not discussing genetic conditions and transgenic strains that exhibit a TLE-like phenotype (Toth et
197 al., 1995; Zeng et al., 2011), but it is worth mentioning that TLE may have a genetic predisposition
198 (Andermann et al., 2005). We do not want to convey the wrong impression that we favor the KA
199 model. All models are interesting as they enable researchers to tap into a rich repertoire of pheno-
7
200 types. Although this brief description of other than KA models does not do justice to them, we start
201 this review with these models to highlight their diversity and richness.
202 The administration of various chemoconvulsants either systemically or directly into the brain is
203 commonly used to trigger epileptogenesis, the process that leads to the development of SRSs. Pi-
204 locarpine and kainic acid are broadly used chemoconvulsants. Pilocarpine, a muscarinic acetylcho-
205 line receptor agonist, was first proposed to generate experimental epilepsy in rats by W. Turski
206 (Turski et al., 1983). Intraperitoneal injection of 100-400mg/kg pilocarpine triggers seizures starting
207 with motor, olfactory, and gustatory automatisms, which evolve into status epilepticus (SE). Histo-
208 logical examination of the brains revealed specific alterations throughout the hippocampal for-
209 mation, amygdala, thalamus, neocortex, olfactory cortex, and substantia nigra (Turski et al., 1983).
210 The most remarkable difference between the pilocarpine and the KA models is the rapidity of the
211 pilocarpine one. Neuronal damage is visible within 3 hours after pilocarpine-induced SE, while in
212 the case of KA, the brain lesion in the same areas is visible 8 hours after SE induction (Covolan &
213 Mello, 2000). Regarding the extension of cellular damage, both KA and pilocarpine models, inject-
214 ed systemically, produce an extensive extrahippocampal cell loss (Levesque & Avoli, 2013). In
215 mice, the pattern of cell loss is strain-dependent (Schauwecker et al., 2012). It is important to stress
216 that each lab used/uses different evaluation methods for cell counting and general damage as-
217 sessment, making comparisons difficult.
218
219 Mortality in the pilocarpine model appears higher. Lithium treatment 24 h prior to the convulsant
220 injection can significantly reduce mortality, leading to a different phenotype (Curia et al., 2008). Mul-
221 tiple reports indicate a strain difference in the pilocarpine model (McKhann et al., 2003, Curia et al.,
222 2008, Inostroza et al., 2011, Levesque & Avoli, 2013). For instance, cell damage and mortality rates
223 are more significant in Long-Evans and Wistar rat strains than Sprague-Dawley rats (Curia et al.,
224 2008; Inostroza et al., 2011). The Sprague-Dawley strain also demonstrates less prominent neu-
225 ronal damage than Wistar rats (Inostroza et al., 2011). Overall, the Long-Evans strain is the most
226 sensitive strain to pilocarpine, followed by Wistar; while the Sprague-Dawley strain exhibits mini-
227 mal sensitivity. The Dose-response to pilocarpine is similar in mice and rats; however, mice appear
228 to be more sensitive and display higher mortality rates than rats (Curia et al., 2008). Also, mice 8
229 treated with pilocarpine are more likely to develop SRSs than KA-treated ones (Levesque & Avoli,
230 2013). Generally speaking, several parameters are involved in phenotype generation in both pilo-
231 carpine and KA models: administration route, dosage, duration and severity of the initial insult, en-
232 vironmental conditions etc. Evidently, the characteristics of experimental animals play crucial role
233 as well. Species, strain, age and sex create multiple variations in the models and will be thoroughly
234 discussed later. As it is hard to navigate between so many factors, we have made an attempt to
235 summarize existing data in the tables, demonstrating the full diversity of the KA models. The pilo-
236 carpine model, not any less complex, is not discussed in details in the current review, but the
237 reader is welcome to read further literature about the model (Curia et al., 2008; Levesque & Avoli,
238 2013).
239
240 It is important to note that the initial experiments performed with KA or pilocarpine showed high
241 death rates. Status epilepticus (SE) was left unchecked, and some drugs used to try to stop it had
242 unwanted effects. Thus, it is difficult to compare the results obtained with these studies, as they
243 may have generated phenotypes different from those described nowadays. More recent TLE mod-
244 els show lower levels of fatality in both mice and rats, in particular when SE is monitored with EEG
245 recordings. In our hands, we noted that SE might start electrographically 5 min before behavioral
246 manifestations, particularly in mice. We also noted that aberrant electrographic activity continues
247 after the injection of the most optimal combination of drugs used to stop SE (Brandt et al., 2015), up
248 to the next day following SE induction. Although the drugs have relaxant effects (no or few motor
249 events), the aberrant activity continues, hence the necessity to monitor continuously with EEG re-
250 cordings. Since SE triggers epileptogenesis, it is difficult to standardize its duration and severity,
251 which could be a variability source within the same group of injected animals. Finally, we observed
252 seasonal variability. In our hands, rodents seem to be more sensitive to pilocarpine and KA, with a
253 greater death rate during the summer, another possible variability source.
254 In terms of behavioral performance, spatial memory seems to be affected significantly in the pilo-
255 carpine model. However, pilocarpine-treated animals show reduced anxiety levels compared to the
256 KA-treated rats (Inostroza et al., 2011).
257 9
258 The injection of tetanus toxin into the hippocampus is also used to trigger epileptogenesis. The first
259 mention of this procedure dates as early as the nineteenth century, demonstrating that intracere-
260 bral injection of the toxin causes seizures in experimental animals (Roux and Borrel, 1889). Unlike
261 KA, tetanus toxin does not elicit SE after its injection but efficiently generates SRSs within 2-21
262 days post-injection, which usually ceases after a few weeks (Jefferys & Walker, 2006). A standard
263 dose causes nearly 30% pyramidal cell loss in CA1 in the unilateral hippocampus and 10% at dis-
264 tant sites. Moreover, loss of the dendritic spines in CA3 pyramidal neurons is also reported (Benke
265 & Swann, 2004).
266
267 The next common approach for modeling TLE in rodents includes various types of electrical stimu-
268 lation. The most widely used model is the kindling model, in which an electrode is implanted into
269 the brain, and a seizure focus is created by repeated electrical stimulation. The term “kindling” was
270 first proposed by G. Goddard and his colleagues (Goddard et al., 1967), where, after several exper-
271 imental trials, they demonstrated that daily electrical stimulation leads to the development of an
272 epileptic focus in the brain, creating generalized convulsions and permanent changes in brain tis-
273 sue (Goddard et al., 1969). The kindling model has been extensively used targeting various regions
274 such as the hippocampal formation (Kairiss et al., 1984; Palizvan et al., 2001), the piriform cortex
275 (Loscher & Ebert, 1996), and the perirhinal cortex (McIntyre et al., 1993). The electrical stimulation
276 model's primary hallmark is the gradual development of an epileptic activity, as compared to the
277 chemical administration, in which the initial brain insult leads to the development of chronic epilep-
278 sy after a latent period. The kindling model is sometimes described as a "functional" model due to
279 the absence of gross morphological damage, which is characteristic of chemical models (Morimoto
280 et al., 2004) and a general failure to induce chronic SRS (Goddard et al., 1983). Thus, it is rather a
281 model of epileptogenesis but not of epilepsy. A variation based on an optogenetic approach (rather
282 than electric stimulation) called “optokindling” has been introduced recently (Cela et al., 2019). Alt-
283 hough it was used to produce a model for neocortical epilepsy, the same technique may create a
284 TLE model. The main advantage of this kindling model is the ability to trigger seizures on demand.
285 At more advanced kindling stages, SRSs can occur (Wada et al., 1975).
10
286 Another way to obtain SRSs using the kindling approach is to trigger SE. Lothman and Bertram
287 developed a model of continuous hippocampal stimulation to induce chronic epilepsy (Lothman et
288 al., 1989). This model, named self-sustaining limbic status epilepticus (SSLSE), triggers SE and
289 thus epileptogenesis leading to the occurrence of SRSs. A similar model was proposed by
290 Mazarati et al., 1998, who suggested a brief 15-30 min perforant path stimulation (previously used
291 as a kindling model (Sloviter, 1987)), which led to continuous self-sustained SE and the develop-
292 ment of SRSs.
293
294 Most chemical and electrical models use SE to trigger epileptogenesis. It is reasonable to propose
295 that SE is the main determinant of epileptogenesis. However, causality has not been clearly estab-
296 lished. This issue could be addressed with optogenetics, which may be used to try to stop SE soon
297 after its onset.
298
299 One of TLE's most common causes in patients is traumatic brain injury (TBI) (Pitkänen et al.,
300 2006). Various TBI models have been developed, in particular, the fluid percussion injury model
301 (D’Ambrosio et al., 2004). A single severe injury produced by fluid percussion injury device is suffi-
302 cient to trigger epileptogenesis in rodents with some similarity with human TLE, including morpho-
303 logical alterations such as neuronal loss in the hippocampus and mossy fiber sprouting
304 (Kharatshvili et al., 2006; Pitkanen & Immonen, 2014).
