Adult Subventricular Zone Gliogenesis in Limbic Epilepsy

描述(由申请人提供)：人类颞叶癫痫(TLE)在神经元丢失和突触重组的程度上有所不同，但始终以海马区“反应性”胶质细胞增生为特征。长期以来，星形胶质细胞增多症一直与局灶性癫痫有关，但迄今为止的研究未能确定神经胶质细胞如何影响TLE的癫痫发作。经匹罗卡品治疗的癫痫大鼠和癫痫切除的人颞叶的海马星形胶质细胞具有未成熟星形胶质细胞的电生理特征。这一提议将检验癫痫发作导致异常胶质生成的假设，最终后果是随后癫痫发作的风险增加。 从理论上讲，癫痫发作后产生的海马区胶质细胞可能来源于脑室下区(SVZ)或颗粒下区(SGZ)前体细胞的迁移和分化，来自局部内源性前体细胞或重新进入成熟星形胶质细胞的细胞周期。在申请人之前对对照组和癫痫组海马区神经胶质细胞特性的研究基础上，这项建议将结合逆转录病毒介导的基因转移、电生理学和免疫组织化学技术来研究癫痫诱导的SVZ和SGZ胶质形成。我们将比较毛果芸香碱边缘癫痫大鼠模型中SVZ和SGZ来源的海马区神经胶质发生的时间进程、细胞命运和生理后果。此外，我们还将确定在癫痫发作诱导前，局灶性消融SVZ和/或海马体前体细胞池的后果。 具体目标1：确定癫痫发作是否诱导前体细胞迁移到海马区，以及随后在海马区内的胶质细胞分化。 具体目标2：通过电生理学和分子标准，确定癫痫发作后产生的神经胶质细胞是否仍未成熟。 具体目标3：确定选择性阻断SVZ和海马区的细胞增殖是否影响神经胶质细胞的发育和癫痫的发生。

DESCRIPTION (provided by applicant): Human temporal lobe epilepsy (TLE) varies in the degree of neuronal loss and synaptic reorganization, but is always characterized by hippocampal "reactive" gliosis. Astrogliosis has long been associated with focal epilepsy, yet studies to date have failed to establish how glial cells may influence seizures in TLE. Hippocampal astrocytes recorded from epileptic rats treated with the convulsant pilocarpine and from resected epileptic human temporal lobe have electrophysiological features of immature astrocytes. This proposal will test the hypothesis that seizures induce abnormal gliogenesis and the ultimate consequence is that the risk of subsequent seizures increases. Hippocampal glial cells generated in response to seizures could theoretically arise from migration and differentiation of sub-ventricular zone (SVZ) or sub-granular zone (SGZ) progenitor cells, from local endogenous precursor cells or from re-entry into the cell cycle of mature astrocytes. Building on the applicant's previous investigation of glial cell properties in the control and epileptic hippocampus, this proposal will use a combination of retroviral mediated gene transfer, electrophysiological and immunohistochemical techniques to investigate seizure induced SVZ and SGZ gliogenesis. We will compare the time course, cell fate and physiological consequences of SVZ and SGZ derived hippocampal gliogenesis in the rat pilocarpine limbic epilepsy model. In addition, we will determine the consequences of focally ablating the SVZ and/or hippocampus progenitor pool prior to the induction of seizures. Specific Aim 1: To determine whether seizures induce migration of progenitor cells to and subsequent gliogenic differentiation within the hippocampus. Specific Aim 2: To determine whether the glial cells that are generated in response to seizures remain immature, by electrophysiological and molecular criteria. Specific Aim 3: To determine whether selective disruption of cellular proliferation in the SVZ and the hippocampus influences glial development and epileptogenesis.