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

• 批准号: 7643796
• 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
• 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/7643796
• 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

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，通常对抗惊厥药物有抗性。近年来，手术效果有所改善，但仍有15 - 30%的患者在手术后5年出现癫痫发作。虽然人们普遍认为癫痫是由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（如缺氧、感染或头部损伤）可能与TIE的表达有关。在许多病例中，沉淀性脑损伤不能被临床识别，因此在第一次自发发作发生之前，癫痫发生可能难以发现和停止。因此，一条治疗路线应该包括一旦自发发作就停止发作。用于限制或预防急性癫痫发作的抗惊厥药可能不能预防慢性癫痫发作。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。为了开发抗慢性癫痫状态的药物，必须阐明潜伏期后自发发作的产生和维持机制。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率的高敏感性提高了NMDA受体在癫痫状态下对低频传入放电的反应增强有助于降低癫痫发作阈值的可能性。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。海马中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。与AMPA受体相比，NMDA受体与谷氨酸的结合具有更高的亲和力，并延长了EPSP的时间。不同受体亚型的生物物理特性的差异，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的时间累积是否增加，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在海马体中产生。本项目的重点是确定谷氨酸受体介导的兴奋如何在海马中癫痫易发CA1锥体细胞中发生变化。