NEUROBIOLOGY AND PATHOGENESIS OF HIPPOCAMPAL EPILEPSY

描述：（研究者摘要）。 该项目旨在 研究海马体内的分子机制， 并引导新的异常突触连接， 通过诱导和跟踪时间过程在人类癫痫中的发作 在大鼠模型中细胞的损失和发芽。 的神经生物学 海马硬化中的异常突触重组将是 与轴突生长的类似分子机制相比， 在发育过程中观察到的突触发生。 这项提案将回答 两个生物学上重要的问题：1）细胞， 损伤后的分子和轴突生长模式遵循 发展计划或 保留其他成熟方案？ 2)并 慢性海马大鼠癫痫模型 癫痫发作间期EEG棘波，局灶性EEG发作，突触 重组和分子表达 这些实验将 测试分子机制，与几个无法解释的 癫痫的现象：1）什么是发展关键期 损伤诱发癫痫的易感性2)什么原因导致 急性损伤/急性癫痫发作和最终 慢性癫痫 3)神经营养因子是否上调， 维持癫痫新神经支配和/或维持突触 兴奋过度？颞叶癫痫是最常见的形式， 人类癫痫，在手术系列中，65%的患者 海马硬化 有一种细胞丢失和发芽的模式 其特征是苔藓纤维对 齿状回的颗粒细胞，这显然有助于 顽固性癫痫发作。关于引起癫痫发作的机制知之甚少。 突触重组。拟议的研究将绘制分子 大鼠出生后到成年发育序列中的信号 使用现代体内探针：1）轴突生长模式，2） 外源性营养因子，3）靶向神经营养因子 因素 信使核糖核酸（mRNA）的原位杂交 将用于进一步确认 这些生长促进分子的发育表达， 突触发生 这些研究将与真正的人类进行比较。 癫痫神经元和电路，我们实验室正在进行的一个机会， 也是了解人类癫痫发生的关键下一步。 到 与大鼠齿状回中正常发育的连接相比， 海马内的神经元会诱发异常的反应性突触发生， 大鼠的损伤会导致过度兴奋和癫痫发作， 往往会发展成慢性癫痫 同时研究， 相同的分子探针将用于癫痫大鼠从早期 从出生后到成年，以比较最终的慢性EEG模式 癫痫大鼠和人类之间的联系，并将这些癫痫变化与 改变或表达的关键蛋白质参与不同的 重组。 这些结果可能提示了 参与人类癫痫的进行性损害 海马体。

DESCRIPTION: (Investigator s Abstract). This project is designed to study in vivo molecular mechanisms in the hippocampus which initiate and guide new, aberrant synaptic connections that may lead to chronic seizure in human epilepsy by inducing and following the time course of cell loss and sprouting in a rat model. The neurobiology of aberrant synaptic reorganization in hippocampal sclerosis will be compared to similar molecular mechanism of axon growth and synaptogenesis seen during development. This proposal will answer two biologically significant questions: 1) Do the cellular, molecular, and axon growth patterns after damage follow the developmental programs or retain other mature programs? 2) Does chronic hippocampal rat epilepsy model true human hippocampal epilepsy in its interictal EEG spikes, focal EEG seizures, synaptic reorganizations, and molecular expressions? These experiments will test for molecular mechanisms that correlate with several unexplained phenomena in epilepsy: 1) What is the developmentalcritical period for susceptibility to damaged-induced epilepsy?2) What causes the long latent period between acute injury/acute seizures and eventual chronic seizures? 3) Are neurotrophic factors upregulated to maintain epileptic neoinnervation and/or to maintain synaptic hyperexcitability? Temporal lobe epilepsy is the most frequent form of human epilepsy, and in surgical series 65% of patients have hippocampal sclerosis. There is a pattern of cell loss and sprouting characterized by an aberrant monosynaptic feedback of mossy fibers on granule cells of the dentate gyrus which apparently contributes to intractable seizures.Little is known about the mechanisms causing the synaptic reorganization.The proposed research will map the molecular signals in the postnatal to adult developmental sequence in rats using modern in vivo probes for: 1) axonal growth patterns, 2) extrinsic tropic and trophic factors, and 3) target neurotrophic factors. In situ hybridization of messenger ribonucleic acids (mRNA) will be used to further confirm significant changes in the developmental expressions of these growth promoting molecules and synaptogenesis. These studies will be compared to true human epileptic neurons and circuits, an opportunity underway in our lab and critical next step for understanding human epileptogenesis. To compare with normally-developed connections in the rat dentate gyrus, aberrant reactive synaptogenesis will be induced by intrahippocampal damage in rats which will cause hyperexcitability and seizures that often develop into chronic seizures. Simultaneous studies with identical molecular probes will be used in epileptic rats from early postnatal to adult ages to compare the eventual chronic EEG patterns between epileptic rat and man and relate these epileptic changes to alterations or expression of critical proteins involved in different reorganizations. These results may suggest antecedent mechanisms involved in progressive damage in human sclerotic epileptic hippocampus.