Temporal lobe epilepsy is the most common epileptic syndrome in adults, and also the most intractable. It is considered to be a symptomatic condition, i.e. one associated with a prior insult. For the most part, the mechanisms mediating the pathological alterations causing epilepsy remain to be elucidated. The present proposal wilt explore synaptic circuit, cellular and molecular alterations in the hippocampal dentate gyrus, and assess the effects of these alterations on seizure frequency and severity in intact, epileptic animals. Studies are designed to specifically test our CENTRAL HYPOTHESIS: Cellular and circuit alterations evident in the epileptic dentate gyrus combine to generate a tonic imbalance in function, which compromises the normal 'gatekeeper' function of this region, and results in a hippocampus which is predisposed to generate seizures. To test this hypothesis, the cellular and circuit properties of the dentate gyrus are to be studied in tissue isolated from epileptic animals, and pharmacological and transgenic interventions are to be explored in intact animals, examining effects on seizure frequency and severity. Research directed at testing our central hypothesis will focus on 3 SPECIFIC AIMS:
AIM 1 : Determine the role played by zinc released from sprouted mossy fiber terminals in dentate gyrus circuit hyperexcitability in epileptic animals.
AIM 2 : Determine the role played by birth of large numbers of new dentate granule cells triggered by the development of epilepsy in the subsequent emergence of dentate gyrus circuit hyperexcitability characteristic of chronic temporal lobe epilepsy AIM 3. Determine the effects of zinc released from sprouted mossy fiber recurrent collaterals and of the birth of large numbers of new neurons on seizure frequency and severity in epileptic animals. Using a combination of electrophysiological, molecular, and whole animal approaches, the present proposal will attempt to better understand how divergent cellular and circuit alterations may interact to predispose the hippocampus to seizure generation in temporal lobe epilepsy. Understanding the nature of epileptogenic changes at the functional, molecular, and whole animal level is necessary to achieve to facilitate the development of new therapeutic strategies to better treat and perhaps cure this devastating disorder.
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