305
306 The previous models involve brain insults triggered in adult animals. Insults occurring during de-
307 velopment can also lead to TLE later in life. For example, febrile seizures are a risk factor for TLE
308 development in humans (French et al., 1993). Hyperthermia-induced seizure models have been de-
309 veloped (Holtzman et al., 1981). Dubé et al., 2010 demonstrated that prolonged 70 min febrile sei-
310 zures in P11 rat pups could trigger epileptogenesis.
311
312 Neonatal hypoxia can also constitute an initial insult, resulting in TLE later in life (Jensen et al.,
313 1991). It is linked to the observation that hypoxic encephalopathy is the most common cause of ne-
314 onatal seizures (Aicardi et al., 1970). Exposing P10-P12 pups to graded global hypoxia (7%-4% 11
315 oxygen) for 15 minutes triggers epileptogenesis (Rakhade et al., 2011). Morphological changes in-
316 clude mossy fiber sprouting, and electrophysiological analysis shows increased excitability, facili-
317 tated long-term potentiation induction, and longer afterdischarges.
318 The developing brain is not a miniature adult brain. Hence, specific models need to be developed
319 to study epilepsies that occur during development. The same issue applies to the aging brain, for
320 which mechanisms of epileptogenesis and seizure genesis may be specific to a given age. These
321 are key questions, but they were beyond the scope of the present review.
322
323 There are various ways to trigger epileptogenesis in the brain, each leading to slightly different
324 phenotypes. We will now focus on the kainic acid model.
325
326 2. The kainic acid model
327
328 Kainic acid, a cyclic analog of L-glutamate and an agonist of the ionotropic KA receptors, was first
329 reported to damage hippocampal pyramidal neurons by Nadler et al., 1978. However, the use of KA
330 as a model for epilepsy was first introduced by Ben-Ari and his colleagues (Ben-Ari & Lagowska,
331 1978; Ben-Ari et al., 1979), who performed a unilateral intra-amygdaloid injection of KA in unanaes-
332 thetized non-paralyzed rats and observed focal seizures evolving into SE as the dosage increased.
333 Moreover, the histological findings revealed neuronal degeneration and gliosis in the CA3 field of
334 the hippocampus. These, and other experiments, suggested using KA as a tool to model TLE in
335 rodents. The injection of KA will lead to the activation of its cognate receptors.
336
337 3.1. Kainic acid receptors
338
339 Extensive biomolecular research has provided us with information about the localization of kainic
340 acid receptors (KARs) in the mammalian brain. Experiments on KAR mapping showed that these
341 receptors could be found at different levels of expression throughout the brain, including the ento-
342 rhinal cortex (Patel et al., 1986), cerebellum (Wisden & Seeburg, 1993), amygdala (Rogawski et al.,
343 2003), basal ganglia (Jin & Smith, 2011) and the hippocampus in which they are particularly abun- 12
344 dant (Bloss & Hunter, 2010). Kainic acid receptors belong to a family of ionotropic glutamate recep-
345 tors, along with AMPA and NMDA receptors. They can be pre- or postsynaptic. Presynaptic KARs
346 act bidirectionally, performing an excitatory action through their ionotropic activity and inhibition via
347 a “non-canonical” metabotropic signaling (Lerma & Marques, 2013). Postsynaptic receptors con-
348 tribute to excitatory neurotransmission (Huettner, 2003). KA receptors can also control GABAergic
349 neurotransmission, both pre- and post-synaptically (Cossart et al., 2001; Cossart & Bernard, 2001).
350 There are five known types of KA receptor subunits: GluR5 (GluK1), GluR6 (GluK2), GluR7 (GluK3),
351 KA1 (GluK4), and KA2 (GluK5). Some subunits are highly expressed in the hippocampus. The
352 GluK4 subunit is almost exclusively found in the CA3 hippocampal field, whereas its expression in
353 CA1 is limited (Bahn et al., 1994; Darstein et al., 2003). GluK5 subunits are expressed in both CA1
354 and CA3 fields (Bahn et al., 1994) and in the cortex and striatum (Gallyas et al., 2003). The fact that
355 these two subunits have a high affinity for kainic acid (dissociation constant of 5-15 nM) and are
356 mainly concentrated in CA3 may explain the pattern of excitotoxic damage found in this region
357 (Fernandes et al., 2009) and suggests that they are likely responsible for neuronal cell death.
358 GluK1 are found in the hippocampus's CA3 field (Bahn et al., 1994), and GluK2 are highly ex-
359 pressed in both CA1 and CA3 (Bloss & Hunter, 2010). Although both subunits have low affinity for
360 KA (KD of 50-100 nM), GluK1 knock-out mice show increased susceptibility to the epileptogenic
361 effect of KA, while GluK2 ablation prevents the generation of epileptiform discharges (Fisahn et al.,
362 2004). GluK2-KO mice are also less sensitive to KA's epileptogenic effect (Mulle et al., 1998). Con-
363 versely, overexpression of GluK2 by HSVGluR6 viral vector injection leads to seizure induction and
364 hyperexcitabilty (Telfeian et al., 2000). Furthermore, Ullal et al., 2005 reported that the GluR7 subu-
365 nit, which has the lowest affinity to glutamate, is down-regulated by KA-induced seizures in the
366 long term. These findings suggest that the KA administration will target all types of kainate recep-
367 tors, with a unique effect in the hippocampus. Interestingly, the GluK1 subunit has been associated
368 with acute seizure induction (Fritsch et al., 2014), since the acute effect is believed to be mediated
369 by regulation of inhibition and GluK1 subunits are especially abundant in hippocampal interneurons
370 (Paternain et al., 2000). Chronic epilepsy, however, likely develops due to GluK2 and GluK5 subu-
371 nits, which are found in the newly formed KARs within the mossy fiber network (Artinian et al.,
372 2015, Pinheiro et al., 2013). Increased expression of GluK4 has been found in the brains of patients 13
373 with refractory TLE (Lowry et al., 2013). Additionally, GluK4 knockout mice demonstrated full neu-
374 roprotection in the CA3 area of the hippocampus following administration of KA (Das et al., 2012).
375 Thus, it is reasonable to assume that GluK4 modulates KA-induced neurodegeneration.
376 It could be interesting to determine which KARs in which cells are the main triggers of epileptogen-
377 esis. The recent development of photoswitchable regulators of ligand-gated channels
378 (Bregestovski et al., 2018) could enable a tight control of specific KARs in a cell type and brain re-
379 gion-dependent manner.
380
381 3.2. Mechanism of action
382
383 Excitotoxicity refers to a process in which neurons experience severe damage to the point of cell
384 death due to overstimulation by excitatory neurotransmitters such as glutamate (Dong et al., 2009).
385 The mechanism behind this includes a cascade of molecular interactions that lead to osmotic im-
386 balance, excessive depolarization, and, eventually, rupture of the postsynaptic membrane (Beck et
387 al., 2003). Several mechanisms are at play. A central one involves the intracellular accumulation of
388 Ca2+, following the excessive activation of glutamate receptors (Fig. 1D). The rise in Ca2+ can
389 strongly impact mitochondria and the endoplasmatic reticulum (Friedman et al., 2006). Elimination
390 of intracellular Ca2+ or blocking its influx into mitochondria can diminish cellular sensitivity to apop-
391 totic stimuli (Lee et al., 2009). The Na+ and Cl− ions are also involved since their removal from the
392 extracellular space stop neurodegeneration (Chen et al., 1998). Finally, extracellular K+ is also en-
393 gaged in KA-induced excitotoxicity (Ha et al., 2002).
394
395 Oxidative stress also plays a central role in cell death in the context of excitotoxic damage. The
396 excess of glutamate initiates reactive oxygen species (ROS) formation, which leads to mitochon-
397 drial dysfunction and molecular damage (Murphy et al., 1989; Nguyen et al., 2011). KA injection
398 leads to high levels of ROS (Chuang et al., 2004; Gano et al., 2018), as seen in brain tissue from
399 TLE patients (Rowley & Patel, 2018).
400 Even though oxidative stress is often considered as the main mechanism of cell death in TLE,
401 many authors argue that apoptotic cell death contributes to the SE-induced brain damage or even 14
402 prevails. Fujikawa et al., 1993 summarized and explained all the pathophysiological mechanisms
403 that are associated with SE. Apparently, gene changes induced by SE can lead to apoptotic neu-
404 ronal death, and it is possibly tied to the excitotoxic damage component. Mitochondrial mem-
405 branes, being a subject of oxidative stress, activate apoptotic-inducing factor (AIF), which gets
406 translocated into the nuclei and initiates DNA fragmentation (Fujikawa et al., 2005). Thus, it can be
407 proposed that excessive glutamate release triggered by KAR activation, leads to excitotoxic cellu-
408 lar damage, which, in turn, activates apoptotic factors, and results in both apoptotic and excitotoxic
409 cell death. However, this aspect is still debated.
410
411 The mechanisms of KA-induced SE remain incompletely understood. However, in different species
412 and strains, KA-induced SE may result in different phenotypic traits. More generally, we observe
413 different phenotypes when we use different independent variables such as the mechanisms of SE
414 induction (e.g. pilocarpine, TBI, KA etc.), species, strain, gender, age etc. Intuitively, the state of
415 the brain circuits at the moment of the induction of SE will be central to the future outcome. Since
416 we cannot have access to the brain's state, it is not yet possible to explain why different pheno-
417 types are obtained. At present, we can only observe and describe them. A full understanding
418 would allow a knowledge-based development of epilepsy models with the desired phenotype.
