The voltage-gated sodium channel Scn8a is a genetic modifier of severe myoclonic epilepsy of infancy

摘要

The mammalian genome contains four voltage-gated sodium channel genes that are primarily expressed in the central nervous system: SCN1A, SCN2A, SCN3A and SCN8A. Mutations in SCN1A and SCN2A are responsible for several dominant idiopathic epilepsy disorders, including generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI). Mutations in SCN8A are associated with cognitive deficits and neuropsychiatric illness in humans and movement disorders in mice; however, a role for SCN8A (Na_v1.6) in epilepsy has not been investigated. To determine the relationship between Na_v1.6 dysfunction and seizure susceptibility, we examined the thresholds of two Scn8a mouse mutants, Scn8amed and Scn8amed-jo, to flurothyl- and kainic acid (KA)-induced seizures. Both mutants were more seizure resistant than wild-type littermates, suggesting that altered Na_v1.6 function reduces neuronal excitability. To determine whether impaired Na_v1.6 function could ameliorate seizure severity in a mouse model of SMEI, we generated Scn1a+/−; Scn8amed-jo/+ double heterozygous mice. Unlike Scn1a+/− mice that are more susceptible to flurothyl-induced seizures, Scn1a+/−; Scn8amed-jo/+ mice displayed thresholds that were comparable to wild-type littermates. The Scn8amed-jo allele was also able to rescue the premature lethality of Scn1a+/− mice and extend the lifespan of Scn1a−/− mutants. These results demonstrate that genetic interactions can alter seizure severity and support the hypothesis that genetic modifiers contribute to the clinical variability observed in SMEI and GEFS+.