Viral neuropathology neuropeptides and epilepsy

描述(申请人提供)：癫痫，或反复发作，是一种所有年龄段的神经系统疾病，影响大约1%的美国人。20%到25%的患者对现有药物的反应很差，作为一个群体，继发于中枢神经系统感染的癫痫患者在医学上是最难治的。持续、病毒对致痫区域的趋向性以及暴露时神经系统的不成熟都预示着癫痫控制不佳。在这项提案中，将检验由于青春期病毒暴露导致海马齿状回强啡肽表达减少导致癫痫样反应的总体假设。我们将研究这一假设的普遍性、作用机制和治疗方法。博尔纳病病毒是一种嗜神经性病毒，在许多哺乳动物物种中会导致海马体退化，是导致人类海马体硬化的罕见原因。博尔纳病病毒感染的大鼠(BD大鼠)是一种生物学上可信的青春期周围病毒损伤和癫痫的动物模型：它具有癫痫表型，可预测的神经病理结果与一致的海马区病变，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。年轻受试者中的病毒损伤传递了由海马区强啡肽减少介导的癫痫易感性的假设，将在BD大鼠中进行特定目的1的测试，使用特定的神经药理学药物、脑电记录、用于定位的即刻早期基因标记和组织学探针。感染期间强啡肽缺乏的一个机制，即海马区表达强啡肽的颗粒细胞成熟失败，将使用组织学探针来跟踪神经发生和细胞随着时间的发展。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辩的联系。博纳病毒以外的病毒对癫痫样反应易感性的假设将在大鼠中进行单纯疱疹病毒和水泡性口炎病毒的测试，以达到特定的目的2使用特定的神经药理学药物和组织学探针。这项工作将加强我们对病毒与未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式基础。

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.