Efficacy of Selective Sodium Channel Block in Dravet Syndrome

Mutation in SCN1A, encoding the voltage-gated sodium channel NaV1.1, is one of the most commonly observed genetic causes of epilepsy in children. More than 800 different heterozygous epilepsy-associated SCN1A mutations have been identified, with more than 70% occurring in children with Dravet syndrome, who suffer the onset of seizures during the first year of life with an ensuing epileptic encephalopathy consisting of cognitive, behavioral and motor impairments as well as premature death. Conventional antiepileptic drugs that target sodium channels may paradoxically worsen the condition in some patients. Heterozygous Scn1a knockout (Scn1a+/-) mice provide an excellent animal model for Dravet syndrome. On a partial C57BL/6 genetic background, Scn1a+/- mice exhibit spontaneous seizures, reduced seizure threshold and premature death. Heterozygous loss of NaV1.1 has been correlated with reduced sodium current density and impaired neuronal excitability in GABAergic interneurons. But recent work has also demonstrated increased sodium current density and/or increased spontaneous excitatory neuronal firing in acutely dissociated hippocampal pyramidal neurons and brain slices from Dravet syndrome mice, and in patient-derived neurons