Viral neuropathology neuropeptides and epilepsy

描述（由申请人提供）：癫痫，或反复发作，是一种所有年龄组的神经系统疾病，影响约1%的美国人。20%到25%的患者对现有药物反应不佳，并且，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愈的。病毒在致癫痫区持续存在、趋向性以及暴露时神经系统不成熟均预示着癫痫控制不良。在这一建议中，将测试海马齿状回中由于青少年时期病毒暴露导致癫痫样反应的dynorphin表达减少的总体假设。将研究假设的普遍性、作用机制和治疗方法。博纳病病毒是一种在许多哺乳动物中引起海马变性的嗜神经病毒，是一种罕见的导致人类海马硬化的原因。博纳病病毒感染大鼠（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，可预测的神经病理结果与一致的海马病变，并再现神经化学变化，肌啡肽缺陷，现在被认为是人类颞叶癫痫的一个危险因素。假设年轻受试者的病毒损伤传达了由海马体中肌啡肽减少介导的癫痫活动易感性，将在BD大鼠中使用特异性神经药理学药物、脑电图记录、即时早期基因定位标记和组织学探针进行特异性Aim 1测试。感染期间肌啡肽缺失的机制，海马表达肌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发育。单纯疱疹病毒是一种重要的人类病原体，与病毒性癫痫有无可争议的联系。假设博纳病毒以外的病毒传递了对癫痫样反应的易感性，将使用特定的神经药理学药物和组织学探针对大鼠的单纯疱疹病毒和大鼠的水泡性口炎病毒进行特异性Aim 2测试。这项工作将增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.