The broad goals of this Project are to identify changes in expression of specific subunits of the GABA/A receptor (GABAR) through the use of morphological methods that include in situ hybridization and immunohistochemistry. The studies will focus on two recently observed alterations in GABAR localization and function. First, a marked decrease in expression of the alpha5 subunit has been identified in the pilocarpine model of recurrent seizures, but the factors directly associated with the changes have not been determined. Second, an increase in zinc sensitivity of GBARs has been discovered in the kindling model of epilepsy by Mody, and a major question is whether this might be related to changes in GABAR subunit expression in the vicinity of reorganized mossy fibers. Such findings have led to the following specific aims: 1) Provide ultrastructural descriptions of alpha5 and alpha2 subunit localization in the hippocampal formation where these subunits are abundant; important questions are whether these subunits are located at synaptic or extra- synaptic sites and whether they are present at the same morphologically defined synapses; 2) Determine the subcellular changes that may occur in the alpha5 and alpha2 subunits as immunolabeling is altered in the chronic pilocarpine-treated animals; 3) Test the hypothesis that increased GABAR activation by GABAR agonists or increased levels of intrinsic GABA in the hippocampus will produce decreases in alpha5 subunit expression that are similar to those in chronic pilocarpine-treated rats; 4) Test the hypothesis that GABAR subunit expression is altered in the dentate gyrus of animals with reorganized mossy fibers in ways that could lead to increased zinc sensitivity of GBARs and associated decreases in GABAR function. Subunit changes will be studied in the chronic pilocarpine model and in fully kindled rats. The morphological findings will be related to studies of GABAR function in both models by Mody (Project 3). Alterations in GABAR subunits in the hippocampal formation have relevance for our understanding and treatment of temporal lobe epilepsy and also serve as model systems for studying GABAR subunit function and plasticity in vivo.
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