Influence of NMDA Receptors on EPSP Summation in Normal and Epileptic Rats

描述（由申请人提供）：颞叶癫痫是成人局灶性癫痫的最常见形式，通常对抗惊厥治疗具有抵抗力。最近，手术结果一直在改善，然而，15 - 30%的患者仍然报告在手术后5年癫痫发作。虽然人们普遍认为癫痫是由于兴奋和抑制之间的平衡被破坏，但遗传和环境因素以及可能的脑损伤如缺氧、感染或头部损伤可能参与TIE的表达。在许多情况下，临床上无法识别沉淀性脑损伤，因此在第一次自发性癫痫发作发生之前，癫痫发生可能难以检测和停止。因此，一条治疗线应该包括一旦发生自发性癫痫发作就停止。用于限制或预防急性癫痫发作的抗惊厥药可能无法预防慢性癫痫发作。这表明，参与产生急性癫痫发作的机制可能与维持慢性癫痫状态的机制不同。为了开发抗慢性癫痫状态的药物，应该阐明自发性癫痫发作产生和潜伏期后维持的机制。据报道，点燃后NMDA受体的突触激活增加。NMDA受体激活对传入放电率的高敏感性提高了在癫痫状态下增强NMDA受体对低频传入放电的反应有助于降低癫痫发作阈值的可能性。突触后谷氨酸受体表达的增加会增加重复刺激时的去极化程度。海马中NMDA受体活性在点燃后改变，但癫痫发生后NMDA受体变化的性质尚未阐明。NMDA受体以比AMPA受体更高的亲和力结合谷氨酸并延长EPSP时程。不同受体亚型的生物物理性质的差异，如谷氨酸解离速率和镁结合亲和力，也可以有助于增加突触后细胞的去极化。我们计划确定是否在慢性癫痫大鼠海马CA 1区锥体细胞中EPSP的时间总和增加，以及这种增加是否由NMDA受体介导。与颞叶癫痫相关的癫痫发作通常在海马体中产生。本研究旨在探讨谷氨酸受体介导的海马CA 1区锥体细胞兴奋性变化。

DESCRIPTION (provided by applicant): Temporal lobe epilepsy, the most common form of adult focal epilepsies, is often resistant to anticonvulsant therapy. Recently, surgery outcome has been improving, however, 15 - 30% of patients still report having seizures 5 years after surgery. Although it is generally agreed that epilepsy results from a disruption of the balance between excitation and inhibition, genetic and environmental factors and possibly a brain insult such as anoxia, infection or head injury may be involved in the expression of TIE. In many cases, the precipitating brain insult cannot be clinically recognized, and thus epileptogenesis may be difficult to detect and stop, prior to the development of the first spontaneous seizure. Thus, one line of treatment should involve cessation of spontaneous seizures once they occur. Anticonvulsants used to limit or prevent acute seizures might not prevent seizures in a chronic epilepsy. This indicates that mechanisms involved in generating acute seizures may be different from those involved in maintaining a chronic epileptic state. To develop drugs against a chronic epileptic state, the mechanisms involved in spontaneous seizures generation and maintenance after the latent phase should be elucidated. Synaptic activation of NMDA receptors has been reported to be increased after kindling. The high sensitivity of NMDA receptor activation to afferent firing rate raises the possibility that enhanced NMDA receptor responses to low frequency afferent firing in the epileptic state contributes to reduced seizure threshold. Increased expression of postsynaptic glutamate receptors would increase the degree of depolarization during repetitive stimulation. NMDA receptor activity in the hippocampus is altered after kindling, but the nature of the changes in NMDA receptors after epileptogenesis has not been elucidated. NMDA receptors bind glutamate with a higher affinity than AMPA receptors and lengthen the EPSP time course. Differences in biophysical properties of different receptor subtypes such as glutamate dissociation rates and magnesium binding affinities can also contribute to increased depolarization in the postsynaptic cell. We plan to determine if temporal summation of EPSPs is increased in CA1 pyramidal cells of the hippocampus in chronically epileptic rats, and if such increases are mediated by NMDA receptors. Seizures associated with Temporal Lobe Epilepsy are often generated in the hippocampus. This project focuses on determining how glutamate receptor mediated excitation changes in seizure prone CA1 pyramidal cells in the hippocampus.