How do mutant Nav1.1 sodium channels cause epilepsy?

Voltage-gated sodium channels comprise pore-forming alpha subunits and auxiliary beta subunits. Nine different alpha subtypes, designated Nav1.1-Nav1.9 have been identified in excitable cells. Nav1.1, 1.2 and 1.6 are major subtypes in the adult mammalian brain. More than 200 mutations in the Nav1.1 alpha subtype have been linked to inherited epilepsy syndromes, ranging in severity from the comparatively mild disorder Generalized Epilepsy with Febrile Seizures Plus to the epileptic encephalopathy Severe Myoclonic Epilepsy of Infancy. Studies using heterologous expression and functional analysis of recombinant Nav1.1 channels suggest that epilepsy mutations in Nav1.1 may cause either gain-of-function or loss-of-function effects that are consistent with either increased or decreased neuronal excitability. How these diverse effects lead to epilepsy is poorly understood. This review summarizes the data on sodium channel mutations and epilepsy and builds a case for the hypothesis that most Nav1.1 mutations have their ultimate epileptogenic effects by reducing Nav1.1-mediated whole cell sodium currents in GABAergic neurons, resulting in widespread loss of brain inhibition, an ideal background for the genesis of epileptic seizures.