Effects of Anticonvulsants and Monoamines on Seizures in Mutant Drosophila

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.