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

描述（由申请人提供）：癫痫最常见的类型之一-内侧颞叶癫痫(MTLE) -以自发和反复的部分癫痫发作为特征。此外，许多MTLE患者不能用现有的抗癫痫药物控制癫痫发作。因此，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发作产生的机制，从而促进发现候选生物标志物和更有效的治疗这种疾病。最近的研究表明，海马中谷氨酰胺合成酶的缺乏与MTLE癫痫发作的产生有关（Eid等）。《柳叶刀》2004年;363年:28-37)。利用最新的连续视频颅内脑电图监测、微透析、免疫金电子显微镜、13C-和15n -同位素标记和串联质谱等方法，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乏在癫痫发作中的作用。在特异性目标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、癫痫发作和海马病理之间的关系。该假说认为，谷氨酰胺合成酶缺乏导致星形胶质细胞和海马细胞外空间长期高浓度谷氨酸，在患有严重癫痫和大面积脑损伤的个体中，谷氨酸水平尤其高。在具体目标2中，自然发生的大脑化学物质的短暂升高将作为MTLE“自发”癫痫发作的潜在触发因素进行探讨。该假说认为，这些触发因素会导致海马体中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Specific Aim 3中，将评估恢复癫痫性海马中谷氨酰胺合成酶可能用于治疗MTLE的概念。假设是，即使存在广泛的脑部病理，海马体内谷氨酰胺合成酶的恢复也会导致癫痫发作的停止。

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.