It is estimated that up to 1 % of the population in the United States has recurrent seizures, among which involvement of the temporal lobe and hippocampus is common. The goal of this research is to study the postictal changes in the physiological and behavioral functions of the hippocampus following experimentally induced seizures in animals, using the kindling model of temporal lobe epilepsy. In the previous grant period, we have found a long-lasting working memory deficit after hippocampal kindling in rats, as well as a decrease in paired-pulse inhibition of the extracellular response in CA1. The first major area of this proposal is to study the changes in electrophysiology after repeated afterdischarges (ADs) delivered to CA1 (CA1 kindling). In rats with chronically implanted electrodes, the change of the population (extracellular) excitatory postsynaptic potentials and population spike in CA1 (an extracellularly recorded signal corresponding to synchronous firing of a population of CA1 neurons) evoked by commissural or association fibers, at the basal or apical dendrites of CA1 pyramidal cells, will be assessed following repeated ADs. Paired-pulse responses, a sensitive measure of evoked inhibition, will also be recorded. In parallel experiments done at various times after in vivo kindling, the in vitro electrophysiology in CA1 cells, following single- or paired- pulse stimulation of the afferent fibers, is studied by intracellular recordings under current- or voltage-clamp condition, using conventional or patch electrodes . The in vitro experiments are designed to identify whether GABA-A and GABA-B-mediated inhibition, stimulus-evoked extracellular potassium concentration, excitation through N-methyl-D-aspartate (NMDA) and non-NMDA receptors, and intrinsic properties of single neurons are modified after kindling. A second major area of this proposal is to characterize the behavioral dysfunctions following kindling. Experiments are designed on the radial 8-arm maze and in the Morris swim pool to investigate whether the behavioral dysfunction applies to reference as well as working memory, to non-spatial as well as spatial tasks, and to task acquisition in addition to retention. The hypothesis whether paired-pulse disinhibition in CA1 is a cause of the task retention deficit will be evaluated by systematic variation of the kindling procedure and by induction of CA1 disinhibition by direct bicuculline injections. The set of experiments should reveal the kind and magnitude of the physiological and behavioral changes induced by (kindled) seizures, an area difficult to study in epileptic patients. Understanding of these postictal changes may offer a new treatment of some neural and behavioral dysfunctions in patients.
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