The surgical management of patients with medically intractable temporal lobe epilepsy has shown that there are at least two classes of brain foci the removal of which produces seizure control. In one class, the focus is confined to the medial temporal lobe, particularly the hippocampus. Investigations in the past period of funding have revealed a number of distinct changes indicative of considerable chemoarchitectural changes at these hippocampal seizure foci. There are three broad aims in the present proposal. (1) To further define the neurochemical organization of these foci particularly in relation to the distribution of non-NMDA glutamate receptors GluR1 to GluR5, and the glutamate metabotropic receptor using in situ hybridization techniques. The inhibitory amino acid Gamma Aminobutyric Acid-A (GABA-A) receptor subtypes alpha 1, alpha2, alpha3, delta and gamma 2 subunits will also be localized by in situ hybridization techniques, while the GABA-B receptor is localized with receptor autoradiography. The regional distribution of protein kinase C (PKC) and its isoenzymes, and inositol triphosphate (IP3), second messenger systems involved in calcium regulation, will be localized with immunocytochemistry and receptor autoradiography. The cellular location of receptors on neurons and glia will be studied with fluorescent agonist or antagonist molecular probes, and their functional state explored by [3H]-cytidine incorporation following pharmacological stimulation of receptors. (2) In order to examine if neurons and glia at seizure foci have been intrinsically modified, these cells in primary culture established from human epileptogenic tissue, will be studied electrophysiologically to determine their membrane biophysics and ion channel activity, and studied biochemically to measure neurotransmitter expression on glia. The functional state of glial receptors will be assessed by calcium imaging studies following receptor stimulation. (3) The development of hippocampal neuronal injury following febrile seizures will be followed in a fever induced seizure model in the rat. The critical period for maximal injury and the effect of seizure intensity on the degree of injury will be assessed by silver degeneration stains and the Timm stain. Clues to the causes of cellular injury will be sought in an examination of the early expression of transcription factors c-fos, c- jun, B-jun and zif/268, and nerve growth factor (NGF); in a study of the role of corticosteroids; and the disruption of the blood brain barrier assessed by the degree of leakage of intravascular horseradish peroxidase into the brain parenchyma following fever induced seizures. These studies together should give us a better appreciation of the pathophysiology and etiology of temporal lope epilepsy.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurological Sciences Subcommittee 1 (NLS)
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Yale University
Schools of Medicine
New Haven
United States
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