Nerve cell death and gliosis in the limbic system are neuropathological hallmarks of temporal lobe epilepsy. In particular, a characteristic seizure-related neurodegeneration of layer III of the EC occurs in animals and in human patients. The proposed work will delineate changes which are associated with an experimentally induced lesion of layer III of the EC. In particular, a primarily glia-derive excitatory amino acid receptor antagonist, kynurenic acid (KYNA), will be examined because of its possible role as an endogenous factor which controls seizure activity and seizure-related brain damage. Two experimental seizure models, produced by continuous electrical stimulation of the ventral hippocampus (SSLSE model) or by intra-entorhinal injection of the indirect excitotoxin aminooxyacetic acid (AOAA), will be used as follows: 1) Biochemical studies in the whole animal will examine the acute disposition of KYNA and related metabolites following a focal intra-entorhinal AOAA injection. Parallel experiments in vitro will investigate the mechanisms of AOAA's actions, and will attempt to identify the unique characteristics of preferentially vulnerable neurons in the EC; 2) Using a multi-disciplinary in vivo/ in vitro approach, anatomical, biochemical and electrophysiological methods will be use to test the hypothesis that abnormal kynurenine pathway function and metabolism is fundamental to the development of chronic epilepsy; 3) Anticonvulsant and neuroprotective strategies based on this work will be evaluated by targeting astrocytes for the in situ delivery of glycine/NMDA receptor antagonists. In particular, attempts will be made to produce sufficient quantities of KYNA and of the specific glycine/NMDA receptor antagonist 7-CK in the brain after systemic administration of their respective precursors. Taken together, these studies will a) provide a comprehensive assessment of the possible role of the endogenous glycine/NMDA receptor antagonist KYNA in epileptogenesis and chronic epilepsy, b) contribute to our understanding of the role of the EC in seizure phenomena, and c) introduce a new therapeutic strategy which may offer advantages for the treatment of seizure disorders.
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