Viral neuropathology neuropeptides and epilepsy

描述（由申请人提供）：癫痫，或复发性癫痫发作，是一种神经系统疾病，所有年龄组和影响约1%的美国人。20%至25%的患者对现有药物反应不佳，并且作为一个群体，继发于CNS感染的癫痫发作患者是最难治的。持续性、病毒对致痫区域的嗜性以及暴露时神经系统的不成熟都是癫痫控制不良的预测因素。在这个建议中，将测试的总体假设，即减少强啡肽的表达在海马齿状回由于围青春期病毒暴露导致癫痫样反应。将研究假设的一般性、作用机制和治疗方法。博尔纳病病毒是一种嗜神经病毒，在许多哺乳动物中引起海马变性，是人类海马硬化的罕见原因。博尔纳病病毒感染的大鼠（BD大鼠）是一种生物学上合理的青春期病毒损伤和癫痫发作的动物模型：它具有癫痫表型、可预测的神经病理学结果和一致的海马损伤，并再现神经化学变化，强啡肽缺陷，现在被认为是人类颞叶癫痫的危险因素。将在BD大鼠中使用特定神经药理学药物、脑电图记录、立即早期基因标记定位和组织学探针，对特定目标1的年轻受试者中病毒损伤传递易受海马中强啡肽降低介导的癫痫活动影响的假设进行检验。感染期间强啡肽缺陷的机制，海马强啡肽表达颗粒细胞成熟失败，将使用组织学探针随时间跟踪神经发生和细胞发育进行检查。单纯疱疹病毒是一种重要的人类病原体，与病毒性癫痫有着无可争议的联系。将使用特定神经药理学试剂和组织学探针，针对特定目的2，检测大鼠中单纯疱疹病毒和大鼠中水泡性口炎病毒是否存在Borna病毒以外的病毒易致癫痫样反应的假设。这项工作将增强我们对病毒与不成熟神经系统相互作用的理解，并为从环境和遗传角度探索癫痫易感性的个体差异提供启发性基础。

DESCRIPTION (provided by applicant): 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.