Glutamine Synthetase and the Mechanism of Seizures in Mesial Temporal Lobe Epilep

描述(由申请人提供)：最常见的癫痫类型之一-内侧颞叶癫痫(MTLE)-以自发性和反复的部分性癫痫为特征。此外，许多MTLE患者无法用现有的抗癫痫药物控制癫痫发作。因此，旨在预测和治疗即将发生的内侧颞叶癫痫的新方法尤为重要。因此，本提案的总体目标是探索MTLE癫痫发作的发生机制，从而促进发现这种疾病的候选生物标记物和更有效的治疗方法。最近的研究表明，海马区谷氨酰胺合成酶的缺乏与MTLE癫痫的发生有关(Eid等人。《柳叶刀》2004；363：28-37)。利用连续视频脑电监测、微透析、免疫金电子显微镜、13C和15N同位素标记以及串联质谱仪等最先进的方法，将在新开发的MTLE实验室模型中系统地探讨谷氨酰胺合成酶缺陷在癫痫发生中的作用。在具体目标1中，将评估海马谷氨酰胺合成酶缺乏、细胞内和细胞外谷氨酸浓度、癫痫发作和海马区病理之间的关系。假设是谷氨酰胺合成酶缺乏会导致星形胶质细胞和海马胞外间隙中谷氨酸的慢性高浓度，在患有严重癫痫和广泛脑损伤的人中，谷氨酸水平尤其高。在具体目标2中，将探索自然产生的大脑化学物质的瞬时升高作为MTLE“自发”癫痫的潜在触发因素。假说是，这些触发因素会导致海马区细胞外谷氨酸的短暂激增，最终导致“自发性”癫痫发作。最后，在具体目标3中，将评估在致痫的海马区恢复谷氨酰胺合成酶可用于治疗MTLE的概念。假说是，海马区谷氨酰胺合成酶的恢复导致癫痫发作的停止，即使在广泛的大脑病理存在的情况下也是如此。

DESCRIPTION (provided by applicant): One of the most common types of epilepsy - mesial temporal lobe epilepsy (MTLE) - is characterized by spontaneous and recurrent partial seizures. Furthermore, many patients with MTLE cannot control their seizures with current antiepileptic drugs. Novel approaches aimed at predicting and treating impending mesial temporal lobe seizures are therefore particularly important. Thus, the overall goal of the present proposal is to explore the mechanism of seizure generation in MTLE, thereby facilitating the discovery of candidate biomarkers of and more efficacious therapies for this disorder. Recent studies have suggested that a deficiency in glutamine synthetase in the hippocampus is implicated in the generation of seizures in MTLE (Eid et al. Lancet 2004; 363: 28-37). Using state-of-the art methods in continuous video intracranial EEG monitoring, microdialysis, immunogold electron microscopy, 13C- and 15N-isotope labeling, and tandem mass spectrometry, the role of the glutamine synthetase deficiency in the generation of seizures will be systematically explored in a newly developed laboratory model of MTLE. In Specific Aim 1, the relationship among hippocampal glutamine synthetase deficiency, intra- and extracellular glutamate concentrations, seizures, and hippocampal pathology will be assessed. The hypothesis is that a deficiency in glutamine synthetase leads to chronic high concentrations of glutamate in astrocytes and the extracellular space of the hippocampus with particularly high glutamate levels in individuals suffering from severe seizures and extensive brain damage. In Specific Aim 2, transient elevations in naturally occurring brain chemicals will be explored as potential triggers of "spontaneous" seizures in MTLE. The hypothesis is that such triggers cause a transient surge in extracellular glutamate in the hippocampus with "spontaneous" seizures as the ultimate consequence. Finally, in Specific Aim 3, the concept that restoration of glutamine synthetase in the epileptogenic hippocampus may be used as a cure of MTLE will be evaluated. The hypothesis is that restoration of glutamine synthetase in the hippocampus leads to cessation of seizures even in the presence of extensive brain pathology.