[POS-3] Voltage-gated sodium ion channels in epileptic encephalopathy
Voltage-gated sodium ion channels (VGSC) are the main generator of the action potential and play crucial roles in nerves and muscles. VGSC consist of the main pore-forming α-subunit and two auxiliary β-subunits. Genetic abnormalities causing epileptic encephalopathy (EE) were found in the α-subunit of the VGSC subtypes Nav1.1, Nav1.2, and Nav1.6, which are encoded by the genes SCN1A, SCN2A, and SCN8A, respectively. Mutations of SCN1A cause Dravet syndrome, while those of SCN2A and SCN8A cause Dravet-syndrome-like EE. In vitro electrophysiological analyses have revealed that SCN1A and SCN2A mutations result in insufficient Nav1.1 and Nav1.2 functions, respectively. In contrast, mutations of SCN8A, of which only missense mutations were reported, lead to a gain-of-function in Nav1.6. Accordingly, there are phenotypic differences between these types of EE, specifically regarding the efficacy of VGSC blockers. VGSC blockers may precipitate Dravet syndrome, but ameliorate seizures in SCN2A EE and SCN8A EE to some extent. The differences among EE types suggest different underlying pathomechanisms. Recently, using human induced pluripotent stem cells (iPSCs), we found that inhibitory GABAergic neurons derived from Dravet syndrome patients had impaired action potentials. The pathomechanisms of Dravet syndrome caused by SCN1A mutations may thus be attributed to dysfunction of inhibitory interneurons, while similar investigations are yet to be completed for SCN2A EE and SCN8A EE. The functional roles of VGSC within the neuronal network should be taken into account when considering exact underlying pathomechanisms and providing precision medicine treatment strategies for EE caused by VGSC abnormalities.