419 Much work is still needed to reach this stage. At present, our personal opinion is that the mecha-
420 nisms of induction of epileptogenesis (how and where KA acts) are less important than the pheno-
421 typic traits that one wishes to study.
422
423 3. Administration routes
424 Kainic acid, like many other drugs, can be administered in various ways, depending on the desired
425 outcome (Fig. 1A-C, Fig. 2). Each method has its advantages and drawbacks and should be cho-
426 sen accordingly. The key parameters one should consider selecting the injection route are mortali-
427 ty rate, labor-intensity, lesion control, and, finally, age, sex, and strain of the animal. The major
428 administration routes are systemic, intracerebral (which could be divided into intraventricular, in-
429 trahippocampal, suprahippocampal, and intra-amygdaloid), and intranasal. Each of them is de-
430 scribed further. The striking feature that will immediately appear is the diversity in terms of fea- 15
431 tures, including the duration of the latent period, seizure properties and morpho-functional altera-
432 tions, even within a given model. This should not be seen as blurring the picture. Rather it unravels
433 the richness and diversity of all these models. The tables listing the different features as a function
434 of model, sex, strain etc. are provided to help researchers choosing the model best fitting their
435 questions.
436
437
438 4.1. Systemic administration
439
440 The first experiments using systemic KA administration were performed in the late 1970s to deter-
441 mine whether the toxin could induce damage via axonal connections (Schwob et al., 1980, Fig. 1A).
442 The studies showed that rats injected by 12 mg/kg of KA intraperitoneally experienced the onset of
443 "wet dog shaking" seizures approximately 30-90 min after injection, which eventually evolved into
444 secondary generalized tonic-clonic convulsions in 88% of cases. Neuronal damage was present
445 already at 3 h post-injection and gradually increased for two weeks. This method has been widely
446 used with different modifications. For instance, it was shown that KA, injected subcutaneously,
447 causes similar behavioral and network alterations as an intraperitoneal injection (Sperk et al., 1983)
448 and can be used as a model for TLE (Bertoglio et al., 2017). The significant advantage of systemic
449 KA administration is its low labor-intensity, which allows the injection of numerous animals in a
450 comparatively shorter time. Moreover, the absence of a surgical procedure eliminates side effects
451 created by anesthesia, surgery invasiveness, and extra damage made by direct contact with brain
452 tissue during the intracerebral injection. However, this model's obvious disadvantages are 1) no
453 control over the bioavailability of KA in the brain and 2) high mortality rates. As it was already men-
454 tioned before, Long-Evans and Wistar rat strains have higher mortality (Curia et al., 2008). In mice,
455 C57 and CH3 strains display an increased mortality rate, while 129/SvJ and SvEms strains have a
456 higher ratio of survival (McKhann et al., 2003). The summarized data for systemic KA administra-
457 tion in mice and rats is presented in Tables 2 and 3. It is important to note that kainic acid is quite
458 expensive (e.g., as compared to pilocarpine) and that the purity of the molecule can vary from one
459 stock to another (personal experience). There are also different forms of the drug, e.g., pure acid 16
460 and its dehydrate, which can sometimes be an issue in terms of result variability. Periods of kainic
461 acid shortage were also experienced in the past.
462
463 Status epilepticus
464 The sequence of events, followed by KA administration, includes the "initial insult," e.g., status epi-
465 lepticus, a latent seizure-free period, and the eventual development of chronic epilepsy. SE is
466 characterized as a condition resulting either from the failure of the mechanisms responsible for
467 seizure termination or the initiation of events, leading to abnormally, prolonged seizures (after time
468 point t 1) (El Houssaini et al., 2015). It is a condition, which can have long‐ term consequences (af-
469 ter time point t 2), including neuronal death, neuronal injury, and alteration of neuronal networks,
470 depending on the type and duration of the status (Trinka et al., 2015). In adult rats, a single dose of
471 KA can trigger SE characterized by a catatonic posture followed by facial myoclonus — stage 1
472 (according to Racine scale, Racine, 1972); masticatory automatisms, wet-dog shakes and head
473 nodding (stage 2); rearing with facial automatisms and forelimb clonus (stages 3-4); and finally re-
474 peated rearing and falling (stage 5) (Raedt et al., 2009). Following systemic KA administration, SE
475 develops within two h and lasts for approximately 5-9 h (if not stopped with an ad hoc injection of a
476 drug), according to multiple experiments on rats (Stafstrom et al., 1992; Giorgi et al., 2005; Lado et
477 al., 2006; Williams et al., 2009; White et al., 2010; Drexel et al., 2012; Bertoglio et al., 2017). Mortality
478 in this model is relatively high (around 22%), which can be reduced with slight alterations of the
479 protocol. Repeated injections of 2.5 mg/kg i/p (Hellier & Dudek, 2005) at 30 min intervals reduce
480 mortality down to approximately 5-6%, as compared to a single full-dose injection. Likewise, to in-
481 crease survival rate, SE can be decreased in severity after a few hours by subcutaneous injection
482 of 10 mg/kg diazepam or zolazepam (Sharma et al., 2008; Gurbanova et al., 2008). Many groups try
483 to stop SE after 20 min. As mentioned above, control of SE duration requires instrumenting the an-
484 imals for EEG recordings. We found a decreased mortality and accelerated recovery when timing
485 SE with electrophysiological recordings (as opposed to timing SE duration with behavior). We are
486 using the protocol to instrument animals with a telemetry device for supradural recordings at least
487 two weeks before KA injection. Two-three days before KA injection, we start EEG recordings in the
488 home cage, including following KA injection. 17
489
490 In mice, the clinical picture of systemically induced SE is similar to those seen in rats with slight
491 differences and nuances. For instance, mice do not always fit in the Racine scale; "wet-dog
492 shakes", while being common for rats, are never observed in mice (Sharma et al., 2018). The be-
493 havioral manifestation of SE occurs within 15-30 min post-injection (Hu et al., 1998; Benkovic et al.,
494 2004). The duration of SE does not exceed 6 hours (McKhann et al., 2003; Puttachary et al., 2015).
495 The mortality of systemic KA administration for mice is relatively significant (around 27%) and can
496 be similarly reduced with repeated injections of 5 mg/kg i/p (Tse et al., 2014). Anticonvulsant injec-
497 tions are likewise efficient in reducing the severity of SE (Araki et al., 2002).
498
499 One important parameter to consider when inducing SE is the time of the day. Human studies
500 show that SE occurs at specific times during the night and day cycle (Sánchez Fernández et al.,
501 2019, Goldenholz et al., 2018). Since the molecular architecture of the hippocampus (and other brain
502 regions) oscillates in a circadian manner, the sensitivity to SE may also depend upon the hour of
503 the day (Debski et al., 2020, Bernard, 2020). Performing injections spread over several hours in a
504 given day may lead to variable outcomes, not only in terms of survival but also in terms of pheno-
505 type.
506
507 The KA-induced SE correlates with epileptogenesis. Although it is intuitively straightforward to pro-
508 pose that SE triggers epileptogenesis, it is still possible that the same cause triggers SE and epi-
509 leptogenesis, i.e. SE does not cause epileptogenesis per se. There is some variability in terms of
510 SE severity and recovery between individual rodents, which may be due to basal biological differ-
511 ences (Manouze et al., 2019), including anxiety levels, social hierarchy, etc. This comment is also
512 valid for all other KA models described hereafter.
513
514 Latent period and spontaneous recurrent seizures
515 The latent period is the time between the initial brain insult (SE in the case of the KA rodent model
516 of TLE), and the development of chronic epilepsy manifested as the first SRSs. The latent phase is
517 considered one of the hallmarks of human epilepsy, and it can last for many years (French et al., 18
518 1993; Mathern et al., 1995). In some cases of epilepsy induced by TBI, stroke, or meningitis, the
519 latent period can be as short as one week (Löscher et al., 2015). The variability of the latent period
520 in humans constitutes a major puzzling question. It would be interesting to determine whether the
521 phenotype depends upon the duration of the latent period. Alternatively, since seizures are physio-
522 logical or built-in activities in any normal brain (Jirsa et al., 2014), the problem can be rephrased as
523 a probability one. The brain insult may trigger reorganizations that will evolve on slow and fast time
524 scales to progressively increase the probability for spontaneous seizures. The path taken to SRSs
525 may be traveled at different speeds, but it could be the same. This is difficult to model in rodents.
526 As previously mentioned, several studies report that some animals never developed SRSs after
527 SE. However, animals were never recorded 24/7 for months. It is possible that some animals de-
528 velop SRSs after a very long-lasting latent period. Such models would be particularly useful to ad-
529 dress the question of the variability of the latent period in humans.
