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). Central to seizure-sensitivity in Drosophila may be a K-C1co-transporter gene called kazachoc (kcc). A kcc mutation acts to enhance seizure-sensitivity in all BS mutants thus far examined. Another useful class of interacting mutations are seizure-suppressors. Seizure- suppression is manifested in two ways: 1) animals carrying suppressor mutations are seizure-resistant compared with normal flies (greater than two-fold 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 includingpara, a Na channel, shakB, a gap junction connexins and esgEP, a dominant, gain-of- function suppressor.
Aim 1 is to identify new seizure-suppressor genes through double mutant combinations with Drosophila mutations (reverse genetics).
Aim 2 is to conduct mutant screens for identifying novel seizure- suppressor mutations.
Aim 3 is to determine how seizures are suppressed by loss-of-function mutations in mei- P26, a RING finger, B-box zinc finger, coiled-coil (RBCC domain) and beta-propeller (NHL domain) protein mediating protein-protein interactions.
Aim 4 is to determine how seizures are suppressed by gain-of-function mutations of esg: the role of esg transcriptional targets.
Aim 5 is to determine how seizure-suppressor mutations and anticonvulsant drugs interact to suppress seizure-susceptibility in BS mutants.
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