A gain-of-function mutation in the sodium channel gene Scn2a results in seizures and behavioral abnormalities

The GAL879-881QQQ mutation in the cytoplasmic S4-S5 linker of domain 2 of t he rat brain IIA sodium channel (Na(v)1.2) results in slowed inactivation a nd increased persistent current when expressed in Xenopus oocytes. The neur on-specific enolase promoter was used to direct in vivo expression of the m utated channel in transgenic mice. Three transgenic lines exhibited seizure s, and line Q54 was characterized in detail. The: seizures in these mice be gan at two months of age and were accompanied by behavioral arrest and ster eotyped repetitive behaviors. Continuous electroencephalogram monitoring de tected focal seizure activity in the hippocampus, which in some instances g eneralized to involve the cortex. Hippocampal CA1 neurons isolated from pre symptomatic Q54 mice exhibited increased persistent sodium current which ma y underlie hyperexcitability in the hippocampus. During the progression of the disorder there was extensive cell loss and gliosis within the hippocamp us in areas CA1, CA2, CA3 and the hilus. The lifespan of Q54 mice was short ened and only 25% of the mice survived beyond six months of age. Four indep endent transgenic lines expressing the wild-type sodium channel were examin ed and did not exhibit any abnormalities. The transgenic Q54 mice provide a genetic model that will be useful fur tes ting the effect of pharmacological intervention on progression of seizures caused by sodium channel dysfunction. The human ortholog, SCN2A, is a candi date gene for seizure disorders mapped to chromosome 2q22-24. (C) 2001 IBRO . Published by Elsevier Science Ltd, All rights reserved.