530 In the rat model, the usual duration of the seizure-free period is approximately 5-30 days (White et
531 al., 2010; Chauvière et al., 2012; Drexel et al., 2012), although in some cases it may take up to 5
532 months (Williams et al., 2006). Experimental animals do not exhibit any behavioral seizures during
533 this phase, but electrophysiological recordings may show some epileptic activity, e.g., non-
534 convulsive seizures, which will be described next. Whether a "true" latent period exists is debated,
535 as the EEGs display evident anomalies in the few hours following SE, particularly interictal-like
536 spikes. In fact, the latent period's definition can be challenging as variability between recording
537 methods, disagreement on the definition of convulsive seizures, and even the differences in elec-
538 trode placement create certain obstacles. Some studies considered only behavioral seizures to be
539 the hallmark of SRSs and the end of the latent period, while others claimed that the presence of
540 electrographic seizures is the beginning of the chronic phase. Thus, the data on the latent period
541 differs greatly. In our hands, pathological activities, as manifested by spikes and bursts of spikes,
542 appear soon after SE induction and never stop, even after the first spontaneous seizure (Chauvière
543 et al., 2012).
544
545 The appearance of SRSs can be considered as the onset of the chronic phase of epilepsy. The
546 average daily frequency of seizures is 8 per day (±5.4) (Stafstrom et al., 1992; Giorgi et al., 2005; 19
547 Lado et al., 2006; Williams et al., 2009; White et al., 2010; Drexel et al., 2012; Bertoglio et al., 2017).
548 SRSs developing following KA injection in rats at different ages last for approximately 40 s. They
549 resemble stage 5 limbic seizures induced by electric kindling: bilateral forelimb clonus, masticatory
550 movements, rearing, and falling (Stafstrom et al., 1992). Subsequent studies, using continuous
551 EEG/video-recording, demonstrated similar results, with the seizure ratio varying from 4 to 21 per
552 day (Lado et al., 2006; Williams et al., 2009). The F344 rat strain has been demonstrated to be sen-
553 sitive to KA with a much lower dose (10.5 mg/kg) needed to induce SRSs (Rao et al., 2006). Promi-
554 nent neurodegeneration in the hippocampus, extensive mossy fiber sprouting, and the consistent
555 SRS ratio, with the same frequency over time, makes this strain interesting to obtain a stable and
556 reproducible model.
557
558 In mice, the latent phase usually is significantly shorter than in rats and could be estimated as 2-3
559 days (Puttachary et al., 2015). Unlike the rat model, the development of SRSs is more difficult to
560 obtain in mice following a systemic administration, and those detected are infrequent and highly
561 variable (McKhann et al., 2003; Umpierre et al., 2017).
562
563 It is important to note that the high rate of SRSs reported in previous studies may be because ani-
564 mals are singly housed, which increases seizure frequency by a factor of 16, at least in the pilo-
565 carpine model (Manouze et al., 2019; Bernard, 2019). Single housing adds stress as an independent
566 variable and a confounding factor to the epilepsy phenotype. We recommend maintaining social
567 interaction (Manouze et al., 2019; Bernard, 2019). This comment applies to all models.
568
569 Take home message #4: it would be particularly informative to perform a classification of patholog-
570 ical events in each model, particularly spikes and seizures, using unsupervised analysis. As spikes
571 and seizures may evolve in time, it is important to describe their dynamics during epileptogenesis
572 and later. This comment is also valid for all other KA models described hereafter.
573
574 Histological evaluation
20
575 Systemic administration of KA induces extensive bilateral neuronal damage throughout the brain.
576 The first noticeable changes appear within 48 hours post-treatment and are present primarily in
577 CA1, CA3, and CA4 hippocampal subregions (Sperk et al., 1983; Sommer et al., 2000; Haas et al.,
578 2001; Drexel et al., 2012.) Subsequently, the entire hippocampus is affected in the rat brain (Kar et
579 al., 1997; Suárez et al., 2012). The typical pattern of KA-induced damage includes necrosis of py-
580 ramidal cells, gliosis, and mossy fiber sprouting within the dentate gyrus's inner molecular layer
581 (Tauck & Nadler, 1985). Additionally, there have been multiple reports indicating damage of various
582 extrahippocampal areas, such as the amygdala (Fritsch et al., 2009), subiculum, entorhinal cortex,
583 thalamus, caudoputamen (Drexel et al., 2012), substantia nigra, hypothalamus (Covolan & Mello,
584 2000), olfactory bulb, anterior olfactory nucleus (Altar & Boudry, 1990) and other areas.
585
586 T2-weighted MRI images of Wistar and Sprague-Dawley rat strains, systemically treated with KA,
587 showed an interesting phenomenon, contradicting previous mortality findings. The extent of neu-
588 ronal damage is higher in the Sprague-Dawley strain, while in Wistar rats, the relative volume of
589 the hippocampus is not different from the control animals (Inostroza et al., 2011). Confirming the
590 MRI data, post-mortem NeuN-staining revealed a significant pyramidal loss in CA1 and CA3 areas
591 of the hippocampus in Sprague-Dawley rats but not in Wistar (Table 1).
592
593 In mice, the predominantly affected areas are CA3 and CA1 (Hu et al., 1998, McKhann et al., 2003,
594 Kasugai et al.; 2007, Mouri et al., 2008). Similarly to rats, damage induced by systemic KA admin-
595 istration includes pyramidal cell loss, mossy fiber sprouting, and reactive gliosis (McKhann et al.,
596 2003, Benkovic et al., 2004). There is also evidence of extra-temporal damage, particularly in the
597 cortical areas, lateral amygdala, and dorsal thalamus (Hu et al., 1998, McKhann et al., 2003, Ben-
598 kovic et al., 2004, Umpierre et al., 2017).
599
600 Take home message #5: As noted above, a better understanding of all morphological changes in
601 different brain regions is needed to obtain a global picture of the model. This comment is also valid
602 for all other KA models described hereafter.
603 21
604 4.2. Intraventricular injection
605
606 Nadler et al., 1978 have demonstrated that the intracerebroventricular (icv) injection of 0.5 nmol KA
607 into the rat brain leads to CA3 neurodegeneration within 1-3 days, whereas higher doses (0.8mg
608 and more) cause damage to both CA1 and CA2. Similar findings were later observed by Lancaster
609 & Wheal, 1982, who confirmed the same neuronal damage pattern and helped establish the icv
610 paradigm, which is still used (Luo et al., 2013; Song et al., 2016). The data of icv KA administration in
611 rats is presented in Table 2.
612
613 Status epilepticus
614 The induction of SE using the icv route is consistent with other methods. It starts within 10-30 min
615 post-injection and manifests as bradypnea, circling behavior, and wet-dog shakes and subsequent-
616 ly progresses into continuous motor seizures (Miyamoto et al., 1997). The duration of SE varies be-
617 tween 2 and 6 h, which can be stopped by a diazepam injection to reduce the mortality rate
618 (Miyamoto et al., 1997; Jing et al., 2009; Song et al., 2016). Typically, the mortality rate does not ex-
619 ceed 10% and is considered relatively low compared to the systemic route of administration
620 (Miyamoto et al., 1997; Gao et al., 2019).
621
622 Latent period and spontaneous recurrent seizures
623 There are multiple reports regarding SRS development following icv KA administration. Having
624 performed a 24/7 continuous video/EEG-recording, few authors reported similar findings, with the
625 latent period duration varying between 1 and 2 weeks and SRSs appearing consistently, several
626 times per day (Song et al., 2016, Gao et al., 2019).
627
628 Histological evaluation
629 Morphological damage induced by an icv KA administration might seem paradoxical; even though
630 the toxin is injected in the ventricular system and thus potentially distributes throughout the brain,
631 the actual lesion appears to be restricted to CA3/C4 hippocampal subfields ipsilaterally to the injec-
632 tion site (Nadler et al., 1978; Miyamoto et al., 1997). The contralateral hippocampus and the ex- 22
633 trahippocampal areas are relatively spared, and in some cases, almost entirely intact (Song et al.,
634 2016). Mossy fiber sprouting is also present in most cases (Jing et al., 2009; Song et al., 2016; Gao et
635 al., 2019). The pathology is mostly unilateral, with occasional signs of damage on the contralateral
636 side (Lancaster & Wheal, 1982; Miyamoto et al., 1997). The model is closer to what is found in pa-
637 tients with MTLE, as the epileptogenic network is usually limited to one hemisphere (Table 1).
