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）-以自发性和复发性部分性癫痫发作为特征。此外，许多患有MTLE的患者不能用当前的抗癫痫药物控制他们的癫痫发作。因此，旨在预测和治疗即将发生的内侧颞叶癫痫发作的新方法尤为重要。因此，本提案的总体目标是探索MTLE中癫痫发作产生的机制，从而促进发现这种疾病的候选生物标志物和更有效的治疗方法。 最近的研究表明，海马中谷氨酰胺合成酶的缺乏与MTLE中癫痫发作的产生有关（Eid等Lancet 2004; 363：28-37）。使用最先进的方法，在连续视频颅内脑电图监测，微透析，免疫金电子显微镜，13 C-和15 N-同位素标记，和串联质谱，谷氨酰胺合成酶缺乏症的作用，在癫痫发作的产生将系统地探讨在一个新开发的实验室模型MTLE。在特定目标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学之间的关系。该假说是谷氨酰胺合成酶的缺乏导致星形胶质细胞和海马细胞外空间中谷氨酸的慢性高浓度，在患有严重癫痫发作和广泛脑损伤的个体中具有特别高的谷氨酸水平。在特定目标2中，将探索自然发生的脑化学物质的短暂升高作为MTLE中“自发性”癫痫发作的潜在触发因素。这一假说认为，这些触发因素会导致海马体细胞外谷氨酸的短暂激增，最终导致“自发”癫痫发作。最后，在具体目标3中，将评价致癫痫海马中谷氨酰胺合成酶的恢复可用作MTLE的治愈的概念。该假说认为，海马中谷氨酰胺合成酶的恢复导致癫痫发作停止，即使在存在广泛的脑病理的情况下。

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.