A missense mutation of the gene encoding voltage-dependent sodium channel (NaV1.1) confers susceptibility to febrile seizures in rats

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

Research output: Contribution to journalArticle

43 Citations (Scopus)

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 Nav1.1 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 v1.1 channel confers susceptibility to FS and the impaired biophysical properties of inhibitory GABAergic neurons underlie one of the mechanisms of FS.

Original languageEnglish
Pages (from-to)5744-5753
Number of pages10
JournalJournal of Neuroscience
Volume30
Issue number16
DOIs
Publication statusPublished - Apr 21 2010

Fingerprint

Febrile Seizures
Sodium Channels
Missense Mutation
Interneurons
Genes
Tonic-Clonic Epilepsy
Ethylnitrosourea
GABAergic Neurons
Induced Hyperthermia
Mutagenesis
Action Potentials
Seizures

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

A missense mutation of the gene encoding voltage-dependent sodium channel (NaV1.1) confers susceptibility to febrile seizures in rats. / Mashimo, Tomoji; Ohmori, Iori; Oouchida, Mamoru; Ohno, Yukihiro; Tsurumi, Toshiko; Miki, Takafumi; Wakamori, Minoru; Ishihara, Shizuka; Yoshida, Takashi; Takizawa, Akiko; Kato, Megumi; Hirabayashi, Masumi; Sasa, Masashi; Mori, Yasuo; Serikawa, Tadao.

In: Journal of Neuroscience, Vol. 30, No. 16, 21.04.2010, p. 5744-5753.

Research output: Contribution to journalArticle

Mashimo, T, Ohmori, I, Oouchida, M, Ohno, Y, Tsurumi, T, Miki, T, Wakamori, M, Ishihara, S, Yoshida, T, Takizawa, A, Kato, M, Hirabayashi, M, Sasa, M, Mori, Y & Serikawa, T 2010, 'A missense mutation of the gene encoding voltage-dependent sodium channel (NaV1.1) confers susceptibility to febrile seizures in rats', Journal of Neuroscience, vol. 30, no. 16, pp. 5744-5753. https://doi.org/10.1523/JNEUROSCI.3360-09.2010
Mashimo, Tomoji ; Ohmori, Iori ; Oouchida, Mamoru ; Ohno, Yukihiro ; Tsurumi, Toshiko ; Miki, Takafumi ; Wakamori, Minoru ; Ishihara, Shizuka ; Yoshida, Takashi ; Takizawa, Akiko ; Kato, Megumi ; Hirabayashi, Masumi ; Sasa, Masashi ; Mori, Yasuo ; Serikawa, Tadao. / A missense mutation of the gene encoding voltage-dependent sodium channel (NaV1.1) confers susceptibility to febrile seizures in rats. In: Journal of Neuroscience. 2010 ; Vol. 30, No. 16. pp. 5744-5753.
@article{4e11527a6bd742b099b3f43bf779671a,
title = "A missense mutation of the gene encoding voltage-dependent sodium channel (NaV1.1) confers susceptibility to febrile seizures in rats",
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 Nav1.1 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 v1.1 channel confers susceptibility to FS and the impaired biophysical properties of inhibitory GABAergic neurons underlie one of the mechanisms of FS.",
author = "Tomoji Mashimo and Iori Ohmori and Mamoru Oouchida and Yukihiro Ohno and Toshiko Tsurumi and Takafumi Miki and Minoru Wakamori and Shizuka Ishihara and Takashi Yoshida and Akiko Takizawa and Megumi Kato and Masumi Hirabayashi and Masashi Sasa and Yasuo Mori and Tadao Serikawa",
year = "2010",
month = "4",
day = "21",
doi = "10.1523/JNEUROSCI.3360-09.2010",
language = "English",
volume = "30",
pages = "5744--5753",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "16",

}

TY - JOUR

T1 - A missense mutation of the gene encoding voltage-dependent sodium channel (NaV1.1) confers susceptibility to febrile seizures in rats

AU - Mashimo, Tomoji

AU - Ohmori, Iori

AU - Oouchida, Mamoru

AU - Ohno, Yukihiro

AU - Tsurumi, Toshiko

AU - Miki, Takafumi

AU - Wakamori, Minoru

AU - Ishihara, Shizuka

AU - Yoshida, Takashi

AU - Takizawa, Akiko

AU - Kato, Megumi

AU - Hirabayashi, Masumi

AU - Sasa, Masashi

AU - Mori, Yasuo

AU - Serikawa, Tadao

PY - 2010/4/21

Y1 - 2010/4/21

N2 - 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 Nav1.1 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 v1.1 channel confers susceptibility to FS and the impaired biophysical properties of inhibitory GABAergic neurons underlie one of the mechanisms of FS.

AB - 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 Nav1.1 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 v1.1 channel confers susceptibility to FS and the impaired biophysical properties of inhibitory GABAergic neurons underlie one of the mechanisms of FS.

UR - http://www.scopus.com/inward/record.url?scp=77951555712&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77951555712&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.3360-09.2010

DO - 10.1523/JNEUROSCI.3360-09.2010

M3 - Article

C2 - 20410126

AN - SCOPUS:77951555712

VL - 30

SP - 5744

EP - 5753

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 16

ER -