638
639
640 4.3. Intrahippocampal and intra-amygdaloid injections
641
642 The first experiment with intra-amygdaloid KA administration in 1978 demonstrated characteristic
643 behavioral, electrophysiological, and histological hallmarks in baboons (Ben-Ari & Lagowska, 1978;
644 Ben-Ari et al., 1979). Other studies used intrahippocampal KA injections in rats to observe the
645 same outcome (Fonnum & Walaas, 1978). Both methods of intracerebral administration are still
646 widely used. The principal advantage is a direct delivery into the brain tissue, bypassing the blood-
647 brain barrier. The idea is to produce focal damage. The mortality rate appears to be lower than
648 systemic administration (Sharma et al., 2007). Moreover, the standardized protocol for the intrahip-
649 pocampal KA administration, combined with the electrode implantation, which has been proposed
650 recently (Bielefeld et al., 2017), enables a good reproducibility and allows the combination of both
651 electrophysiological and behavioral approaches. A brief summary of both methods is presented in
652 Tables 2 and 3.
653
654 Status epilepticus
655 SE, following an intracerebral KA injection, develops rapidly. Experiments showed that in rats,
656 which underwent intrahippocampal KA administration in the dose of 0.4-2.0 μg, SE emerges within
657 5-30 min after the injection (Bragin et al., 1999; Raedt et al., 2009). Similar effects were observed
658 after the intra-amygdaloid injection of 0.75 μg of KA (Gurbanova et al., 2008). SE, elicited by in-
659 trahippocampal administration appears to be longer than systemic administration and can last for
660 more than 17 h (Rattka et al., 2013). Intra-amygdaloid KA administration in rats is efficient in trigger-
23
661 ing SE lasting 4-6 h on average (Ben-Ari et al., 1979; Tanaka et al., 1992). Generally, intracerebral
662 administration's lethality does not exceed 10% (Rattka et al., 2013).
663
664 Mice demonstrate the same pattern of SE starting within 30 min after intrahippocampal (Lee et al.,
665 2012) or within 20 min after intra-amygdaloid (Mouri et al., 2008) administration. The duration is ap-
666 proximately the same as for rats and can last for up to 12 h (Gröticke et al., 2008). However, there
667 is a common approach to termination seizures via an anticonvulsant injection after 40 min of sei-
668 zure activity, thus reducing mortality rate to a minimum (Shinoda et al., 2004). FVB/N mouse
669 strain exhibits prolonged seizure activity as compared to C57BL/6 strain after intra-amygdaloid KA
670 administration, although the overall SE pattern is similar in both strains (Kasugai et al., 2007). The
671 mortality rate is relatively low compared to the systemic mode of drug administration (Bouilleret et
672 al., 1999; Mouri et al., 2008).
673
674 Latent period and spontaneous recurrent seizures
675 One of the first successful experiments on intrahippocampal KA administration was performed by
676 Cavalheiro et al., 1982, when he and his colleagues conducted a series of tests in rats, using sev-
677 eral different doses of KA in the range of 0.1-3.0 μg, thus creating three distinct cohorts: animals
678 which were injected with either 0.1-0.4 μg or 0.8-2.0 μg experienced SE, but only the latter group
679 developed SRSs approximately 5-21 days after treatment. The rats injected with 3.0 μg of KA died
680 due to severe SE. The SRSs resembled those happening during the acute phase: lasting for 40-60
681 seconds, involving salivation, masticatory movements, bilateral forelimb clonus, rearing, and fall-
682 ing. The chronic period continued for 22-46 days, after which behavioral seizures ceased, and an-
683 imals entered a post-seizure period. Generally, the occurrence of SRSs after the intrahippocampal
684 administration of KA is consistent in rats and resembles the pattern of systemic injection (Rattka et
685 al., 2013).
686
687 Intra-amygdaloid administration is efficient for inducing chronic epilepsy in rats. The average
688 amount of intrahippocampal KA-induced SRSs is 12 per day (Gurbanova et al., 2008). Latency to
24
689 the first SRS is reported to be 1-4 weeks (Cavalheiro et al., 1982, Klee et al., 2017) in both intrahip-
690 pocampal and intra-amygdaloid administration.
691
692 The first experiment on intrahippocampal KA injection in mice was performed in 1999, and SRSs
693 were observed with the frequency of 1-2 seizures per week (Bouilleret et al., 1999). Unlike rats, the
694 EEG results in mice are highly variable, with some authors reporting the frequency of electrograph-
695 ic SRSs to reach dozens per hour (Riban et al., 2002, Gouder et al., 2003), which could be due to
696 social isolation-induced stress (Manouze et al., 2019; Bernard, 2019). According to a recent study,
697 this phenomenon of frequent electrographic seizures is specific to mice but not to rats (Klee et al.,
698 2017).
699 It is important to highlight the study of Sheybani and coll (Sheybani et al., 2018). To the best of our
700 knowledge, with the study performed in the pilocarpine model (Toyoda et al., 2015), this is the only
701 other study in which multisite recordings have been performed to assess an experimental model of
702 TLE at the large-scale network level. The study clearly shows that epileptiform activity progressive-
703 ly expands beyond and independently from the seizure focus. This result is particularly important
704 as it clearly shows that time-dependent alterations in neuronal circuits need to be considered when
705 studying epilepsy in chronic experimental models, including during epileptogenesis (Słowiński et
706 al., 2019).
707
708 Following the intra-amygdaloid KA administration, SRSs developing in mice have a frequency of 1-
709 5 per day (Mouri et al., 2008; Tanaka et al., 2010; Li et al., 2012; Liu et al., 2013). The latent period
710 does not exceed two weeks for both types of intracerebral administration (Lee et al., 2012; Mouri et
711 al., 2008).
712
713 An interesting phenomenon was noticed following an intrahippocampal KA administration in mice.
714 The dentate gyrus is the major zone of adult neurogenesis (Hochgerner et al., 2018). Normally, sys-
715 temic administration of KA induces bilateral neurogenesis in the hippocampus, which, combined
716 with the data collected from human patients, led to an assumption that increased neurogenesis
717 might contribute to epileptogenesis in TLE (Parent, 2007). However, findings in the intrahippocam- 25
718 pal KA mouse model of TLE suggest the opposite. Fritschy et al., 2005 demonstrated that KA, uni-
719 laterally injected into the hippocampus, causes a massive reduction of the neurogenesis on the
720 injection site and a compensatory neurogenic activity in the contralateral dentate gyrus. It could be
721 speculated that, according to this data, neurogenesis does not contribute to the genesis of the epi-
722 leptogenic zone and that, perhaps, it gets disrupted by changes induced in the hippocampus, e.g.
723 granule cells dispersion. This topic is interesting to pursue. A useful review on this topic was pub-
724 lished in 2012, and it partly covers the KA model (Parent & Kron, 2012).
725
726 Histological evaluation
727 Histological studies reveal similarities between the two intracerebral KA administration routes,
728 which are fairly similar in rats and mice (Table 1). The intrahippocampal injection creates a focal
729 lesion in the hippocampus, damaging predominantly the ipsilateral CA3 subfield and, to some ex-
730 tent, CA4 and CA1, regardless of the site of injection (French et al., 1982; Bouilleret et al., 1999;
731 Raedt et al., 2009; Twele et al., 2015). Interestingly, intra-amygdaloid administration induces massive
732 neuron destruction in the same hippocampal regions, along with a lesion in the amygdala (Tanaka
733 et al., 1992; Araki et al., 2002). Some authors reported extensive damage on the contralateral side
734 (Ben-Ari et al., 1980; Araki et al., 2002; Mouri et al., 2008) and the resistance of the CA2 hippocam-
735 pal subfield to the KA-induced toxicity (Shinoda et al., 2004). Mossy fiber sprouting was also ob-
736 served in both rats and mice (Raedt et al., 2009; Zeidler et al., 2018; Gurbanova et al., 2008; Mouri et
737 al., 2008). Granule cell dispersion in the dentate gyrus, however, is only reported with the intrahip-
738 pocampal administration (Rattka et al., 2013; Bielefeld et al., 2017). Additionally, there is multiple
739 evidence of damage in extra-temporal regions induced by intra-amygdaloid injection, such as thal-
740 amus (Ben-Ari et al., 1980), entorhinal, and perirhinal cortices (Mouri et al., 2008; Tanaka et al.,
741 2010). There is a significant strain difference in mice. The C57BL/6 mouse strain is resistant to cel-
742 lular damage induced by KA (Schauwecker & Steward, 1997; Kasugai et al., 2007). In contrast, the
743 FVB/N strain shows increased sensitivity and extensive neurodegeneration in the CA1 and CA3
744 areas of the hippocampus following intra-amygdaloid KA administration (Kasugai et al., 2007). A
745 representative image of the FluoroJade B (FjB) staining of murine hippocampus and cortex after
746 intra-amygdaloid KA injection is presented in Figure 3. It has to be stated that the figure does not 26
747 represent all the possible variations in histological findings but only a particular case. The variabil-
748 ity of KA-induced damage is high, and it should be assessed with a stereological method, if possi-
749 ble. Since it is difficult to summarize the data pool regarding histological studies, we chose only
750 one image.
751
752
753 4.4. Suprahippocampal
754
755 One of the variations of the intrahippocampal administration route is the so-called suprahippocam-
756 pal injection, where KA is injected in the cortical area just above the hippocampus. This technique
757 was introduced by Bedner et al., 2015, who performed an intracortical injection to reproduce the fea-
758 tures of the intrahippocampal administration and avoid damaging the CA1 subfield of the hippo-
759 campus. All animals experienced SE, triggering epileptogenesis. Subsequently, other researchers
760 tested this method several times, proving to be efficient in mice (Table 3).
761
762 Status epilepticus
763 Starting soon after recovery from anesthesia, SE induced by the intracortical KA application lasts
764 for up to 12 hours and consists of forelimb clonus and repetitive rearing and falling (Jefferys et al.,
765 2016). The reported mortality is relatively low and ranges from 0% (Pitsch et al., 2019) to 9.7%. As
766 mentioned by the authors, death occurred mostly due to surgical complications and not seizures
767 (Bedner et al., 2015).
