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

NMDA 受体对正常和癫痫大鼠 EPSP 总和的影响

基本信息

批准号：
7869254
负责人：
Morris J. Benveniste
金额：
$ 24.5万
依托单位：
MOREHOUSE SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-15 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7869254
关键词：
AMPA Receptors Action Potentials Acute Adult Affinity Age Amygdaloid structure Animals Anoxia Anticonvulsants Binding Brain Calmodulin Cell Death Cells Cessation of life Chronic Craniocerebral Trauma Development Dissociation Environmental Risk Factor Epilepsy Epileptogenesis Equilibrium Excitatory Postsynaptic Potentials Frequencies Generations Genetic Glutamate Receptor Glutamates Harvest Hippocampus (Brain)Homer 1 In Vitro Infection Interneurons Kindling (Neurology)Lasers Magnesium Maintenance Measures Mediating Membrane Membrane Potentials Microscopy N-Methyl-D-Aspartate Receptors Nature Operative Surgical Procedures Outcome Partial Epilepsies Patients Pharmaceutical Preparations Pharmacotherapy Phase Physiological Preparation Probability Property Pyramidal Cells RNA Rattus Receptor Activation Relative (related person)Reporting Research Personnel Resistance Rest Reverse Transcriptase Polymerase Chain Reaction Scaffolding Protein Seizures Slice Status Epilepticus Stimulus Synapses Temporal Lobe Epilepsy Testing Time Training Transcript alpha Actinin axonal sprouting entorhinal cortex genetic regulatory protein granule cell hippocampal pyramidal neuron improved postsynaptic presynaptic prevent programs receptor receptor binding receptor function research study response voltage voltage clamp

项目摘要

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.

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，通常对抗惊厥治疗有抵抗力。最近，手术结果一直在改善，然而，15 - 30% 的患者在术后 5 年后仍报告出现癫痫发作。尽管人们普遍认为癫痫是由于兴奋和抑制之间的平衡被破坏引起的，但遗传和环境因素以及可能的脑损伤（例如缺氧、感染或头部损伤）可能与TIE的表达有关。在许多情况下，临床上无法识别诱发性脑损伤，因此在第一次自发性癫痫发作之前可能难以检测和阻止癫痫发生。因此，一种治疗方法应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的癫痫发作。这表明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。为了开发针对慢性癫痫状态的药物，应阐明潜伏期后自发性癫痫发作发生和维持的机制。据报道，NMDA 受体的突触激活在点燃后增加。 NMDA 受体激活对传入放电速率的高度敏感性提出了这样的可能性：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阈值。突触后谷氨酸受体表达的增加会增加重复刺激期间的去极化程度。海马中的 NMDA 受体活性在点燃后发生改变，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特性（例如谷氨酸解离速率和镁结合亲和力）的差异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 CA1 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体中。该项目的重点是确定谷氨酸受体如何介导海马中容易癫痫发作的 CA1 锥体细胞的兴奋变化。