Effects of Anticonvulsants and Monoamines on Seizures in Mutant Drosophila

Saturday, 14 February 2015
Exhibit Hall (San Jose Convention Center)
Eden Barragan, University of California, Irvine, Irvine, CA
Mutations in the voltage-gated sodium channel gene SCN1A cause a wide spectrum of epilepsy disorders, from the mild form of genetic epilepsy with febrile seizures plus (GEFS+) to the severe form of Dravet Syndrome (DS). Both diseases are characterized by febrile seizures. We used two knock-in fly lines, one with GEFS+ (K1270T) mutation and one with DS (S1231R) mutation, as model systems to search for new therapies. Consistent with disease symptoms in humans, GEFS+ and DS flies exhibit heat-induced seizures and the seizure phenotype is more severe in DS compared to GEFS+ flies. Our initial studies focused on 3-day feeding of anticonvulsants, but none were found to alleviate seizure behavior in either mutant. Additional experiments focused on monoamine signaling since we found that seizure-sensitivity was altered in DS and GEFS+ flies in a genetic background (white eyes) that affects monoamine levels. Feeding adult flies for 3 days with the serotonin precursor, 5-hydroxytryptophan (5-HTP), significantly reduces seizure sensitivity in a dose-dependent manner in DS mutants, but increases seizures in GEFS+ mutants. Injecting serotonin, 5-hydroxytryptamine (5-HT), into the dorsal vein of adult flies also significantly reduces seizure sensitivity in DS mutants one hour post-injection although the magnitude of reduction is less than induced by feeding. These data demonstrate that manipulation of serotonin signaling can result in both acute and long-term suppression of heat-induced seizures in DS flies, suggesting this pathway as an alternative therapeutic target for treatment of DS.