768
769 Latent period and spontaneous recurrent seizures
770 SRSs in this model appear after a brief latent period of 4-13 days and are consistent and frequent.
771 Bedner et al., 2015 reported a frequency of 7.5 ± 6.2 seizures per day 7-9 months post-SE and pro-
772 gressive nature of chronic epilepsy development, consistent with previous data on KA-induced sei-
773 zure progression (Williams et al., 2009). Another study demonstrated success inducing SRSs in
774 100% of treated animals with the seizure frequency of 1-1.5 per day (Pitsch et al., 2019).
775 27
776 Histological evaluation
777 The lesion created by suprahippocampal injection of KA is unilateral and predominantly situated in
778 the CA1/CA3 hippocampal subfields. Three months post-treatment, there is a complete neuronal
779 loss in CA1, significant damage in CA3, and massive dentate granule cell dispersion (Bedner et al.,
780 2015, Jefferys et al., 2016, Pitsch et al., 2019). Mossy fiber sprouting is not characteristic of this mod-
781 el (Table 1).
782 It would be particularly interesting to determine whether the epileptogenic network develops as in
783 the intrahippocampal model (Sheybani et al., 2018).
784
785
786 4.5. Intranasal injection
787
788 The idea of delivering KA via nasal epithelium absorption first emerged as an attempt to trigger SE
789 in the most common strain of transgenic laboratory mice, C57BL/6, known for its resistance KA-
790 induced neuronal death (Schauwecker & Steward, 1997). The first experiments showed that KA,
791 dissolved in water and delivered intranasally in the dose of 40-60 mg/kg, causes focal seizures,
792 which then generalize into SE, in 100% of treated C57BL/6 mice (Chen et al., 2002). Behavioral and
793 anatomical findings were consistent with the previous results, obtained via standard drug delivery
794 protocols. Likewise, another study demonstrated that a dose of 30 mg/kg KA intranasally is asso-
795 ciated with low mortality and >90% success in developing SE (Sabilallah et al., 2016). Even though
796 the mechanism is not fully understood, it is assumed that the drug is absorbed by olfactory epithe-
797 lium and reaches the hippocampus (as well as other brain areas) via olfactory pathways (Frey et
798 al., 1997, Fig.1C), as the olfactory bulb has widespread connections with different regions of the
799 brain (Chen et al., 2002). Although this method has not been studied thoroughly and so far has not
800 found widespread success in the neuroscience community, it has its advantages, such as repro-
801 ducibility, low labor-intensity and low mortality (Table 3).
802 Status epilepticus
803 The induction of SE appears to be consistent in all existing studies; it starts within 15-30 min after
804 administration (Chen et al., 2002; Duan et al., 2006) with the first symptoms being immobility and 28
805 staring, followed by generalized tonic-clonic seizures, lasting for 1-5 h (Chen et al., 2002). The mor-
806 tality rate is relatively low and can be compared to intrahippocampal routes, ranging from 0% to
807 12% (Chen et al., 2002; Duan et al., 2006; Zhang et al., 2008; Lu et al., 2008; Sabilallah et al., 2016).
808 Generally, there are no specific SE features associated with the intranasal administration route
809 compared to the conventional methods.
810
811 Latent period and spontaneous recurrent seizures
812 Seizure progression was reported by at least one research group; Sabilallah et al., 2016 reported
813 latency of 15-30 days before electrographic SRSs are observed in most animals in the form of
814 spontaneous spike activity and occasional seizures. However, the study lacked continuous 24/7
815 video/EEG-recording, so the actual outcome might slightly differ. Other authors reported increased
816 locomotor activity (Chen et al., 2002; Zhang et al., 2008; Lu et al., 2008), perhaps in relationship with
817 the development of chronic epilepsy.
818
819 Histological evaluation
820 Morphological damage induced by intranasal KA administration has been studied. The brain re-
821 mains mostly intact, except for the hippocampus and the olfactory bulbs (Chen et al., 2002; Zhang
822 et al., 2008). The CA3 area of the hippocampus shows the most prominent damage (Duan et al.,
823 2006; Zhang et al., 2008). Mossy fiber sprouting and granule cell dispersion have not been reported.
824 There is evidence of massive astrogliosis and microglial response in the hippocampus (Chen et al.,
825 2002; Duan et al., 2006; Zhang et al., 2008; Lu et al., 2008; Sabilallah et al., 2016). Overall, there is
826 evidence for characteristic pathological features of “classic” KA-induced epilepsy. However, the
827 damage seems to be localized and restricted to the CA3 area of the hippocampus (Table 1).
828
829
830 4. Electrophysiology
831
832 SE elicited by KA administration is characterized by typically isolated spikes, polyspikes, spike and
833 wave complexes (Stafstrom et al., 1992; Riban et al., 2002; Jagirdar et al., 2015). With the advantage 29
834 of simultaneous EEG and video recording, it is possible to distinguish electrographic SE (ESE)
835 from the convulsive SE (CSE), since numerous studies reported ESE to last much longer than
836 CSE (Fritsch et al., 2010; Drexel et al., 2012; Sabilallah et al., 2016; Umpierre et al., 2016). Consider-
837 ing 20 min of ESE rather CSE results in better survival and more rapid recovery. However, this re-
838 quires instrumenting the animals. It is important to remember that any invasive procedure (like im-
839 planting electrodes/transmitters under anesthesia) may change an unknown number of biological
840 parameters in each experimental animal. In other words, we do not know whether instrumenting
841 animals produces a different model/phenotype as compared to non-instrumented animals.
842
843 In our hands, after a drug injection to stop SE, we observe the occurrence of spikes, which fre-
844 quency decreases during the first hours after SE, while the EEG slowly returns to the pre-SE level
845 (between spikes). Then, the spikes start to organize themselves in bursts. During this phase, we
846 see epileptiform discharges, which look like very short seizures (2 sec long). A few days after SE,
847 SRSs start to occur with a typical >10 s duration. In the pilocarpine model, two types of interictal
848 spikes can be distinguished during the latent period: type 1 is a spike followed by a long-lasting
849 wave, and type 2 is a spike without a wave (Chauvière et al., 2012). The authors suggest that type 1
850 spikes correspond to the activity of both excitatory and inhibitory neurons, while type 2 spikes re-
851 flect the activity of a small pool of excitatory cells. While the number, amplitude, and duration of
852 type 1 spikes decreases while type 2 spikes become more frequent before the first spontaneous
853 seizure. A similar study should be performed in the various KA models.
854
855 Spikes can evolve into hippocampal paroxysmal discharges (HPDs) (Riban et al., 2002; Jagirdar et
856 al., 2015), which are essentially short periods of epileptiform activity in the absence of any behav-
857 ioral symptoms (Pallud et al., 2011). Latency for electrographic seizures is shorter than for convul-
858 sive seizures (Lado, 2006, Williams et al., 2009). During this time, occasional interictal spikes and
859 HPDs can be observed (Riban et al., 2002; White et al., 2010).
860 The detection of electrographic SRSs precedes motor symptoms observation and does not always
861 correlate to it (Bragin et al., 2005; Li et al., 2012; Tse et al., 2014).
862 30
863 Various electrographic patterns were reported in KA studies. For example, Riban et al., 2002 classi-
864 fied seizures emerging during the chronic period as low voltage spikes (600–900 μV, 100–150 ms),
865 which persisted for 2 weeks and were never observed again, bursts of high-frequency, low voltage
866 spikes (300–500 μV, 18–26 Hz), appearing just for 1-2 days, high voltage sharp waves (1500–
867 4500 μV, 150–200 ms), persisting until termination of the experiment, and HPDs, which, being the
868 hallmark of the latent period, were still present during the chronic phase. Other authors (Bragin et
869 al., 2005; Lévesque et al., 2012) reported two distinct seizure onset patterns for SRSs: hypersyn-
870 chronous (HYP) and low-voltage fast (LVF) onset patterns, which are also found in patients with
871 epilepsy (Velasco et al., 2000, Ogren et al., 2009). HYP seizures, which represent 50% to 70% of
872 SRSs, are essentially multiple periodic spikes with a frequency of approximately 2 Hz, restricted to
873 a small portion in the hippocampus. LVF onset pattern consists of a single spike followed by high-
874 frequency activity (> 25Hz) originating from hippocampal or extrahippocampal networks. The typi-
875 cal electrographic recordings of SRSs are presented in Figure 4. A taxonomy of 16 types of sei-
876 zures has also been proposed and validated in patients (Jirsa et al., 2014; Saggio et al., 2020) and in
877 the tetanus toxin model of epilepsy (Crisp et al., 2020), in which individual animals switch between
878 different types of seizures during epilepsy. Future work is needed in the KA models to determine
879 the type of seizures they express and how they evolve. This requires Direct Current recordings, as
880 opposed to the most commonly used Alternative Current recordings.
