  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.
