吊灯样细胞功能异常与癫痫发生发展机制的研究

既往认为在癫痫病灶中出现GABA能中间神经元数量减少的现象可能是导致癫痫发生发展的重要原因之一。然而在颞叶癫痫患者的海马区却发现GABA能中间神经元中的吊灯样细胞对轴突起始段支配增多。轴突起始段是动作电位起始发放的位置，因此在该区域GABA能输入的增加可能直接影响神经元的电发放。本项目前期通过构建特异性标记吊灯样细胞的转基因工程鼠，首次在动物模型中重现了在癫痫患者中观察到的吊灯样细胞对海马锥体神经元轴突起始段支配的增加，同时也记录到了吊灯样细胞在癫痫发作期的钙信号。我们认为，癫痫灶中吊灯样细胞支配的增加可能是神经元过度发放的代偿性变化，但这种支配的增加也可能进一步促进锥体神经元发放的同步化而推动继发性癫痫的产生。为了验证以上假说，本项目将结合形态学、在体电生理、光遗传学和化学遗传学等手段，旨在研究吊灯样细胞异常和癫痫发生发展的关系，为癫痫治疗提供可能的干预手段。

Temporal lobe epilepsy (TLE), as the most common form of epilepsy in adult, is drug ineffective. It has been shown that the number of GABAnergic interneuron was decreased in epilepsy foci，which may contribute to the onset and propagation of epilepsy. Particularly, there is an increase of chandelier cell axonal terminal in hippocampus of TLE patients. As axon initial segment (AIS) is the site where action potential is initiated, receiving more GABAnergic input will affect neuronal firing. In order to study whether the change of chandelier cell axonal terminals contribute to the etiology of epilepsy, a transgenetic mouse line which specifically labels chandelier cells was established. By using this mouse line, for the first time, we recapitulated the phenotype of chandelier cells in human epileptic patient. Meanwhile, we recorded the Ca2+ signal in chandelier cells during seizure. We hypothesize that the increased innervation on AIS by chandelier cells can be the result of compensation over the excessive neuronal firing, however, it might further strengthen the synchronous firing in neuronal population to promote the secondary seizure. To verify these hypotheses, morphology analysis, in vivo electrophysiology, optogenetics and pharmocogenetics will be implemented to demonstrate the relationship between chandelier cell dysfunction and epilepsy etiology. A possible intervention to alleviate epilepsy expression is expected to achieve eventually.