Neurons die following certain brief seizures. Such neuronal death may contribute to cognitive decline in patients with poorly managed seizures, or contribute to more severe seizures in epileptic brain. Brief seizures activate a coordinated molecular pathway within the hippocampus that involves dimerization interactions of pro- and antiapoptotic members of the Bcl-2 gene family and their satellite regulators, protein kinase B and 14-3-3 proteins. Pharmacological interventions confirm this pathway drives as much as half of cell death after seizures. Our preliminary data reveals that expression and interaction of two cell death regulators, Bcl-w and Bim, are fundamentally critical to whether seizures cause neuronal death. Seizure-induced activation of forkhead transcription factors drive Bim overexpression, which quenches Bcl-w, an endogenous molecular brake on cell death. In turn, mice deficient in the Bcl-w gene exhibit a lowered threshold for injury following seizures, despite reactive upregulation of protective genes. Our central hypothesis is: Bim and Bcl-w regulate the majority of neuronal death after brief seizures.
The specific aims of this project are: 1. Characterize the expression and interactions of cell death regulators Bcl-w and Bim following brief seizures and in long-term epilepsy. 2. Investigate the effects of manipulating Bcl-w expression on seizure-induced damage and epileptogenesis. 3. Demonstrate the in vivo functional significance of Bcl-w and Bim by examining seizure-induced neuronal damage in mice deficient in each gene. 4. Determine the consequence of Bim and Bcl-w gene deletions on the generation of an epileptic phenotype. These studies will identify potent regulatory sites in the molecular pathways by which neurons die following .brief, electrographically defined seizures, thereby offering novel, focused neuroprotective targets beyond anticonvulsants for treating at-risk epilepsy patients.
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