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：
7317068
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/7317068
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 Chromosome Pairing Chronic Craniocerebral Trauma DLG4 gene Development Disruption Dissociation Environmental Risk Factor Epilepsy Epileptogenesis Equilibrium Excitatory Postsynaptic Potentials Fire - disasters 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 Numbers Operative Surgical Procedures Outcome Partial Epilepsies Patients Pharmaceutical Preparations Pharmacotherapy Phase Physiological Preparation Probability Property Pyramidal Cells RNA Rate 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 presynaptic density protein 95 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）：颞叶癫痫是最常见的成人局灶性癫痫的形式，通常对抗惊厥疗法有抵抗力。最近，手术结果一直在改善，但是，有15-30％的患者仍报告手术后5年癫痫发作。尽管人们普遍认为，癫痫病是由于激发与抑制，遗传和环境因素以及可能涉及诸如缺氧，感染或头部损伤之类的大脑侮辱的平衡而引起的。在许多情况下，在临床上无法识别出沉淀的大脑侮辱，因此在首次自发癫痫发作之前，可能难以检测和停止癫痫发生。因此，一系列治疗应涉及自发癫痫发作后的停止。用于限制或预防急性癫痫发作的抗惊厥药可能无法阻止慢性癫痫中的癫痫发作。这表明涉及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。为了针对慢性癫痫状态开发药物，应阐明潜在阶段后自发发作和维持的机制。据报道，NMDA受体的突触激活在点燃后增加。 NMDA受体激活对传播发射速率的高灵敏度增加了增强的NMDA受体对癫痫状态低频率传播发射的反应增强的可能性，这有助于降低癫痫发作阈值。突触后谷氨酸受体的表达增加将增加重复刺激过程中去极化的程度。点燃后海马中的NMDA受体活性会改变，但是尚未阐明癫痫发生后NMDA受体变化的性质。 NMDA受体与AMPA受体具有更高的亲和力结合谷氨酸，并延长EPSP时间过程。不同受体亚型（如谷氨酸解离率和镁结合亲密亲和力）的生物物理特性的差异也会导致突触后细胞的去极化增加。我们计划确定在慢性癫痫大鼠海马的CA1锥体细胞中，EPSP的时间求和是否增加，以及是否由NMDA受体介导这种增加。与颞叶癫痫相关的癫痫发作通常在海马中产生。该项目的重点是确定谷氨酸受体介导的癫痫发作的激发如何变化，俯卧的CA1 CA1锥体细胞。