GABA (A) Receptor Subunit Regulation in Epileptogenesis

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Temporal lobe epilepsy (TLE)is the most common form of epilepsy and is frequently medically intractable. There is abundant evidence that abnormalities in inhibitory neurotransmission play an important role in TLE. GABA(A) receptors (GABARs) are the most abundant inhibitory neurotransmitter receptors in forebrain, however, relatively little is known regarding regulation of their expression either in health or in disease. We have demonstrated long-term changes in expression of GABAR subunits, including decreases in thecc1 subunit, in hippocampal dentate granule neurons (DGNs) following status epilepticus (SE)in adult rats, that are associated with marked changes in receptor pharmacology and function. Further, changes in a1 levels are highly dependent on the age at which SE occurs, and vary inversely with the likelihood of subsequent epilepsy development. In addition, we find that enhancing a1 subunit levels using viral mediated gene transfer inhibits development of epilepsy after SE. These findings suggest that diminished cc1levels in DGN may contribute to epileptogenesis and that elevated a1 levels could be protective. To utilize this therapeutic potential requires an understanding of how the GABAR a1 subunit gene (GABRA1) is regulated. We therefore propose to investigate potential regulatory mechanisms that control GABRA1 expression. We will examine the role of two identified candidate signaling pathways, the cAMP response element binding protein (CREB) pathway and the glucocorticoid receptor pathway, in regulating GABRA1 following SE. Further, using proteomics techniques we will identify the constellation of transcription factors that interact with the GABRA1 promoter in the region of concensus sites for CREB and GRs and determine if this constellation changes after SE. The proposed studies are expected to elucidate mechanisms that control GABRA1 expression and determine how this regulation is altered during epileptogenesis. Results of these studies should facilitate development of new therapies for the prevention or cure of epilepsy by identifying potential new therapeutic targets that specifically regulate GABAR subunit gene expression. Relevance to Public Health: Epilepsy affects more than 2.5 million Americans. Severe seizures that resist treatment occur in up to 20% of epilepsy patients and can be associated with a shortened life span, social and intellectual impairment, underemployment and a reduced quality of life. The proposed studies should identify how expression of key genes involved in nerve cell transmission are regulated after seizures and may lead to new and better ways to treat or prevent epilepsy.