Genetic complexity of absence seizures in substrains of C3H mice

Absence epilepsy is a common form of idiopathic generalized epilepsy whose etiology is poorly understood because of genetic and phenotypic heterogeneity. The inbred mouse strain C3H/He exhibits spontaneous absence seizures characterized by spike and wave discharges (SWD) on the electroencephalogram concomitant with behavioral arrest. Previous studies using the C3H/HeJ (HeJ) substrain identified a mutation in the Gria4 gene as a major susceptibility locus. In the present study, we found that two closely related substrains C3H/HeOuJ (OuJ) and C3H/HeSnJ, which have a similar SWD incidence as HeJ, do not contain the Gria4 mutation. Further analysis of backcross mice segregating OuJ and C57BL/6J alleles shows that, unlike the HeJ substrain, OuJ does not have a major locus for SWD but has suggestive loci at best that would explain only a fraction of the phenotypic variance. These results illustrate how the genetic etiology of a common neurological disorder can differ between substrains with similar phenotypes. We infer that all C3H strains are sensitized to SWD and that additional mutations affecting SWD arose or were fixed independently in the years since the substrains diverged.