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: 7773821
• 负责人: XIAOMING JIN
• 金额: $ 24.9万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 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 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7773821
• 关键词: Address; Antiepileptic Agents; Brain; Brain Injuries; Cells; Chronic; Confocal Microscopy; Cortical Malformation; Coupling; Development; Electroencephalography; Epilepsy; Epileptogenesis; Freezing; Interneurons; Knockout Mice; Lasers; Learning; Lesion; Maps; Measures; Microgyria; Modeling; Modification; Monitor; Neocortex; Neurons; Phase; Play; Prevention therapy; Research; Research Proposals; Role; Scanning; Seizures; Slice; Source; Synapses; Synaptic Transmission; Techniques; Time; Transgenic Mice; Traumatic Brain Injury; Whole-Cell Recordings; axonal sprouting; base; density; gene gun; hippocampal pyramidal neuron; improved; in vitro Model; in vivo; insight; neural circuit; novel; prevent; research study

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.

外伤性脑损伤常常导致癫痫，而抗癫痫药物控制效果不佳。虽然有 事实证明，轴突萌芽增强了兴奋性突触连接并减少了抑制性突触 传输与创伤后癫痫发生有关，有关这些变化如何的进一步信息 发生并导致癫痫发生是不完整的。这些信息对于提供合理的基础至关重要 表彰其开发旨在破坏创伤后癫痫发生的新疗法。在杰提出的研究中， 我将使用部分皮质隔离（“底切”）niodel 和一种新颖的原代切片培养模型 创伤后癫痫发生研究兴奋性和抑制性突触连接的变化， 将解决三个具体问题：（1）轴突出芽在创伤后恢复中发挥关键作用吗？ 癫痫发生？ (2)兴奋性突触耦合是否存在增强；慢性部分皮质隔离后第五层锥体神经元之间？我将结合使用单孔细胞记录和成对孔细胞记录、激光扫描光刺激（LSP）、转基因小鼠、器官型脑切片培养、基因枪转染和延时共聚焦显微镜技术。将开发 LSP 引导的双全细胞记录系统，以提高配对记录的效率。这些实验的结果将识别和表征致癫痫新皮质中兴奋性突触传递的变化，记录创伤性脑损伤后轴突萌芽期间的形态动态，并建立创伤后癫痫发生的新型体外模型。该研究的结果将有助于进一步了解与创伤后癫痫有关的正常突触回路和病理变化，并为开发预防脑外伤后癫痫发生的新疗法提供见解。