Neurobiology of Disease A Knock-In Model of Human Epilepsy in Drosophila Reveals a Novel Cellular Mechanism Associated with Heat-Induced Seizure

Over 40 missense mutations in the human SCN1A sodium channel gene are linked to an epilepsy syndrome termed genetic epilepsy with febrile seizures plus (GEFS ). Inheritance of GEFS is dominant, but the underlying cellular mechanisms remain poorly understood. Here we report that knock-in of a GEFS SCN1A mutation (K1270T) into the Drosophila sodium channel gene, para, causes a semidominant temperature-induced seizure phenotype. Electrophysiological studies of GABAergic interneurons in the brains of adult GEFS flies reveal a novel cellular mechanism underlying heat-induced seizures: the deactivation threshold for persistent sodium currents reversibly shifts to a more negative voltage when the temperature is elevated. This leads to sustained depolarizations in GABAergic neurons and reduced inhibitory activity in the central nervous system. Furthermore, our data indicate a natural temperature-dependent shift in sodium current deactivation (exacerbated by mutation) may contribute to febrile seizures in GEFS and perhaps normal individuals.