Investigation of modifiers for epilepsy by using mouse models

严重的婴儿期肌阵挛癫痫(SMEI)是由编码电压门控钠通道α-亚基类型1，Nav1.1的SCN1A基因突变引起的。我们最近培育和报告的带有Scnla无感突变(Scnla-Ki)的小鼠(Ogiwara，et.等，J Neurosci 22：5903-5914,2007)表现出严重的癫痫发作，纯合子在2周内死亡。在Scnla-Ki小鼠中，未检测到Nav1.1蛋白，表明SMEI的病理基础是单倍体不足，而不是截短的Nav1.1蛋白的显性负效应。我们还发现了抑制性神经元的功能缺陷，而兴奋性神经元则没有。此外，我们发现在野生型小鼠中，nev1.1定位于抑制性神经元的轴突和胞体中，即小白蛋白阳性篮子细胞。具有B6遗传背景的Scnla-Ki与Wit 129背景的Scnla-Ki相比，表现出更严重的表型。以MSM小鼠为研究对象，对X染色体上的修饰基因进行了定位，并利用白石敏彦博士培育的家系小鼠缩小了修饰基因的区域。

Severe myoclonic epilepsy in infancy (SMEI) is caused by mutations in the SCN1A gene encoding a voltage-gated sodium channel alpha-subunit type-1, Nav1.1. The mouse with Scnla nonsence mutation (Scnla-KI) that we recently generated and reported (Ogiwara, et. al., J Neurosci 22: 5903-5914, 2007) shows severe epileptic seizures and the homozygote die within 2 weeks.In Scnla-KI mouse, no Nav1.1 protein is detected indicating that haploinsufficiency, rather than dominant-negative effects of truncated Nav1.1 proteins, is the pathological basis for SMEI. We also showed the functional defects specifically in inhibitory neurons and not in excitatory neurons. Furthermore, we found that in wild-type mouse Nev1.1 is localized at axon and somata of a subclass of inhibitory neurons, parvalbumin-positive basket cells.The Scnla-KI with B6 genetic background shows severee phenotypes compared to that wit 129 background. By using MSM mice, we identified the modifier gene locus at X-chromosome, and narrowed the region by usin the consomic mouse developed by Dr. Toshihiko Shiroishi.