TLR1调控GABA能神经元Cacng2受体在颞叶癫痫的作用及机制

GABAergic neurons have the important role in epilepsy,but the mechanism is as yet unknown. The studies showed that TLRs involved of the seizures of epilepsy by regulate the abnormal discharge of neurons. Our preliminary study confirmed TLR1 high expression in the inhibitory GABA neurons of epilepsy tissues, and the kainic acid induced TLR1 KO mice significantly increased the threshold of seizures. The data indicated that TLR1 has the obvious effect on epileptic seizures by regulate the GABAergic neurons. From the result of whole-genome transcriptional group scanning analysis, we find that TLR1 KO mice significantly increased the expression of Cacng2, as one of the key components which regulating the activity of AMPA receptor and mediated the current of excitatory glutamate receptor caused the seizures of epilepsy. Accordingly, we presume that TLR1 directly inhibited the activity of Cacng2 on GABA neurons, and change the function of calcium ion channels and AMPAR receptors, and those effects may be as the main mechanism of TLR1 regulates the seizures of epilepsy. Therefore, in this study, to explore the effect of TLR1 directly regulate the Cacng2 receptor on GABA neurons on the seizures change of epilepsy with the techniques of multiple conductive physiology, light genetics, patch clamp light, etc. The good study provides the better treatment of epilepsy in the future.

Toll样受体（TLRs）在颞叶癫痫的发生发展中起重要作用，TLRs不同的分布存在不同的功能。我们先前证实TLR1高表达于癫痫组织，预实验显示TLR1特异表达GABA抑制性神经元上，TLR1敲除小鼠增加癫痫发作阈值，提示TLR1可能通过调控GABA神经元参与调控癫痫发作，但作用机制仍不清楚。通过全基因转录组扫描发现TLR1敲除小鼠Cacng2表达明显上调。鉴于Cacng2作为调控钙离子流和影响突触的可塑性及兴奋性AMPA受体的一个关键组分，我们推测：TLR1通过直接抑制GABA神经元的Cacng2，影响了钙离子通道和AMPAR受体功能可能是TLR1调控癫痫的主要机制。因此，本项目运用多导电生理等技术，从TLR1独立于炎症信号通路，直接调控GABA神经元Cacng2受体的功能模式来探讨TLRs在调控癫痫发作中的重要功能，进而揭示颞叶癫痫调控的新机制，为顽固性颞叶癫痫治疗提供理论依据。

我们从病理形态学、分子生物学、电生理特点及微环路的水平上，对TLR1的表达与作用特点进行了初步的研究。首先，从临床角度探讨了TLR1在临床癫痫组织中的表达和分布特点，细胞定位特征。其次，我们使用敲基因小鼠，结果在体脑电检测，证实了TLR1在癫痫发作中的保护作用，并且影响了病理特征的改变。最后，我们使用示踪技术发现，TLR1可能通过影响齿状回局部网络环路，从而影响了癫痫发作。该结果对于我们理解TOLL受体在神经元兴奋性改变中的作用和机制提供了新思路。