论文标题
SCN 1A /NA V 1.1通道病：表达系统，动物模型和人IPSC模型中的机制
SCN 1A /Na V 1.1 channelopathies: Mechanisms in expression systems, animal models, and human iPSC models
论文作者
论文摘要
致病性SCN1A/NAV1.1突变引起明确定义的癫痫病，包括带有发热性癫痫发作的遗传癫痫加上（GEFS+）和严重的癫痫性脑病Dravet综合征。此外，它们会与Aura，家族性偏瘫偏头痛引起严重的偏头痛。此外，已将SCN1A/NAV1.1变体推断为其他类型的癫痫中的风险因素。我们在这里审查了研究SCN1A/NAV1.1突变通过实验系统的病理机制获得的进步。我们提出了通过体外表达系统，基因靶向动物模型和IPSC技术获得的结果，突出了每个系统的优势，限制和陷阱。 总体而言，在过去的二十年中获得的结果证实，癫痫发作SCN1A/NAV1.1突变的初始病理机制是NAV1.1的功能丧失，导致至少某些类型的GABA能神经元（包括皮质和海马Parvalbumin--和somaTostinsostin和SomaToStinsposistin）的功能不足。相反，更有限的结果指向FHM突变的NAV1.1功能获得。在这些相对简单的病理机制的背后，已经观察到了意外的复杂性，部分是由实验研究中的技术问题所产生的，部分是与本质上复杂的病理生理反应和重塑有关的，但仍将完全分解。
Pathogenic SCN1A/NaV1.1 mutations cause well defined epilepsies, including Genetic Epilepsy with Febrile Seizures Plus (GEFS+) and the severe epileptic encephalopathy Dravet syndrome. In addition, they cause a severe form of migraine with aura, Familial Hemiplegic Migraine. Moreover, SCN1A/NaV1.1 variants have been inferred as risk factors in other types of epilepsy. We review here the advancements obtained studying pathological mechanisms of SCN1A/NaV1.1 mutations with experimental systems. We present results gained with in vitro expression systems, gene targeted animal models and the iPSC technology, highlighting advantages, limits and pitfalls for each of these systems. Overall, the results obtained in the last two decades confirm that the initial pathological mechanism of epileptogenic SCN1A/NaV1.1 mutations is loss-of-function of NaV1.1 leading to hypoexcitability of at least some types of GABAergic neurons (including cortical and hippocampal parvalbumin- and somatostatin-positive ones). Conversely, more limited results point to NaV1.1 gain-of-function for FHM mutations. Behind these relatively simple pathological mechanisms, an unexpected complexity has been observed, in part generated by technical issues in experimental studies and in part related to intrinsically complex pathophysiological responses and remodeling, which yet remain to be fully disentangled.
