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.
Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, California 92697-1280, USA.
Lei
L
Sun
Jeff
J
Gilligan
Cynthia
C
Staber
Ryan J
RJ
Schutte
Vivian
V
Nguyen
Diane K
DK
O'Dowd
Robert
R
Reenan
D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics; D004331:Drosophila melanogaster; D004827:Epilepsy / Q000235:genetics / Q000503:physiopathology; D004829:Epilepsy, Generalized / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D055879:Gene Knock-In Techniques / Q000379:methods; D006358:Hot Temperature / Q000009:adverse effects*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics*; D012640:Seizures / Q000235:genetics / Q000503:physiopathology; D003294:Seizures, Febrile / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology
D029721:Drosophila Proteins; D062550:NAV1.1 Voltage-Gated Sodium Channel; C568242:SCN1A protein, human