881
882 The arguments developed previously clearly show complex dynamical phenomena that occur dur-
883 ing the latent period. As soon as SRSs start to occur, it is essential to remember that a steady
884 state is never reached. Seizures tend to progress over time (Table 2). Williams et al., 2009 pro-
885 posed that the evolution of seizures consists of 4 stages, where stage 1 represents a latent period,
886 stage 2 is characterized by a slow increase in seizure frequency, e.g., “slow growth phase," stage
887 3 is marked as the “exponential growth phase” and stage 4 is a final steady-state plateau phase,
888 which, however, was not observed in all the animals (Fig.5). This result agrees with other findings,
889 most of which described a progressive increase of SRSs during the chronic period of KA-induced
890 epilepsy (Gorter et al., 2001; White et al., 2010; Rattka et al., 2013; Van Nieuwenhuyse et al., 2015).
891 Thus, the evolution of seizures can perhaps be best represented by a sigmoid Boltzmann function, 31
892 showing the exponential growth phase. However, recent works depict a more complex picture as
893 circadian and multidien rhythms need to be considered (Bernard, 2020).
894
895 Human studies clearly show that seizure activity follows various rhythms: circadian, ultradian, mul-
896 tidien or multi-day, seasonal, etc. (Quigg, 2000; Manfredini et al., 2004; Spencer et al., 2016; Karoly
897 et al., 2018; Baud et al., 2018). The circadian rhythmicity has been recognized for millennia in hu-
898 mans, but multidien rhythms have been identified recently in patients (Baud et al., 2018). The au-
899 thors found that interictal activity, in addition to its circadian rhythmicity, has a slow envelope of
900 several days period, which is patient-specific. Interestingly, seizures tend to occur during the rising
901 phase of this low rhythm. Besides, clusters of seizures are also found during the rising phase.
902 Similar features have been found in the KA model with a robust periodicity of 5-7 days, each ani-
903 mal following its own cycle (Baud et al., 2019). Although rendering data analysis and interpretation
904 more complex, it is important to take circadian and multidien cycles into account, particularly when
905 investigating the molecular mechanisms underpinning seizure genesis (Debski et al., 2020). The
906 fact that the molecular architecture of the hippocampus oscillates in a circadian manner (Debski et
907 al., 2020), provides an entry point to understand the circadian rhythmicity of seizures (Bernard,
908 2020). It is important to stress again that KA's sensitivity (e.g. the threshold to induce SE) may
909 change during the night and day cycle (Debski et al., 2020).
910
911 Finally, as mentioned above, the way animals are housed appears as a key determinant of SRS
912 frequency. When animals are singly housed, they are highly stressed, and their seizure frequency
913 is 16 times greater than in animals maintaining social interaction (Manouze et al., 2019; Bernard,
914 2019). Solutions have been developed to maintain social interaction when animals are instrument-
915 ed (Manouze et al., 2019; Bernard, 2019).
916
917 Take home message #7. Studying seizure frequency requires several weeks of 24/7 continuous
918 recordings to account for circadian and multidien rhythms. Large discrepancies found in animals
919 recorded during one week may stem from the fact that these animals were going through a high or
920 low SRS frequency part of their multidien cycle. 32
921
922 5. Age, sex and strain specificity
923
924 The outcome of KA administration depends not only on the used species and strains but also on
925 the sex and age. This diversity is an advantage as it may allow us to reproduce the diversity of
926 phenotypes found in TLE patients. For instance, C57BL/6 mice, the most widely used transgenic
927 strain, are resistant to KA-induced damage, which can be, however, compromised by intranasal
928 drug administration. Other strains with known resistance are BALB/c (Schauwecker & Steward,
929 1997), C3HeB/FeJ, 129/SvEms, 129/SvJ (McKhann et al., 2003), ICR, and FVB/N (McLin et al.,
930 2006). It has also been proposed to differentiate between behavioral resistance (129/SvEms), lack
931 of anatomical alterations (C57, C3H), and combined resistance (129/SvJ) (McKhann et al., 2003).
932 In contrast, other mouse strains have increased sensitivity to KA, such as C57BL/10, DBA/2J, and
933 F1 C57BL/6*CBA/J (McLin et al., 2006). Also, DBA/2J and FVB/N mouse strains exhibit higher sei-
934 zure-induced mortality as compared to C57BL/6J (Ferraro et al., 1995; Royle et al., 1999). Overall,
935 the difference between rodent strains is crucial and should always be taken into account. Investi-
936 gating different outcomes in different strains could also help to understand the model better. In
937 fact, not all researchers agree that KA, injected into a mouse brain, leads to chronic epilepsy de-
938 velopment. Considering failures in inducing seizures followed systemic KA administration, incon-
939 sistent histological data, and great variability between strains and even within one strain, it is nec-
940 essary to point out that any result should be analyzed with care. However, current advances in sci-
941 ence allow us to investigate the issue in more detail. Perhaps, over the next few years, there will
942 be an agreement on whether mice indeed develop KA-induced epilepsy and how to interpret any
943 related strain differences.
944
945 It is important to note that we have found a large variability between animal vendors in Europe for
946 a given strain because the genetic background, the housing conditions etc. may differ. For exam-
947 ple, we experienced a major issue with several batches of animals from a given vendor. Our proto-
948 col was not working anymore. After probing, the vendor told us that they had changed the feeding
949 conditions to accelerate weight gain. Since some injections are per kg, we were injecting a "much 33
950 younger" animal. Besides, whatever they added to the food may have changed the biology of ani-
951 mals. This is also a source of variability and discrepancy between laboratories.
952
953 Another important factor one should consider when working with a rodent model of TLE induced by
954 KA administration is the animals' age. The first indications of different seizure susceptibility in
955 younger and older rats appeared in the late 1980s when it was demonstrated that an i/p injection of
956 KA in P12 rat pups causes more severe SE as compared to P27 adult rats (Holmes & Thompson,
957 1988). Subsequently, other authors reported similar results: shorter latency before developing SE
958 in younger (P5-10) rats compared to P20-60 (Stafstrom et al., 1992), and higher mortality in P15
959 rats as compared to P53 after an i/p KA injection (Mikati et al., 2003).
960
961 Aged rodents are more prone to seizure activity than adults (Wozniak et al., 1991, McCord et al.,
962 2008), and that this tendency does not depend on a strain (McCord et al., 2008). Aged rats have a
963 shorter latency to SE onset and exacerbation of pre-seizure behavioral manifestations than middle-
964 aged animals (Darbin et al., 2004). The reasons behind this are debated and include multiple theo-
965 ries including age-related changes in synaptic connectivity (Rapp et al., 1999), electrotonic coupling
966 (Barnes et al., 1997), number and type of neurons (Stanley & Shetty, 2004) and diminished density of
967 glutamate receptors in the aged brain (Wenk & Barnes, 2000; Lerma et al., 2001). Overall, this data
968 seems to describe a parabolic pattern of KA-induced seizure susceptibility, where rodents of young
969 and old age are more vulnerable than middle-aged animals. This correlates well with findings in
970 human epilepsy, where age-specific incidence peaks in childhood and then, after a decline in mid-
971 dle age, raises again at the age of 60 years and older (Kotsopoulos et al., 2004).
972
973 An important point regarding age differences was already mentioned before and includes multiple
974 models of TLE in immature rodents (Holtzman et al., 1981, Jensen et al., 1991, Dubé et al., 2010,
975 Rakhade et al., 2011). Given the high prevalence of epilepsy during development and the fact that a
976 developing brain is not a small adult brain, there is a dire need for specific developmental models
977 of epilepsy, as information gained in adults does not translate automatically to the developing
34
978 brain. Developmental epilepsy is a field in itself, and we refer the reader to the relevant literature,
979 as we mostly focused here on adult TLE.
980
981 It is remarkable to notice that the vast majority of epilepsy studies have been and are being per-
982 formed in male rodents. We do not know whether the wealth of data obtained in males applies to
983 females. There is a dire need for research on female subjects of various strains. The currently
984 available data demonstrates some clear differences between male and female rodents regarding
985 the phenotype, epileptogenic processes in the brain, and anatomical alterations. Limiting research
986 to male animals creates a possible misunderstanding of the model and epilepsy in general. This
987 key issue remains to be addressed. Differences are expected, if only when considering structural
988 arguments. The rodent hippocampus, particularly the CA3 area, contains various receptors for
989 gonadal steroids. For instance, the concentration of androgen receptors in stratum lucidum of the
990 CA3 subfield appears to be higher than in any other hippocampal region (Tabori et al., 2005), and
991 mossy fibers express ERα and ERβ estrogen receptors (Torres-Reveron et al., 2009). Several stud-
992 ies have shown that mossy fiber pathway stimulation evokes different levels of BDNF protein ex-
993 pression response in males, females in various stages of oestrus cycle and ovariectomized female
994 rats (Skucas et al., 2013; Scharfman et al., 2003, Scharfman et al., 2007). Only females in proestrus
995 and estrous stages of menstrual cycles exhibit epileptiform activity after a 10 s 1 Hz train of paired
996 pulses and exhibit a strong BDNF expression (Scharfman et al., 2003; Scharfman et al., 2007).
