惊厥后发育期海马网络高频振荡的演变及其可能机制

Convulsive status (SC) induced selective hippocampal neuron death and the formation of abnormal neural circuits result in brain injuries, such as secondary epilepsy and cognitive disorders. The establishment of normal synaptic contacts with the hippocampus are necessary for the rehabilitation of brain function, in addition to the promotion of neuron survival, proliferation, and differentiation to replace dead neurons. This study aimed to establish the normal electrical synapse responses of the immature hippocampus after SC, compared the age difference expression of four main connexin (Cx) proteins, gap junction (GJ)communication,and neural high-frequency oscillations (HFOs) in the hippocampus of immature and adult rats after SC. The secondary aims of the study were to confirm which kind of connexin in forming GJ play important role in epilepsy activity, define whether hippocampal Cx established abnormal synaptic transmission via the formation of pathological HFOs, and whether these could influence seizure-induced brain injury during development. This would provide evidence for the treatment of seizures by a targeted blockade of GJ transmission in addition to establishing a new method for the endogenous repair of brain damage.

惊厥持续状态（SC）易导致选择性海马神经元死亡，形成异常神经回路，从而 继发癫痫、认知障碍等脑损伤。实现脑功能康复，除促进惊厥后脑内神经元存活、神经干细 胞增殖分化替代死亡神经元外，必须在海马神经元间建立正常突触联系。本项目拟以促进SC 后，未成熟脑建立正常海马电突触应答为目标，以年龄差异为切入点，对比观察SC 前后，幼年与成年海马网络生理与病理性神经高频振荡（HFOs）的动态表达，缝隙连接（GJ）传递功能的改变；探索生理性HFOs的发育规律，病理性HFOs在癫痫发生发展中的作用；阐明海马HFOs产生的神经元机制，确认海马缝隙链接蛋白（Cx ）是否通过参与病理性HFOs 形成，从而建立异常突触传递，影响发育期惊厥性脑损伤；为针对性阻断GJ 传递的作用靶点，有效促进惊厥后神经元内源性修复、建立正常突触应答，提供新的方法与途径；同时也为认识癫痫发作启动和传播的神经网络提供重要的理论依据。

惊厥持续状态易导致选择性海马神经元死亡，形成异常神经回路，从而继发癫痫、认知障碍等脑损伤。实现脑功能康复，除促进惊厥后脑内神经元存活、神经干细胞增殖分化替代死亡神经元外，必须在海马神经元间建立正常突触联系。本项目发现急性惊厥发作可诱导海马HFOs的能量明显增加，并持续至持续惊厥后1天。慢性癫痫模型发作间期HFOｓ与癫痫的发作并无明确相关性。广谱缝隙莲接(Gap junction，GJ) 阻断剂甘珀酸可以明显减少惊厥发作，其作用机理可能与阻断了HFOs的表达密切相关。无论是体外海马神经元培养，还是海马脑片干预试验，均可发现惊厥发作诱导海马神经元GJ 偶联增多。GJ 抑制剂的应用，可以阻断海马神经元间GJ表达，减少体外培养海马神经元惊厥样放电，对神经元起保护作用。惊厥发作后，(connexin，Cx)可能通过参与病理性HFOs 的形成，从而建立异常的电突触传递，增加惊厥易感性。结合不同龄期大鼠海马惊厥前后均以CX36表达为主。SC 发作后，幼鼠脑内神经元可能正是因为存在能快速下调CX表达的机制，尤其抑制CX43的表达，从而较成年鼠能更早地启动抵抗惊厥的内在保护性机制。以上研究结果为针对性阻断GJ 传递的作用靶点，有效促进惊厥后神经元内源性修复、建立正常突触应答，提供新的方法与途径；同时也为认识癫痫发作启动和传播的神经网络提供重要的理论依据。