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 language | English |
|---|---|
| Pages (from-to) | 5744-5753 |
| Number of pages | 10 |
| Journal | Journal of Neuroscience |
| Volume | 30 |
| Issue number | 16 |
| DOIs | |
| Publication status | Published - Apr 21 2010 |
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- Neuroscience(all)
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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 journal › Article
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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 -