MOLECULAR MECHANISMS OF MESIAL LIMBIC EPILEPSY

在内侧颞叶癫痫综合征（MTLE）中，65%的外科手术 标本显示海马硬化，包括严重的神经元 缺失和异常轴突发芽。我们假设它是 重组对存活神经元的抑制。此外，最近的人类研究 表明硬化与以下变化有关：1）NMDA和AMPA mRNA亚基;和2）GABA和谷氨酸和转运蛋白。不幸的是， 人类研究的一个问题是病理学是最终的和静态的， 这是很难辨别的"原因"的癫痫从 反复癫痫发作的"后果"，无动物时间过程研究 模型本研究项目旨在了解 人海马硬化病理生理时程研究 自发性边缘癫痫动物模型的变化。我们将：1） 使用原位杂交技术和免疫细胞化学， NMDA R1 - 2a-d和AMPA GluR1 - 3受体时程和演变 亚单位，与自发性癫痫发作在三个慢性模型， 边缘癫痫（海马内红藻氨酸盐，全身性匹鲁卡品，和 自我维持的边缘系统癫痫持续状态）;和2）在相同的大鼠模型中， 确定谷氨酸（EAAC 1; GLT-1，和 GLAST）和GABA转运蛋白（GAT-1;和GAT 4）。慢性动物模型 将与点燃的动物和我们最近的人类研究进行比较， 结果与海马神经元丢失和异常轴突信号相关 发芽我们假设，与对照组和点燃大鼠相比， 患有自发性边缘系统癫痫的动物将显示海马增加 AMPA和NMDA亚单位; 2）减少星形胶质细胞谷氨酸和GABA 转运蛋白;和3）神经元EAAC 1转运蛋白增加。增加 AMPA和NMDA受体的异常可能导致神经元的过度兴奋， GABA和谷氨酸转运体的变化会增加或减少细胞内 突触和细胞外GABA和谷氨酸水平，这些因素 与异常轴突发芽相互作用， 癫痫发作这些具体目标将通过执行多个 组织学技术对同一大鼠， 监测自发性癫痫发作，由此产生的数据将提供一个 对海马神经元的分子病理生理学的重要认识 癫痫，提示边缘癫痫发作的致病机制，并提供 深入了解控制慢性癫痫发作的可能方法。

In the mesial temporal lobe epilepsy syndrome (MTLE), 65% of surgical specimens show hippocampal sclerosis which consists of severe neuronal loss, and aberrant axon sprouting. We hypothesized that it is the reorganized inhibition on surviving neurons. Also, recent human studies indicate that sclerosis is associated with changes in: 1) NMDA and AMPA mRNA subunits; and 2) GABA and glutamate and transporters. Unfortunately, one problem with human studies is that the pathology is final and static, and it is difficult to discern the "cause" of the epilepsy from the "consequence" of repeated seizures without time course studies in animal models. This research project is designed to understand the pathophysiology of human hippocampal sclerosis by studying time course changes in animal models of spontaneous limbic epilepsy. We will: 1) Determine, using in situ hybridization techniques and immunocytochemistry, the time course and evolution of NMDA R1-2a-d and AMPA GluR1-3 receptor subunits, associated with spontaneous seizures in three chronic models of limbic epilepsy (intra-hippocampal kainate, systemic pilocarpine, and self-sustained limbic status epilepticus); and 2) in the same rat models, determine the time course and evolution of glutamate (EAAC1; GLT-1, and GLAST) and GABA transporters (GAT-1; and GAT4). The chronic animal models will be compared to kindled animals and our recent human studies, and the results correlated to hippocampal neuron loss and signals of aberrant axon sprouting. We hypothesize that compare to controls and kindled rats, animals with spontaneous limbic epilepsy will show increased hippocampal AMPA and NMDA subunits; 2) decreased astroglial glutamate and GABA transporters; and 3) increased in neuronal EAAC1 transporters. An increase in AMPA and NMDA receptors could lead to neuronal hyperexcitability, changes in GABA and glutamate transporters would raise or decrease intra- synaptic and extracellular GABA and glutamate levels, and these factors interacting with aberrant axon sprouting could generate mesial limbic seizures. These Specific Aims will be accomplished by performing multiple histologic techniques on the same rats that have been intensively monitored for spontaneous seizures, and the resulting data will provide an important understanding of the molecular pathophysiology of hippocampal epilepsy, suggest pathogenic mechanisms of limbic seizures, and provide insights into possible ways of controlling the chronic seizures.