SCN1A/NaV 1.1 channelopathies: Mechanisms in expression systems, animal models, and human iPSC models.

Pathogenic SCN1A/NaV 1.1 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/NaV 1.1 variants have been inferred as risk factors in other types of epilepsy. We review here the advancements obtained studying pathologic mechanisms of SCN1A/NaV 1.1 mutations with experimental systems. We present results gained with in vitro expression systems, gene-targeted animal models, and the induced pluripotent stem cell (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 pathologic mechanism of epileptogenic SCN1A/NaV 1.1 mutations is loss-of-function of NaV 1.1 leading to hypoexcitability of at least some types of γ-aminobutyric acid (GABA)ergic neurons (including cortical and hippocampal parvalbumin-positive and somatostatin-positive ones). Conversely, more limited results point to NaV 1.1 gain-of-function for familial hemiplegic migraine (FHM) mutations. Behind these relatively simple pathologic mechanisms, an unexpected complexity has been observed, in part generated by technical issues in experimental studies and in part related to intrinsically complex pathophysiologic responses and remodeling, which yet remain to be fully disentangled. Wiley Periodicals, Inc.