A Missense Mutation of the Gene Encoding Voltage-Dependent Sodium Channel (Nav1.1) Confers Susceptibility to Febrile Seizures in Rats
A Missense Mutation of the Gene Encoding Voltage-Dependent Sodium Channel (Nav1.1) Confers Susceptibility to Febrile Seizures in Rats
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DOI：
10.1523/jneurosci.3360-09.2010
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发表时间：
2010-04-21
影响因子：
5.3
通讯作者：
Serikawa, Tadao
中科院分区：
文献类型：
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作者：
Mashimo, Tomoji;Ohmori, Iori;Serikawa, Tadao
虽然热性惊厥（FS）是婴儿和儿童最常见的惊厥综合征，但FS的病因仍不清楚。Na（v）1.1通道（SCN 1A）的几个错义突变改变了通道特性，已在GEFS+（全身性癫痫伴热性惊厥+）家族综合征中报道。在这里，我们通过基因驱动的ENU（N-乙基-N-亚硝基脲）诱变产生了在钠通道的第三孔区域携带错义突变（N1417 H）的Scn 1a靶向大鼠。尽管它们在普通情况下外观正常，但Scn 1a突变大鼠对高血压诱导的癫痫发作表现出非常高的易感性，其中涉及全身性阵挛性和/或强直-阵挛性惊厥伴阵发性癫痫样放电。全细胞膜片钳记录从HEK细胞表达N1417 H突变通道和海马GABA能中间神经元的N1417 H突变大鼠揭示了一个显着的移动的失活曲线在超极化方向。此外，钳夹记录清楚地显示这些大鼠海马中间神经元的动作电位振幅降低。这些发现表明Na（v）1.1通道的错义突变（N1417 H）赋予FS的易感性，并且抑制性GABA能神经元的生物物理特性受损是FS的机制之一。
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.