Advances on genetic rat models of epilepsy

Abstract

Considering the suitability of laboratory rats in epilepsy research, we and other groups have been developing genetic models of epilepsy in this species. After epileptic rats or seizure-susceptible rats were sporadically found in outbred stocks, the epileptic traits were usually genetically-fixed by selective breeding. So far, the absence seizure models GAERS and WAG/Rij, audiogenic seizure models GEPR-3 and GEPR-9, generalized tonic-clonic seizure models IER, NER and WER, and Canavan-disease related epileptic models TRM and SER have been established. Dissection of the genetic bases including causative genes in these epileptic rat models would be a significant step toward understanding epileptogenesis. N-ethyl-N-nitrosourea (ENU) mutagenesis provides a systematic approach which allowed us to develop two novel epileptic rat models: heat-induced seizure susceptible (Hiss) rats with an Scn1a missense mutation and autosomal dominant lateral temporal epilepsy (ADLTE) model rats with an Lgi1 missense mutation. In addition, we have established episodic ataxia type 1 (EA1) model rats with a Kcna1 missense mutation derived from the ENU-induced rat mutant stock, and identified a Cacna1a missense mutation in a N-Methyl-N-nitrosourea (MNU)-induced mutant rat strain GRY, resulting in the discovery of episodic ataxia type 2 (EA2) model rats. Thus, epileptic rat models have been established on the two paths: ‘phenotype to gene’ and ‘gene to phenotype’. In the near future, development of novel epileptic rat models will be extensively promoted by the use of sophisticated genome editing technologies.

Methodological standards and interpretation of video‐electroencephalography in adult control rodents. A TASK1‐WG1 report of theAES/ILAETranslational Task Force of the ILAE

“… a Automated EEG analysis; data for WAG/Rij strain of rats considered as standard models of genetic absence epilepsy are not included. …”

“…Although there is no description of the epidemiology of various types of epilepsies in naive rodents, the possibility that epilepsies may occur spontaneously in naive control rodents cannot be excluded. Several strains or inbred populations of rodents that reliably manifest certain types of epilepsies were bred specifically from naive “control” rodents to create epilepsy‐prone rodents modeling specific epilepsy syndromes . For instance, selective breeding of Wistar rats from a colony with a 30% incidence of SWDs resulted, in just a few generations, in substrains in which either all animals or no animals developed such absencelike events .…”

“…For instance, selective breeding of Wistar rats from a colony with a 30% incidence of SWDs resulted, in just a few generations, in substrains in which either all animals or no animals developed such absencelike events . Classic Mendelian analyses have shown that this SWD trait in both the WAG/Rij and GAERS rat strains exhibits autosomal dominant transmission …”

The genetic audiogenic seizure hamster from Salamanca: The GASH:Sal

“…Although there is no single model of epilepsy that fully recapitulates the human disease spectrum, those models that are genetically predisposed to mimic the variable and complex genetic architecture of epilepsy have proven invaluable [3,4]. Notably, models susceptible to audiogenic seizures, which are genetically susceptible to sound-induced reflex seizures, have vastly contributed to the knowledge of this disease [5][6][7][8].…”

Neural Engineering

“…Primary neurons from various species have been utilized, with the rodent as the most popular source for neural culture Hollenbeck and Bamburg 2003 ). By integrating advances in genetics, primary neurons with various genetic modifi cations have become available to model the nervous system with genetic defects, providing a powerful tool for understanding basic biology, neurological diseases, and therapeutic investigation (Dawson et al 2010 ;McGoldrick et al 2013 ;Philips and Rothstein 2015 ;Serikawa et al 2015 ). The main disadvantages of using primary cultures are that procurement of these cells relies on the sacrifi ce of animals (Levy 2012 ), and the species gap between animals and humans presents a substantial hurdle for translating the fi ndings to clinical usage (Sterneckert et al 2014 ).…”