Excitatory and Inhibitory Synaptic Connectivity in Posttraumatic Epileptogenesis

创伤后癫痫发生中的兴奋性和抑制性突触连接

• 批准号: 7320408
• 负责人: XIAOMING JIN
• 金额: $ 9万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-15 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7320408
• 关键词: Address; Antiepileptic Agents; Award; Axon; Brain; Cells; Chronic; Confocal Microscopy; Coupling; Development; Epilepsy; Epileptogenesis; Evaluation; Exhibits; Faculty; Frequencies; Glutamates; Image; In Vitro; Injury; Interneurons; Investigation; Knockout Mice; Laboratory Research; Lasers; Lesion; Maps; Measures; Mentors; Modeling; Mus; Neocortex; Neurology; Neurons; Neurosciences; Phase; Play; Presynaptic Terminals; Proteins; Pyramidal Cells; Research; Research Personnel; Role; Scanning; Slice; Source; Students; Support of Research; Synapses; Synaptic Transmission; Techniques; Time; Training; Training Activity; Transfection; Transgenic Mice; Traumatic Brain Injury; Universities; Whole-Cell Recordings; axonal sprouting; base; gene gun; hippocampal pyramidal neuron; improved; in vitro Model; in vivo; insight; knockout gene; neocortical; neural circuit; novel; postsynaptic; presynaptic; prevent; research study; somatosensory

DESCRIPTION (provided by applicant): Traumatic brain injury often results in epilepsy that is poorly controlled by antiepileptic drugs. Although there is evidence that axonal sprouting, enhanced excitatory synaptic connectivity and reduced inhibitory synaptic transmission are associated with posttraumatic epileptogenesis; further information on how these changes occur and contribute to epileptogenesis is incomplete. This information is crucial in providing a rational basis for the development of new therapies aimed to disrupt posttraumatic epileptogenesis. In the proposed study, I will use the partial cortical isolation ("undercut") model and a novel organotypic slice culture model of posttraumatic epileptogenesis to investigate alterations in excitatory and inhibitory synaptic connectivity. Three specific questions will be addressed: (1) Is there an increase in excitatory synaptic coupling between layer V pyramidal neurons after a chronic partial cortical isolation? (2). Is there a decrease in inhibitory synaptic input from fast-spiking interneurons to layer V pyramidal cells after such a lesion? (3) Does axonal sprouting play a critical role in posttraumatic epileptogenesis? I will use a combination of single and paired whole cell recording, laser scanning photostimulation (LSP), transgenic mice, organotypic brain slice culture and time-lapse confocal microscopy techniques. An LSP-guided dual whole cell recording technique will be developed to improve efficiency of paired recordings. The results of these experiments will identify and characterize alterations in excitatory and inhibitory synaptic transmission in the epileptogenic neocortex, document morphological dynamics during axonal sprouting following injury, and establish a novel in vitro model of posttraumatic epileptogenesis. Results will contribute to a further understanding of normal synaptic circuitry and pathological changes involved in posttraumatic epilepsy and provide insights for development of novel therapies for preventing posttraumatic epileptogenesis. The investigations during the mentored phase will occur in a fully equipped and well-supported research laboratory of the Department of Neurology at the Stanford University. The sponsor has trained numerous students and fellows, many of whom are now prominent in the field of neuroscience. The training activities support by this award will greatly benefit the candidate's transition to become an independent investigator in the field of epilepsy research. A faculty committee will provide advice and evaluations of progress to the grantee during the award period.

描述（由申请人提供）： 创伤性脑损伤常导致抗癫痫药物控制不佳的癫痫。虽然有证据表明，轴突发芽，兴奋性突触连接增强和抑制性突触传递减少与创伤后癫痫发生有关，这些变化如何发生，并有助于癫痫发生的进一步信息是不完整的。这一信息是至关重要的，提供了一个合理的基础，旨在破坏创伤后癫痫发生的新疗法的发展。在拟议的研究中，我将使用部分皮层隔离（“底切”）模型和一种新的器官型切片培养模型的创伤后癫痫调查兴奋性和抑制性突触连接的改变。三个具体的问题将得到解决：（1）是否有一个增加兴奋性突触耦合层V锥体神经元慢性部分皮层隔离后？（二）、在这样的损伤后，从快速发放的中间神经元到第V层锥体细胞的抑制性突触输入是否减少？(3)轴突发芽在创伤后癫痫发生中起关键作用吗？我将使用单个和成对的全细胞记录，激光扫描光刺激（LSP），转基因小鼠，器官型脑切片培养和延时共聚焦显微镜技术的组合。将开发LSP引导的双全细胞记录技术以提高配对记录的效率。这些实验的结果将识别和表征癫痫致新皮层中兴奋性和抑制性突触传递的改变，记录损伤后轴突发芽过程中的形态学动力学，并建立一种新的创伤后癫痫发生的体外模型。研究结果将有助于进一步了解创伤后癫痫的正常突触回路和病理变化，并为开发预防创伤后癫痫发生的新疗法提供见解。指导阶段的研究将在斯坦福大学神经病学系一个设备齐全、支持良好的研究实验室进行。赞助者已经培训了许多学生和研究员，其中许多人现在在神经科学领域很突出。该奖项支持的培训活动将大大有利于候选人成为癫痫研究领域的独立研究者。一个教师委员会将在奖励期间向受赠者提供建议和进展评估。