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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.

创伤性脑损伤经常导致癫痫，而抗癫痫药物对癫痫的控制效果很差。尽管在那里轴突出芽增强兴奋性突触连接，减少抑制性突触传递与尿毒症后癫痫的发生有关，关于这些变化是如何发生的进一步信息发生和促进癫痫的发生是不完整的。这些信息在提供合理的基础上是至关重要的用于开发旨在破坏创伤后癫痫发生的新疗法。在Jai-pposed；研究中，我将使用部分皮质隔离(“底切”)模型和一种新的组织切片培养模型创伤后癫痫发生研究兴奋性和抑制性突触连接的变化，三个具体的问题将被解决：(1)轴突萌发在创伤后是否起关键作用癫痫的发生？(2)慢性部分皮质隔离后，V层锥体神经元之间的兴奋性突触耦合是否增加？我将结合使用单个和成对的vvhole细胞记录、激光扫描光刺激(LSP)、转基因小鼠、器官型脑片培养、基因枪转染术和延时共聚焦显微镜技术。为了提高配对记录的效率，将开发一种以LSP为导向的双全细胞记录电路。这些实验的剩余部分将识别和描述致痫新皮质兴奋性突触传递的变化，记录创伤性脑损伤后轴突萌发过程中的形态动力学，并建立一种新的创伤后癫痫发生的体外模型。本研究的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改变，并为开发预防脑外伤后癫痫发生的新疗法提供启示。