An animal model of genetic predisposition to develop acquired epileptogenesis: The FAST and SLOW rats

Abstract

Epidemiological data and gene association studies suggest a genetic predisposition to developing epilepsy after an acquired brain insult, such as traumatic brain injury. An improved understanding of genetic determinants of vulnerability is imperative for early disease diagnosis and prognosis prediction, with flow‐on benefits for the development of targeted antiepileptogenic treatments as well as optimal clinical trial design. In the laboratory, one approach to investigate why some individuals are more vulnerable to acquired epilepsy than others is to examine unique rodent models exhibiting either vulnerability or resistance to epileptogenesis. This review focuses on the most well‐characterized of these models, the FAST (seizure‐prone) and SLOW (seizure‐resistant) rat strains, which were derived by selective breeding for differential amygdala electrical kindling rates. We describe how these strains differ in their seizure profiles, neuroanatomy, and neurobehavioral phenotypes, both at baseline and after a brain insult, with this knowledge proving fruitful to identify common pathological abnormalities associated with seizure susceptibility and psychiatric comorbidities. It is important to note that accruing data on strain differences in multiple biological processes provides insight into why some individuals may be more vulnerable to epileptogenesis, although future studies are evidently needed to identify the precise molecular and genetic risk factors. Together, the FAST and SLOW rat strains, and other similar experimental models, are invaluable neurobiological tools to investigate the effect of genetic background on acquired epilepsy risk, as well as the poorly understood relationship between epilepsy development and associated comorbidities.

Hyperexcitability: From Normal Fear to Pathological Anxiety and Trauma

“…Genetic strains of rats that kindle fast or slow have been developed by selective breeding to assess genetic predispositional contributions to acquiring epilepsy and reactivity to uncertainty and threat ( McIntyre et al, 2002 ; McIntyre and Gilby, 2007 ; Leung et al, 2019 ). Initial afterdischarge thresholds are not different between fast and slow kindling rats but fast kindling rats develop generalized motor seizures about 4 times as fast as slow kindling rats ( Racine et al, 1999 ).…”

Immune Challenges and Seizures: How Do Early Life Insults Influence Epileptogenesis?

“…Similarly, in a population-based cohort study of more than 1.6 million Danish adults and children, a family history of epilepsy was associated with an approximately 10-fold higher risk of developing late-onset seizures following a severe brain injury (Christensen et al, 2009). Limited studies to date have specifically probed for gene associations with acquired epilepsy risk, as recently reviewed (Leung et al, 2019). Consistent with the abovementioned evidence on IL-1b polymorphisms and PTE risk, a meta-analysis found that specific alleles of both IL-1b and IL-1a have also been associated with risk of epilepsy after FS (Saghazadeh et al, 2014).…”