HIPPOCAMPAL NETWORK STRUCTURE AND FUNCTION IN EPILEPSY

描述(改编自调查人员摘要)：尽管复杂，但部分 起源于颞叶的癫痫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，他们经常 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，一种长期发热性癫痫发作的先证者， 感染或头部创伤经常被报告，但原因不明。这 临床病史导致了一种假设，即最初的损伤会改变 以这样一种方式形成颞叶/海马区网络，最终成为 缉获物释放的来源。对这一主题的实验研究可以 外推到人类的情况，因为结构和功能 哺乳动物颞叶的特性一直高度保守 从进化论上讲。此应用程序描述了旨在测试 假设：损伤后非主细胞(中间神经元)死亡或 功能障碍导致海马主细胞去抑制和。 过度兴奋。拟议的实验旨在：1)继续 为了阐明正常的结构和功能组织 海马区结构，特别是参照识别 具有远距离轴突投射的中间神经元群是 建立“侧方”吞噬；2)确定小白蛋白是否阳性 抑制性篮子细胞的死亡是长期癫痫发作的结果，或者仅仅是 停止表达小白蛋白；3)确定神经元本身的丢失是否会导致 主细胞去抑制和过度兴奋，以及；4)利用 实验性癫痫模型阐明结构和功能的变化 在损伤之后，在突触重组之前和之后 自发性癫痫的发展。第一批实验涉及 正常海马区中间神经元群的特征 它们的纵向/联想和连合投影，以及 它们含有神经活性物质。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。这个 第二个实验利用电子核磁共振和共定位 免疫细胞化学用于确定篮子细胞亚群是死亡还是存活 在癫痫发作后。第三组实验涉及皂苷类神经毒素。 相对选择性地针对不同的中间神经元群体。这些 研究直接解决了“神经元间丢失”和“侧向抑制‘ 申请人先前提出的假设。实验的最后一套 利用穿孔路径刺激和匹罗卡品模型来阻止 哪些结构性网络缺陷可能导致网络异常 兴奋性和自发性癫痫。这些研究涉及麻醉后的 和清醒记录，以及解剖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。

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.