Investigation of modifiers for epilepsy by using mouse models

婴儿严重肌阵挛性癫痫（SMEI）是由编码电压门控钠通道α -亚基1型（Nav1.1）的SCN1A基因突变引起的。我们最近生成并报道的scla无义突变（scla - ki）小鼠（Ogiwara, et al., 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scla - ki小鼠中，未检测到Nav1.1蛋白，这表明单倍体功能不全是SMEI的病理基础，而不是截断的Nav1.1蛋白的显性负作用。我们还发现了抑制性神经元的功能缺陷，而非兴奋性神经元。此外，我们发现野生型小鼠的Nev1.1定位于抑制性神经元亚类的轴突和体细胞，即小蛋白阳性篮细胞。具有B6遗传背景的scla - ki比具有129遗传背景的scla - ki表现出严重的表型。通过使用MSM小鼠，我们确定了x染色体上的修饰基因位点，并使用Toshihiko Shiroishi博士开发的经济小鼠缩小了该区域。

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.