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

基本信息

批准号：
7470084
负责人：
XIAOMING JIN
金额：
$ 9万
依托单位：
STANFORD UNIVERSITY
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：
2007-07-15 至 2009-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7470084
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

项目摘要

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）：脑损伤通常会导致癫痫病，而癫痫受到抗癫痫药的控制不佳。尽管有证据表明，轴突发芽，增强的兴奋性突触连通性和抑制性突触传递降低与创伤后的癫痫发生有关。有关这些变化如何发生并导致癫痫发生的更多信息是不完整的。该信息对于为开发旨在破坏创伤后癫痫发生的新疗法提供合理的基础至关重要。在拟议的研究中，我将使用部分皮质分离（“底切”）模型和创伤后癫痫发生的新型器官切片培养模型来研究兴奋性和抑制性突触连通性的改变。将解决三个具体问题：（1）慢性部分皮质隔离后V层V锥体神经元之间的兴奋性突触耦合增加？（2）。在这种病变后，抑制性突触输入抑制性突触输入降低到V型锥体细胞的层？（3）轴突发芽在创伤后癫痫发生中是否起关键作用？我将使用单个和配对的全细胞记录，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。将开发出LSP引导的双重整体记录技术，以提高配对记录的效率。这些实验的结果将确定并表征癫痫新皮层中兴奋性和抑制性突触传播的改变，损伤后轴突发芽期间的形态学动力学记录，并建立了一种新型的创伤后癫痫发生模型。结果将有助于进一步理解创伤后癫痫中涉及的正常突触回路和病理变化，并为预防新疗法提供预防创伤后癫痫发生的见解。在指导阶段的调查将发生在斯坦福大学神经病学系设备齐全且支持的研究实验室中。赞助商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。该奖项的培训活动支持将极大地使候选人过渡成为癫痫研究领域的独立研究者。教师委员会将在奖励期间向受赠人提供建议和评估。