Adult Subventricular Zone Gliogenesis in Limbic Epilepsy

边缘性癫痫成人室下区胶质生成

• 批准号: 7008904
• 负责人: Guy M McKhann
• 金额: $ 17万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7008904
• 关键词: astrocytes; cell differentiation; cell migration; cell morphology; cell proliferation; cellular pathology; disease /disorder model; glutamates; green fluorescent proteins; hippocampus; immunocytochemistry; laboratory rat; microarray technology; microelectrodes; neuropathology; neurotransmitter transport; partial seizure; pilocarpine; single cell analysis; stereotaxic techniques; temporal lobe /cortex disorder; voltage /patch clamp

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.

描述（由申请人提供）：人类颞叶癫痫（TLE）的神经元损失和突触重组程度各不相同，但始终以海马“反应性”神经胶质增生为特征。星形胶质细胞增生长期以来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。从用惊厥药毛果芸香碱治疗的癫痫大鼠和切除的癫痫人颞叶中记录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。该提案将检验癫痫发作引起异常胶质生成的假设，最终结果是随后癫痫发作的风险增加。 癫痫发作时产生的海马神经胶质细胞理论上可能来自室下区 (SVZ) 或颗粒下区 (SGZ) 祖细胞的迁移和分化、局部内源性前体细胞或重新进入成熟细胞周期。星形胶质细胞。基于申请人之前对对照海马和癫痫海马中神经胶质细胞特性的研究，该提案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发作诱导的 SVZ 和 SGZ 胶质细胞生成。我们将比较大鼠毛果芸香碱边缘癫痫模型中 SVZ 和 SGZ 衍生的海马胶质细胞生成的时间过程、细胞命运和生理后果。此外，我们将确定在诱发癫痫发作之前局部消融 SVZ 和/或海马祖细胞池的后果。 具体目标 1：确定癫痫发作是否会诱导祖细胞迁移至海马体以及随后在海马体内的胶质细胞分化。 具体目标 2：通过电生理学和分子标准确定响应癫痫发作而产生的神经胶质细胞是否仍处于不成熟状态。 具体目标 3：确定 SVZ 和海马细胞增殖的选择性破坏是否会影响神经胶质发育和癫痫发生。