Genetic and phenotypic heterogeneity of inherited spike-wave epilepsy: two mutant gene loci with independent cerebral excitability defects

Abstract

Two recessive gene loci controlling cerebral excitability in the mouse ( tg, chr 8 and stg, chr 15) share generalized neocortical spike-wave seizures as a common mutant phenotype. Although the primary molecular defects are unknown, homozygous tg mutants display a gene-linked hyperplasia of central noradrenergic axons originating in the locus ceruleus, and early selective lesions of these fibers correct the epileptic phenotype in the adult. In contrast, we find that stg homozygotes, despite a more severe seizure disorder, show no alterations in regional noradrenergic fiber innervation, and seizure frequency is unaffected by neonatal noradrenergic depletion. These mutations demonstrate that excessive synchronous neuronal discharges alone are insufficient to trigger abnormal growth of locus ceruleus fibers, and reveal the existence of two distinct intervening brain neuromodulatory mechanisms, norepinephrine (NE)-dependent and NE-independent, underlying the inheritance of this common pattern of epilepsy.