Temporal lobe epilepsy (TLE) is the most common epileptic syndrome in adults, and also the most intractable. It is a symptomatic condition, i.e. one associated with a prior insult. The processes involved in generation of pathological, epileptogenic alterations following brain injury are largely unknown. The objectives of this proposal are to elucidate the mechanisms initiated by epileptogenic insults to the brain which combine to make the initial injury difficult to treat, and which go on to initiate a cascade of events culminating in epilepsy. Once pivotal events in the epileptogenic process are identified, additional studies are to be initiated to intervene in the development of these pathological processes, and assess whether this reduces the severity of or blocks the subsequent development of epilepsy. This program combines the expertise of three principal investigators, with expertise in neurophysiology, biochemistry, and molecular biology. This combination of approaches allows for synergistic interactions between investigators, and constitutes a significant strength of the program. Using a combination of electrophysiological, molecular, biochemical and whole animal approaches, the present proposal will elucidate 1) how injury-initiated changes in metabolic processes within inhibitory synapses compromise inhibitory efficacy and predispose the hippocampus to seizure generation in TLE; and 2) how GABA receptor trafficking may be altered by brain injuries which go on to induce epilepsy, and how these trafficking alterations may contribute to progressive intractabilty in status epilepticus, as well as 3) determine whether interventions designed to block metabolic and receptor trafficking alterations evident in animals following epileptogenic injuries may be viable strategies to block epilepsy development. Understanding the nature of epileptogenic changes at the functional, molecular, and whole animal level is an absolute prerequisite to facilitate the development of new therapeutic strategies to better treat and perhaps cure this progressive and devastating disorder. ?
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