Seizures are a serious problem in many human neuropathologies. They are a major symptom associated with fever, mechanical trauma, electroconvulsive shock, drugs, alcohol, tumors, and epilepsy. The long-term objective of this research is to discover novel treatments for nervous system seizures. The general approach is to establish a model for seizure disorders in the fruitfly Drosophila by taking advantage of a) electrophysiological methods developed to quantify levels of seizure susceptibility and b) mutations that modify this susceptibility. One useful class of mutants are seizure-sensitive, about 5-10 times more sensitive than normal flies. These mutants are called bang sensitive (BS) paralytics and are caused by mutations in several identified genes, including bangsenseless (bss), easily shocked (eas), and slamdance (sda). Another useful class of mutations are seizure-suppressor mutations. Seizure-suppression is manifested in two ways: 1) animals carrying suppressor mutations are seizure-resistant compared with normal flies (greater than twofold more resistant); and 2) suppressor mutations confer seizure resistance to seizure-sensitive strains in homozygous double mutant combinations. That is, suppressor mutations """"""""cure"""""""" the seizure defect of Drosophila """"""""epilepsy"""""""" mutants. Several seizure-suppressor genes having been identified thus far including mle napts, an RNA helicase involved in Na+ channel regulation and shakB, a gap junction connexin.
Aim 1 is to determine how seizures are suppressed by mutations in the seizure-suppressor gene, shakB (gap junction connexin).
Aim 2 is to identify new seizure-suppressor genes through double mutant combinations with existing Drosophila mutations.
Aim 3 is to conduct mutant screens for identifying novel seizure-suppressor mutations.
Aim 4 is to determine how seizures are suppressed by gain-of-function mutations in the transcription repressor gene, esg.
Aim 5 is to determine the effect of anticonvulsant drugs on seizure susceptibility in BS mutants.
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