GABA (A) Receptor Subunit Regulation in Epileptogenesis

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DESCRIPTION (provided by applicant): 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. GABAA 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 the a1 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 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 levels using viral mediated gene transfer inhibits development of epilepsy after SE. These findings suggest that diminished a1 levels in DGN may contribute to epileptogenesis and that elevated a1 levels could be protective. To utilize this therapeutic potential, however, requires an understanding of how GABAR a1 subunit expression is regulated. We therefore propose to investigate potential regulatory mechanisms that control GABAR a1 gene 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 GABAR a1 subunit expression following SE. Further, using a combination of bioinformatics and proteomics we will perform a screen for other transcription factors that show enhanced interaction with the a1 promoter after SE. The proposed studies are expected to elucidate how a1 expression is regulated and 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 target regulation of GABAR subunit gene expression.