Temporal lobe epilepsy is the most common form of epilepsy in adults and one of the most difficult types to treat. My long-range research goal is to help reveal the mechanisms of temporal lobe epilepsy so that more effective treatments and preventative strategies can be developed. It has been proposed that epileptogenic injuries kill interneurons in the dentate gyrus reducing inhibition of granule cells and lowering seizure threshold. Recent results from my laboratory provide new support for this mechanism. We propose to test the hypotheses that granule cells lose inhibitory synaptic contacts after epileptogenic injuries (Specific Aim 1) and that surviving interneurons form new inhibitory synaptic contacts with granule cells after epileptogenic injuries (Specific Aim 2). To achieve these specific aims we will estimate the total number of inhibitory synaptic contacts with granule cells at three time points during the epileptogenic process: before injury, during the latent period, and during the stage of chronic epilepsy. A newly developed stereological electron microscopic method will be used with post-embedding immunocytochemistry for gamma-aminobutyric acid (GABA) to estimate synapse numbers in control and pilocarpine-treated rats. In addition to loss of inhibitory synapses, granule cell inhibition could be reduced by decreased release of GABA from surviving interneurons. Basket cells are an important source of GABAergic synaptic input to granule cells. We propose is to test the hypothesis that basket cell-to-granule cell synapses become less effective after epileptogenic injuries (Specific Aim 3). To achieve this specific aim we will measure frequency-dependent synaptic depression at basket cell-to-granule cell synapses by recording unitary inhibitory postsynaptic currents of synaptically coupled pairs. The proposed experiments will provide new data on how inhibitory circuits in the dentate gyrus change in epileptic animals and how those changes may contribute to compensatory mechanisms and epileptogenesis.
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