Temporal lobe epilepsy (TLE), the most common form of partial epilepsy, remains the cause of seizures most resistant to treatment. Understanding the pathophysiological factors inducing chronic seizure development is a necessary prerequisite to devising more effective therapies. Human TLE is marked by major pathology of the mesial temporal lobe, particularly the hippocampal formation and parahippocampal structures. A mesial temporal lobe epilepsy syndrome has been described which is often typified by a nervous system insult followed by a seizure-free interval and eventual onset of chronic epilepsy. It is generally agreed that an increased propensity for epileptiform activity arises from a disequilibrium between neuronal excitation and inhibition, particularly that mediated by the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). A fundamental question which remains unanswered is the nature of the process occurring during the post-status epilepticus, seizure-free interval which may reduce GABAergic inhibition and lead to an increased propensity for epileptiform activity. This proposal examines the evolution of impairments to GABAA receptor-mediated inhibition during the period preceding the onset of spontaneous seizures using an animal model of chronic epilepsy. Three hypotheses are considered: 1. The changes in GABAA receptor-mediated inhibition in hippocampal region CA1 appear incrementally following status epilepticus and precede the appearance of chronic epilepsy. 2. Alterations in the pharmacology of the GABAA receptor evolve and are complete before the onset of spontaneous seizures. 3. The properties of spontaneous inhibitory postsynaptic currents alter between the induction of status epilepticus and the onset of spontaneous seizures. The information gained in these studies will better define development of GABAergic deficiencies preceding seizures and will aid in the development of new anti-epileptogenic therapies.
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