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

描述(申请人提供)：颞叶癫痫，成人局灶性癫痫最常见的形式，通常对抗惊厥治疗有抵抗力。最近，手术结果一直在改善，然而，15%-30%的患者在手术后5年仍报告有癫痫发作。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所致，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)可能参与了Tie的表达。在许多情况下，突发性脑损伤不能在临床上识别，因此在第一次自发发作之前，癫痫的发生可能很难被发现和阻止。因此，一旦自发性癫痫发作发生，一种治疗方法应该是停止发作。用于限制或预防急性癫痫发作的抗癫痫药可能无法预防慢性癫痫的发作。这表明，导致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。为了开发针对慢性癫痫状态的药物，应阐明潜伏期后自发发作的产生和维持的机制。据报道，点燃后NMDA受体的突触激活增加。NMDA受体的激活对传入放电频率的高度敏感性增加了癫痫状态下NMDA受体对低频传入放电的反应增强导致癫痫阈值降低的可能性。突触后谷氨酸受体的表达增加会增加重复刺激时的去极化程度。点燃后海马区NMDA受体活性发生改变，但致痫后NMDA受体变化的本质尚不清楚。NMDA受体以比AMPA受体更高的亲和力结合谷氨酸，并延长EPSP的时间进程。不同受体亚型的生物物理性质的差异，如谷氨酸解离率和镁结合亲和力，也可能导致突触后细胞去极化的增加。我们计划确定慢性癫痫大鼠海马区CA1区锥体细胞中EPSP的时间总和是否增加，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发生在海马区。本项目的重点是确定谷氨酸受体如何介导癫痫发作易感的海马区CA1锥体细胞的兴奋变化。

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.