Temporal lobe epilepsy (TLE) is a symptomatic condition, associated with known precipitating causes. Implicit in this statement is the concept that, following an insult, TLE develops in an otherwise normal brain. The mechanisms involved in generation of pathological central nervous system alterations underlying the development of epilepsy remain to be elucidated. The present proposal will explore cellular and molecular alterations occurring in the hippocampus in two animal models of TLE. In both of these models, following an initial severe seizure, animals recover, and then begin to develop spontaneous limbic seizures within 2-3 weeks. Using these spontaneously epileptic animals, the applicant intends to investigate physiological and molecular alterations in the function of synaptic transmission in the hippocampus. The central hypothesis of this proposal is that the hyperexcitability in the limbic system in animals with TLE is due at least in part to pathological loss of inhibitory function, which triggers regionally selective alterations in the balance of hippocampal excitatory and inhibitory synaptic transmission. In order to test this hypothesis, GABAergic inhibitory synaptic transmission will be studied in both control and epileptic animals, to explore potential epilepsy-associated alterations in this system in the hippocampus. Alterations in GABAergic inhibitory function are to be studied at two main time points. One focus of research will be to examine alterations in the epileptic hippocampus at a chronic, end stage point, where the seizure disorder is fully developed. A second focus of research will be to examine the development of alterations in GABAergic receptor function during the latent period, prior to expression of seizures. Changes in inhibitory synaptic transmission, postsynaptic GABA-A receptor physiology and pharmacology, and relative levels of expression of GABA-A receptor subunit mRNAs are to be assessed using patch clamp recording techniques in brain slices and acutely isolated cells, as well as molecular techniques to examine expression of GABA receptor subunit mRNAs in individual cells. It is hoped that through these combined techniques, epileptogenic alterations in GABAergic neurotransmission can not only be identified, but the molecular mechanisms involved in generating these permanent changes in the properties of the epileptic brain can begin to be identified. Understanding of the nature of epileptogenic changes at both the functional and molecular levels is necessary to achieve in order to some day have the potential to develop a cure for this devastating disorder.
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