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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-1 (01))
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Finkelstein, Robert
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University of California Berkeley
Public Health & Prev Medicine
Schools of Earth Sciences/Natur
United States
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Saras, Arunesh; Wu, Veronica V; Brawer, Harlan J et al. (2017) Investigation of Seizure-Susceptibility in a Drosophila melanogaster Model of Human Epilepsy with Optogenetic Stimulation. Genetics 206:1739-1746
Saras, Arunesh; Tanouye, Mark A (2016) Mutations of the Calcium Channel Gene cacophony Suppress Seizures in Drosophila. PLoS Genet 12:e1005784
Saras, Arunesh; Tanouye, Mark A (2016) Seizure Suppression by High Temperature via cAMP Modulation in Drosophila. G3 (Bethesda) 6:3381-3387
Kroll, Jason R; Wong, Karen G; Siddiqui, Faria M et al. (2015) Disruption of Endocytosis with the Dynamin Mutant shibirets1 Suppresses Seizures in Drosophila. Genetics 201:1087-102
Kroll, Jason R; Saras, Arunesh; Tanouye, Mark A (2015) Drosophila sodium channel mutations: Contributions to seizure-susceptibility. Exp Neurol 274:80-7
Rusan, Zeid M; Kingsford, Olivia A; Tanouye, Mark A (2014) Modeling glial contributions to seizures and epileptogenesis: cation-chloride cotransporters in Drosophila melanogaster. PLoS One 9:e101117
Howlett, Iris C; Tanouye, Mark A (2013) Seizure-sensitivity in Drosophila is ameliorated by dorsal vessel injection of the antiepileptic drug valproate. J Neurogenet 27:143-50
Howlett, Iris C; Rusan, Zeid M; Parker, Louise et al. (2013) Drosophila as a model for intractable epilepsy: gilgamesh suppresses seizures in para(bss1) heterozygote flies. G3 (Bethesda) 3:1399-407
Kroll, Jason R; Tanouye, Mark A (2013) Rescue of easily shocked mutant seizure sensitivity in Drosophila adults. J Comp Neurol 521:3500-7
Parker, Louise; Howlett, Iris C; Rusan, Zeid M et al. (2011) Seizure and epilepsy: studies of seizure disorders in Drosophila. Int Rev Neurobiol 99:1-21

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