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：
8070343
负责人：
XIAOMING JIN
金额：
$ 24.4万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
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 2013-04-30
项目状态：
已结题

项目摘要

Trauniatic brain injury often results in epilepsy that is poorly controlled by antiepileptic drugs. Although there is evitjence that axonal sproutingvenhanced excitatory synaptic connectivity and reduced inhibitory synaptic tranismisision are associated with posttraurriatic epileptogenesis, further information on how these changes occur and contribute to epileptogenesis is inconriplete. This information is crut^ial in providing a rational basis for the development of new therapies aimed to disrupt posttraumatic epileptogenesis. in the jai-pposed;study, I will use the partial cortical isolation ("undercut") niodel and,a novel prganotypic slice culture model of posttraumatic epileptogenesis to investigate alterations in excitatory and inhibitory synaptic connectivity, Three specific questions will be addressed: (1) Does axonal sprouting play a critical role in posttraumatic epileptogienesis? (2) is there an incfeaise in excitatory synaptic coupling; between layer V pyramidal neurons after a chronic partial cortical isolation? I will use a combination of single and paired vvhole ceil recording, laser scanning photostimulation (LSP), transgenic mice, organotypic brain slice culture, gene gun transfectibn, and time-lapse confocal microscopy techniques. An LSP-guided dual whole cell recording tiechiiit^ue will be developed to improve efficiency of paired recordings. The resiilts of these experiments will identify and characterize alterations in excitatory synaptic transmission in the epileptogenic neocortex, document morphological dynamics during axonal sprouting after traumatic brain injury, and establish a novel in vitro model of posttraumatic epileptogenesis. Results from the pi'bposed study will contribute to a further understanding of normal synaptic circuitry and pathological ciianges involved in posttraumatic epilepsy and provide insights for- development of noveltherapies for preventing epileptogenesis after brain trauma.

创伤性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。虽然那里敏感的是，轴突发芽的兴奋性突触连通性和抑制性突触降低 tranismisis与龙龙后癫痫发生有关，进一步有关这些改变的信息发生并导致癫痫发生的是不同步。此信息在提供合理的基础上是有效的为了开发旨在破坏创伤后癫痫发生的新疗法。在Jai的研究中；我将使用部分皮质隔离（“底切”）niodel和一种新型的预型切片培养模型创伤后的癫痫发生以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）轴突发芽在创伤后起关键作用癫痫病？（2）在兴奋性突触耦合中是否存在裂纹；慢性部分皮质分离后V层锥体神经元之间？我将使用单个和配对的VVHOLE CEIL记录，激光扫描光刺激（LSP），转基因小鼠，器官型脑切片培养，基因枪trandfectibn和延时综合显微镜技术。将开发LSP引导的双重整个细胞记录Tiechiiit^ue，以提高配对记录的效率。这些实验的重新构成将识别并表征癫痫新皮层中兴奋性突触传播的改变，创伤性脑损伤后轴突芽期间的形态学动力学，并建立了创伤后癫痫发生的新型体外模型。 PI'BPES研究的结果将有助于进一步理解与创伤后癫痫有关的正常突触回路和病理ciianges，并提供有关防止脑创伤后癫痫发生的新颖性的见解。