997 Furthermore, in C57BL/6 mice, KA injected at 20mg/kg or 30mg/kg causes SE in ~100% of aged
998 female mice compared to the young females and males of both groups and the highest level of
999 BDNF expression (Zhang et al., 2008). Altogether, this data provides a valuable insight into the in-
1000 fluence of sex on KA administration and susceptibility to seizures, showing that the oestrus cycle
1001 should be considered while modeling epilepsy in female mice. However, a tremendous amount of
1002 research effort is required to study epilepsy in experimental female TLE models.
1003
1004
1005 6. Concluding remarks
35
1006 In this review, we have described the different versions of the kainic acid model. This model has
1007 been extensively used for decades and is proven to be a reliable tool to mimic numerous behav-
1008 ioral, electrophysiological, and anatomical features of epilepsy. In our opinion, whether or not the
1009 KA models are mimicking human TLE is not a relevant question if only because a rodent brain is
1010 not a human brain. What is important are the questions addressed in the rodent models and the
1011 hypotheses being tested. We argue that all models are interesting as long as they are character-
1012 ized by spontaneous seizures.
1013
1014 Diversity is a hallmark of human epilepsy, even for some specific types such as TLE. Interestingly,
1015 different kainic acid models are also very diverse. The results vary as a function of how kainic acid
1016 is administered, species, strain, sex, and age. We argue that this is a strength as the different
1017 models may cover some of the patients' diversity.
1018 Because diversity is the hallmark of human epilepsy, clinicians consider patients as individuals. We
1019 argue that a similar approach should be used with rodents. We have started to consider each rat or
1020 mouse as an individual (Manouze et al., 2019). Given the existing individual variability, averaging
1021 values for a given observable may blur the reality. Although more time-consuming, we argue that
1022 an individual approach may allow the extraction of categories, which may bear translational values
1023 (e.g., responders vs. non-responders to a treatment).
1024
1025 Each model only revealed the tip of the iceberg. Many important issues remain unaddressed. Per-
1026 haps the most important one is determining the seizure onset zone(s) and the propagation pattern
1027 in the brain. This requires multi-site recordings, which are regularly done in patients during presur-
1028 gical evaluation. Such a study has been performed in the pilocarpine model (Toyoda et al., 2015)
1029 and the intrahippocampal kainate model (Sheybani et al., 2018). The same approach should now be
1030 used in the various KA models. More generally, we argue that the phenotype of each animal model
1031 is far from being completely described. Considerable work is needed regarding the type of seizures
1032 expressed, their time evolution, their site of origin, their zone of propagation, the morpho-functional
1033 reorganizations in different brain regions, and comorbidities (depression, anxiety, cognitive deficits,
1034 etc.). Another pressing question is sex. As mentioned, the number of studies performed in males 36
1035 far outweigh those done in females. It is like half of the field is missing. Although more work is
1036 done during development and aging, more work is also clearly needed as the mechanisms are
1037 likely to be age-dependent. Finally, recent studies highlight the necessity to consider circadian and
1038 multidien rhythms, the existence of different classes of seizures, and the impact of housing (single
1039 or colony), which can add the confounding factor of stress. Perhaps accepting the diversity of the
1040 different models and experimental conditions has to offer is the best way to understand human
1041 phenotypes' diversity.
1042
37
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2143
76
2144 Table 1. Neuropathological alterations in different KA models in rats and mice.
2145
Administration Neuropathology References
mode
Rats Mice Rats Mice
Systemic Bilateral damage Bilateral damage Stafstrom et al., 1992 Hu et al., 1998
Entire hippo- CA3/CA1 Lado et al., 2006 McKhann et al., 2003
campus Cortical areas Williams et al., 2009 Benkovic et al., 2004
Subiculum Lateral amygdala White et al., 2010 Umpierre et al., 2017
Entorhinal cortex Dorsal thalamus Drexel et al., 2012
MF sprouting MF sprouting Bertoglio et al., 2017
ICV Unilateral lesion Unilateral damage Miyamoto et al., 1997 Cho et al., 2002
CA3/CA4 areas CA3/CA1 areas of Jing et al., 2009 Jeon et al., 2004
of the hippo- the hippocampus Gordon et al., 2014 Park et al., 2008
campus MF sprouting Song et al., 2016 Jin et al., 2009
MF sprouting Gao et al., 2019
Intra-HC Unilateral lesion Unilateral lesion Cavalheiro et al., 1982 Bouilleret et al., 1999
CA3/CA4 CA3/CA1 Bragin et al., 2005 Riban et al., 2002
DG granule cells DG granule cells Arkhipov et al., 2008 Gouder et al., 2003
dispersion dispersion Rattka et al., 2013 Gröticke et al., 2008
MF sprouting MF sprouting Klee et al., 2017 Lee et al., 2012
Zeidler et al., 2018
Intraamygdaloid Ipsilateral Am Ipsilateral Am Ben-Ari et al., 1979 Araki et al., 2002
Contralateral HC Contralateral HC Tanaka et al., 1992 Shinoda et al., 2004
Contralateral Am Contralateral Am Ueda et al., 2001 Mouri et al., 2008
CA3/CA1 CA3/CA1 Takebayashi et al., Tanaka et al., 2010
MF sprouting MF sprouting 2007 Li et al., 2012
Extratemporal Extratemporal Gurbanova et al., 2008 Liu et al., 2013
77
Administration Neuropathology References
mode
Supra-HC - Unilateral lesion - Bedner et al., 2015
CA3/CA1 Jefferys et al., 2016
DG granule cells Pitsch et al., 2019
dispersion
Intranasal - Bilateral damage - Chen et al., 2002
CA3 area of the Duan et al., 2006
hippocampus Zhang et al., 2008
Olfactory bulbs Lu et al., 2008
Sabilallah et al., 2016
2146 2147 2148 2149
2150 Am — amygdala; DG — dentate gyrus; HC — hippocampus; ICV — intraventricular; MF — mossy
2151 fibers;
2152
2153
78
2154 Table 2. Post-KA chronic epilepsy in rats.
2155
Administra- SE Latent SRS Comorbidities References
tion mode period
Systemic Starts within 2h 12-36 days 8 per day Cognitive im- Stafstrom et al., 1992
Lasts for 5-9 h (± 5.4) pairment Lado et al., 2006
22% mortality Aggressiveness Williams et al., 2009
Drexel et al., 2012
Bertoglio et al., 2017
ICV Starts within 7-14 days 5 per day Cognitive im- Miyamoto et al., 1997
10-30 min (± 3.5) pairment Jing et al., 2009
Lasts for 2-6h Gordon et al., 2014
<10% mortality Song et al., 2016
Gao et al., 2019
Intra-HC Starts within 5- 13-30 days 8 per day Cognitive im- Cavalheiro et al., 1982
20 min (± 6.3) pairment Bragin et al., 2005
Lasts for Perseverative Arkhipov et al., 2008
3-15 h behavior Rattka et al., 2013
<5% mortality Hyperexcitablty Klee et al., 2017
Intra-Am Starts within 5- 11-24 days 12 per day No data Ben-Ari et al., 1979
30 min (± 6.2) Tanaka et al., 1992
Lasts for 4-6 h Ueda et al., 2001
10% mortality Takebayashi et al., 2007
Gurbanova et al., 2008
2156 2157 2158 2159
2160
2161 Am — amygdala; HC — hippocampus; ICV — intraventricular; SE — status epilepticus; SRS — 79
2162 spontaneous recurrent seizures;
80
2163 Table 3. Post-KA chronic epilepsy in mice.
Administration SE Latent pe- SRS Comorbidities References
mode riod
Systemic Starts within 2-3 days Rarely ob- Hyperactivity Hu et al., 1998
15-30 min served Delayed mortality McKhann et al., 2003
Lasts for Infrequent Benkovic et al., 2004
2-6 h Puttachary et al., 2015
27% mortality Umpierre et al., 2016
Intra-HC Starts within 30 2-14 days 1-2 per Cognitive impair- Bouilleret et al., 1999
min week ment Riban et al., 2002
Lasts for Highly vari- Hyperexcitabiity Gouder et al., 2003
3-12 h able Depression (le- Gröticke et al., 2008
<5% mortality eSRS +++ sioned ventral Lee et al., 2012
hippocampus) Zeidler et al., 2018
Intra-Am Starts within 20 3-12 days 3 per day (± Anxiety Araki et al., 2002
min 2.5) Shinoda et al., 2004
Usually termi- Mouri et al., 2008
nated at 30-40 Tanaka et al., 2010
min Li et al., 2012
No mortality Liu et al., 2013
Supra-HC Lasts for 2-7 h 4-13 days 2.8 per day No data Bedner et al., 2015
<10% mortality (± 3.5) Jefferys et al., 2016
Pitsch et al., 2019
Intranasal Starts within 15-30 days Reported Increased locomo- Chen et al., 2002
15-30 min tion Duan et al., 2006
Lasts for 1-5h Zhang et al., 2008
~ 6.5% mortali- Lu et al., 2008
ty Sabilallah et al., 2016
2164 81
2165 2166 2167
2168
2169 Am — amygdala; eSRS — electrographic spontaneous recurrent seizures; HC — hippocampus;
2170 SE — status epilepticus; SRS — spontaneous recurrent seizures;
82