HIPPOCAMPAL NETWORK STRUCTURE AND FUNCTION IN EPILEPSY

癫痫中的海马网络结构和功能

• 批准号: 6529519
• 负责人: Robert S Sloviter
• 金额: $ 39.65万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-12-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6529519
• 关键词: brain electrical activity; brain mapping; calcium binding protein; cell death; dentate gyrus; disease /disorder model; fluorescence microscopy; hippocampus; immunocytochemistry; immunoelectron microscopy; interneurons; laboratory rat; neural degeneration; neural inhibition; neural plasticity; neural transmission; neuroanatomy; neurophysiology; neurotoxins; partial seizure

DESCRIPTION (Adapted from Investigator's Abstract): Although complex partial seizures of temporal lobe origin can occur as the apparent result of tumors, arteriovenous malformations, and disorders of cortical development, they often occur "spontaneously," in the absence of any obvious cause. In these "cryptogenic" patients, an antecedent episode of prolonged febrile seizures, infection, or head trauma is often reported, but of unproved causation. This clinical history led to the hypothesis that an initial injury alters the temporal lobe/hippocampal network in such a way that it ultimately becomes a source of seizure discharges. Experimental studies on this subject can be extrapolated to the human condition because the structural and functional properties of the mammalian temporal lobe have been highly conserved phylogenetically. This application describes experiments designed to test the hypothes:is that post-injury non-principal cell (interneuron) death or dysfunction causes hippocampal principal cell disinhibition and. hyperexcitability. The proposed experiments have been designed to: 1) continue to elucidate the normal structural and functional organization of the hippocampal formation with particular reference to the identification of the interneuron populations that have distant axonal projections necessary for establishing "lateral'' inbibition; 2) determine whether parvalbumin-positive inhibitory basket cells die as a consequence of prolonged seizures, or simply stop expressing parvalbumin; 3) determine if interneuron loss per se induces principal cell disinhibition and hyperexcitability, and; 4) utilize experimental epilepsy models to elucidate the structural and functional changes that follow injury, and precede and follow synaptic reorganization and the development of spontaneous seizures. The first experiments involve the characterization of normal hippocampal interneuron populations in terms of their longitudinal/associational and commissural projections, as well as the neuroactive substances they contain. These studies utilize retrograde and anterograde tracer injections and double fluorescence immunocytochemistry. The second experiments utilize electron nucroscopy and colocalization immunocytochemistry to determine if a subset of basket cells dies or survives after seizures. The third set of experiments involve saporin-based neurotoxins that target different interneuron populations relatively selectively. These studies directly address the "interneuron loss" and "lateral inhibition't' hypotheses proposed previous,ly by the applicant. The f inal set of experiments utilizes the perforant path stimulation-, and pilocarpine models to deterrrune which structural network defects may give rise to abnorrnal network excitability and spontaneous seizures. These studies involve both anesthetized and awake recording, as well as anatomical and irnmunocytochernical methods designed to elucidate the functional and structural basis of epileptogenesis.

描述（改编自研究者摘要）：虽然复杂的部分 颞叶起源的癫痫发作可作为肿瘤的明显结果而发生， 动静脉畸形和皮质发育障碍， 在没有任何明显原因的情况下“自发地”发生。在这些 “隐源性”患者，长期热性惊厥的前期发作， 感染或头部创伤经常被报道，但原因不明。这 临床病史导致了一种假设，即最初的损伤改变了 颞叶/海马网络，最终成为一个 癫痫发作的来源。关于这个问题的实验研究可以 推断到人类的状况，因为结构和功能 哺乳动物颞叶的特性是高度保守的 遗传学上。本申请描述了设计用于测试 假设：损伤后非主细胞（中间神经元）死亡或 功能障碍引起海马主细胞去抑制， 兴奋过度拟议的实验旨在：1）继续 阐明正常的结构和功能组织的 海马结构，特别是关于识别 中间神经元群体具有必要的远端轴突投射， 建立“侧向”抑制; 2）确定是否小白蛋白阳性 抑制性篮状细胞由于长时间的癫痫发作而死亡，或者仅仅是 停止表达小清蛋白; 3）确定中间神经元损失本身是否诱导 主细胞去抑制和过度兴奋，以及; 4）利用 实验性癫痫模型，以阐明结构和功能变化 损伤后，突触重组前后， 自发性癫痫发作。第一个实验涉及 正常海马中间神经元群体的表征 它们的纵向/联合和连合突起，以及 含有的神经活性物质。这些研究利用逆行和 顺行示踪剂注射和双荧光免疫细胞化学。的 第二个实验利用电子核镜和共定位 免疫细胞化学以确定篮状细胞的亚群是否死亡或存活 癫痫发作后第三组实验涉及基于皂草素的神经毒素 相对有选择性地针对不同的中间神经元群体。这些 研究直接针对“中间神经元损失”和“横向抑制”， 申请人先前提出的假设。最后一组实验 利用穿通径刺激和毛果芸香碱模型来阻止 哪些结构性网络缺陷会导致网络异常 兴奋性和自发性癫痫这些研究包括麻醉的 以及解剖学和免疫细胞化学方法 旨在阐明癫痫发生的功能和结构基础。