Referenced in: none

Automatically associated channels: Kir2.3 , Nav1.1

Title: A missense mutation of the gene encoding voltage-dependent sodium channel (Nav1.1) confers susceptibility to febrile seizures in rats.

Authors: Tomoji Mashimo, Iori Ohmori, Mamoru Ouchida, Yukihiro Ohno, Toshiko Tsurumi, Takafumi Miki, Minoru Wakamori, Shizuka Ishihara, Takashi Yoshida, Akiko Takizawa, Megumi Kato, Masumi Hirabayashi, Masashi Sasa, Yasuo Mori, Tadao Serikawa

Journal, date & volume: J. Neurosci., 2010 Apr 21 , 30, 5744-53

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/20410126

Abstract
Although febrile seizures (FSs) are the most common convulsive syndrome in infants and childhood, the etiology of FSs has remained unclarified. Several missense mutations of the Na(v)1.1 channel (SCN1A), which alter channel properties, have been reported in a familial syndrome of GEFS+ (generalized epilepsy with febrile seizures plus). Here, we generated Scn1a-targeted rats carrying a missense mutation (N1417H) in the third pore region of the sodium channel by gene-driven ENU (N-ethyl-N-nitrosourea) mutagenesis. Despite their normal appearance under ordinary circumstances, Scn1a mutant rats exhibited remarkably high susceptibility to hyperthermia-induced seizures, which involve generalized clonic and/or tonic-clonic convulsions with paroxysmal epileptiform discharges. Whole-cell patch-clamp recordings from HEK cells expressing N1417H mutant channels and from hippocampal GABAergic interneurons of N1417H mutant rats revealed a significant shift of the inactivation curve in the hyperpolarizing direction. In addition, clamp recordings clearly showed the reduction in action potential amplitude in the hippocampal interneurons of these rats. These findings suggest that a missense mutation (N1417H) of the Na(v)1.1 channel confers susceptibility to FS and the impaired biophysical properties of inhibitory GABAergic neurons underlie one of the mechanisms of FS.