突触外N-甲基D-天门冬氨酸受体可塑性及Jacob信号通路在癫痫与抑郁症共病中的作用机制研究

The prevalence of comorbidity between epilepsy and depression is high, and the mechanisms underlying have not been fully elucidated yet. In our previous study, we demonstrated that hippocampal glutamate level was associated with the comorbidity of epilepsy and depression. Glutamate synaptic NMDA receptor (syn-NMDAR) and extrasynaptic NMDA receptor (ex-NMDAR) have opposite effects. Jacob is a crucial messenger protein which transmits the signal of NMDAR to cell nuclei. The effect of pJacob is to promoting the signal transmission of syn-NMDAR, increasing the expression of ERK1/2 and pCREB, and mediating cell survival; while Jacob has effects of promoting the signal transmission of ex-NMDAR, decreasing the expression of ERK1/2 and pCREB, and causing cell death and neurological diseases. Therefore, we hypothesize that ex-NMDAR and Jacob signal pathway may be involved in the common pathogenesis of epilepsy and depression. This study is to investigate it from the following three aspects: 1) to establish rat model of comorbidity of epilepsy and depression, and observe changes of ex-NMDAR plasticity and function; 2) to explore effects of regulating rat hippocampal ex-NMDAR on Jacob signal pathway and their pathogenesis in the comorbidity of epilepsy and depression; 3) to further investigate the influence of regulating Jacob signal pathway on behaviours and electrophysiology in rat model of comorbidity of epilepsy and depression.

癫痫与抑郁症共病的发病率高且机制尚未阐明。我们前期研究显示海马谷氨酸增高与癫痫和抑郁症共病相关。谷氨酸的突触间（syn-NMDAR）和突触外NMDA受体（ex-NMDAR）发挥相反作用。Jacob是将NMDAR信号传入细胞核的重要信使蛋白，pJacob促进syn-NMDAR 信号传递、ERK1/2和pCREB表达增加，介导细胞生存；而Jacob则促进ex-NMDAR信号传递、ERK1/2和pCREB表达减少，介导细胞死亡和神经系统疾病发生。我们认为ex-NMDAR及Jacob信号通路可能参与了癫痫与抑郁症发病的共同通路。本项目拟从以下三方面进行研究：1) 探讨癫痫与抑郁症共病大鼠模型海马中ex-NMDAR可塑性和功能变化；2) 探索调控ex-NMDAR对Jacob信号通路的影响及其在癫痫与抑郁症共病中的作用；3)进一步调控Jacob信号通路后对癫痫与抑郁症共病模型的行为学和电生理等的影响。

癫痫是一种常见的神经系统疾病，除了具有癫痫发作的易感性之外，还伴有认知、情绪和社会功能损害等后果。研究表明癫痫患者中抑郁症的发病率高达30%。目前癫痫与抑郁症共病机制尚不明确，且缺乏循证有效而又安全的药物。本研究在前期基础上，完成了癫痫与抑郁症共病大鼠模型的建立、行为学评估、大鼠海马中神经元、胶质细胞和树突棘可塑性的变化，探讨了Jacob下游ERK1/2-CREB信号通路的变化情况，以及其与炎症机制的关系。本研究采用了动物行为学评估、免疫荧光、高尔基染色、ELISA和Western-blot等实验方法。研究结果表明氯化锂-匹鲁卡品诱导的癫痫和抑郁症共病大鼠模型（Licl-Pilo）与CUMS原发性抑郁症大鼠模型在行为学表现上具有不同点，其海马的病理学表现也存在明显差异；氯化锂-匹鲁卡品癫痫持续状态大鼠模型和慢性自发性癫痫发作模型均存在海马神经元树突棘的损害，大鼠海马中ERK1/2-CREB信号通路的蛋白磷酸化表达明显下降。同时，海马和前额叶皮层中炎症因子(TNF-α , IL-1β and IL-6)的水平明显增高，应用炎性抑制剂TPPU后大鼠脑内炎症因子水平明显下降，而ERK1/2-CREB信号通路的蛋白表达水平则明显回升。本研究解释了在临床上癫痫患者的抑郁行为不典型的原因，为下一步寻找癫痫与抑郁症共病的治疗靶点打下基础，并为今后是否可将TPPU应用于临床中添加治疗癫痫与抑郁症共病提供了实验依据。