The goal of the proposed research is to obtain information pertaining to the basic mechanisms underlying epileptogenesis in mammalian hippocampus. Clinical observations support the premise that the epileptogenic properties of the central nervous system vary dramactically during development. It has been postulated that the hippocampus is one area of the immature brain that is unusually susceptible to seizures. We have found that hippocampal slices from rats 9-19 days of age have a pronounced capacity to generate prolonged (20-30 sec) afterdischarges when exposed to the convulsant, penicillin. More recently we have found that hippocampal slices from rats of the same age group are markedly more sensitive to iontophoretically-applied glutamate than slices obtain from rats greater than 25 days of age. This observation fits well with reports of an increased glutamate receptor population in immature hippocampus. Our current source density analysis has also shown negative extracellular field potentials and current sinks, areas of current entry into the neurons, in both the apical and basilar dendrites of the hippocampal CA3 region. These current sinks were shown to be congruent with areas increased extracellular K+ ([K+]0) generated during the interictal spike. It is generally accepted that there are at least three distinct populations of excitatory amino acid receptors, separable by their preferential excitation by specific agonists. Of these receptor subclasses, the one which prefers N-methylaspartate (NMA) may play an important role in the mechanisms of epileptogenesis. We have observed that the putative NMR-receptor antagonist, kynurenic acid, has anticonvulsant-like properties when applied by bath application to slices undergoing penicillin-induced epileptiform activity. Further indication that excitatory amino acids are involved in ictal phenomena comes from our observations that their iontophoretic application to regions of the hippocampal slice that contain the epileptiform current sinks mimic epileptic events in the production of negative extracellular field potentials and local increases in [K+]o. We have also seen that kynurenic acid, at levels that dramatically effect epileptiform activity, can specifically block NMR-induced local field potentials. Based on these observations a series of experiments are proposed, designed to use the developmental changes in hippocampal excitatory amino acid sensitivity and epileptogenic properties to investigate the role of specific excitatory amino acid receptors in the mechanism of epileptogenesis.
