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The Kainic Acid Models of Temporal Lobe Epilepsy

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The Kainic Acid Models of Temporal Lobe Epilepsy 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 This Early Release article has been peer-reviewed and accepted, but has not been through the composition and copyediting processes. The final version may differ slightly in style or formatting and will contain links to any extended data. Alerts: Sign up at www.eneuro.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Copyright © 2021 Rusina et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. 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.
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