Synaptic transmission during status epilepticus

癫痫持续状态期间的突触传递

• 批准号: 7006633
• 负责人: Howard P Goodkin
• 金额: $ 16.81万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7006633
• 关键词: GABA receptor; benzodiazepines; confocal scanning microscopy; electroencephalography; electrostimulus; generalized seizures; hippocampus; immunocytochemistry; interneurons; laboratory rat; neural transmission; neuropathology; neurotransmitter transport; protein localization; receptor binding; tissue /cell culture; voltage /patch clamp

DESCRIPTION (provided by applicant): A five-year training program providing the applicant with the opportunity to develop the knowledge and skills required to perform future independent investigations in synapse physiology and the basic mechanisms of epilepsy is proposed. Having completed clinical training in child neurology and clinical neurophysiology at Children's Hospital Boston, the principal investigator is now an Assistant Professor of Neurology and Pediatrics at the University of Virginia. The opportunity to expand upon his scientific skills under the mentorship of Dr. Jaideep Kapur, a recognized leader in the basic mechanisms of epilepsy, and the UVA Department of Neurology's commitment to this candidate makes UVA the ideal setting for the applicant's training as a physician-scientist. The proposed research will focus on providing an improved understanding of the changes that occur at inhibitory synapses during status epilepticus. First line therapies for the treatment of status epilepticus, which target inhibitory synaptic transmission, often fail leaving the patient at risk for mortality or significant neurological morbidity. It is posited that an improved understanding of the changes that occur at inhibitory synapses during status epilepticus will provide a framework on which to base new therapies with the goal of improving the prognosis for those who present in status epilepticus. While two distinct lines of evidence suggest that an alteration in inhibitory synaptic transmission does occur during status epilepticus and that this alteration is, in part, the result of a modification in the complement of GABAA receptors present at the synapse, the mechanism underlying the modification is not known. Using an in vitro and an in vivo model of status epilepticus combined with electrophysiological and cellular imaging techniques, the mechanism underlying the modification in the post-synaptic GABAA receptor population will be investigated by completing four Specific Aims: 1) To characterize the impact of in vitro status epilepticus on GABA-mediated synaptic transmission by means of patch clamp recording, 2) To characterize the impact of in vivo status epilepticus on GABA-mediated synaptic transmission by means of patch clamp recording, 3) To characterize the impact of status epilepticus on the rate of internalization and distribution of GABAA receptors by means of immunocytochemistry combined with microscopy and 4) To characterize the impact of status epilepticus on GABA release from the pre-synaptic terminals by means of patch clamp recording.

描述（由申请人提供）：一项为期五年的培训计划，为申请人提供了开发对突触生理学的未来独立调查所需的知识和技能的机会，并提出了癫痫病的基本机制。在波士顿儿童医院完成了儿童神经病学和临床神经生理学的临床培训后，首席研究员现在是弗吉尼亚大学神经病学和儿科助理教授。在Jaideep Kapur博士的指导下扩大他的科学技能的机会，Jaideep Kapur博士是癫痫基本机制的公认领导者，UVA神经病学部门对该候选人的承诺使UVA成为申请人作为医师科学家的理想培训。拟议的研究将着重于对癫痫持续性抑制性突触发生的变化有更深入的了解。靶向抑制性突触传播的状态癫痫症治疗的第一线疗法常常使患者处于死亡率或明显的神经系统发病率的风险。人们认为，对癫痫持续状态期间抑制性突触发生的变化的改进理解将为基础新疗法提供一个框架，目的是改善癫痫持续状态的人的预后。虽然两种不同的证据表明，在癫痫持续状态下确实发生了抑制性突触传播的改变，并且这种改变部分是突触中存在的GABAA受体补充的变化结果，而修饰的机制尚不清楚。使用体外和体内癫痫持续体的体内模型与电生理和细胞成像技术结合，将通过完成四个特定目的来研究后突触后GABAA受体种群修饰的机制：1）通过对2）对植物的影响进行粘贴型粘膜的影响，以表征粘膜对粘膜的影响。通过贴片夹记录对GABA介导的突触传播的体内状态癫痫群，3）表征癫痫持续状态对GABAA受体对GABAA受体的内在化和分布的影响，通过与显微镜相结合的免疫细胞化学和4）表征了epilepticus对Gaba终端释放的影响。