Epilepsy, or recurrent seizures, is a neurologic disease of all age groups and affects approximately 1% of Americans. Twenty to 25% of patients respond poorly to existing medications, and, as a group, patients with seizures secondary to CNS infections have been the most medically refractory. Persistence, tropism of virus for epileptogenic areas, and immaturity of the nervous system at the time of exposure are each predictive of poor epilepsy control. In this proposal, the overall hypothesis that reduced dynorphin expression in the dentate gyrus of the hippocampus due to periadolescent virus exposure leads to epileptic-like responses will be tested. The generality of the hypothesis, the mechanism of effect, and treatments will be studied. Borna Disease virus, a neurotropic virus causing hippocampal degeneration in many mamma an species, is a rare cause of hippocampal sclerosis in man. The Borna Disease virus infected rat (BD rat), is a biologically plausible animal model of periadolescent viral injury and seizures: it has an epileptic phenotype, predictable neuropathologic outcome with consistent hippocampal lesions, and reproduces a neurochemical change, dynorphin deficit, now recognized as a risk factor in human temporal lobe epilepsy. The hypothesis that viral injury in young subjects conveys a vulnerability to epileptic activity that is mediated by decreased dynorphin in the hippocampus will be tested in the BD rat for Specific Aim 1 using specific neuropharmacologic agents, electroencephalographic recording, immediate early gene labeling for localization, and histologic probes. A mechanism of dynorphin deficit during infection, failure of maturation of dynorphin-expressing granule cells of the hippocampus, will be examined using histologic probes to track neurogenesis and cell development over time. Herpes simplex virus is a significant human pathogen, with undisputed links to viral epilepies. The hypothesis that viruses other than Borna viruses convey vulnerability to epileptic-like responses will be tested for herpes simplex virus in rats and vesicular stomatitis virus in rats for Specific Aim 2 using specific neuropharmacologic agents and histologic probes. This work will enhance our understanding of viral interaction with the immature nervous system and provide a heuristic basis for exploring individual differences in vulnerability to epilepsy both from an environmental and genetic perspective. ? ?
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