细胞因子对ERK1/2和ERK5信号通路在孤独症中的调控和致病机制的研究

Autism is a severe neurodevelopmental disorder and the pathogenesis of this disorder is unknown. Our recent work showed that ERK1/2 and ERK5 signaling pathways were significantly up-regulated in the cortex of autistic individuals and in the BTBR murine model of autism and we found that ERK1/2 up-regulation in cortical neurons could alter neural cell migration, inhibit neurogenesis, as well as affect synaptic transmission and dendritic spine maturation. However, the exact activation mechanism of ERK1/2 and ERK5 signaling pathways remains undefined. A number of studies have shown that immune dysfunction and various cytokines upregulation are associated with autism, which suggests that the upregulation of ERK1/2 and ERK5 signaling activities in autism could result from increased cytokines. Based on these findings, we propose to upregulate and downregulate cytokines expression in the cortex of B6 mice, a highly social control strain, and BTBR mice respectively both in vitro and in vivo with a lentivirus approach and conduct studies to investigate the modulation of ERK1/2 and ERK5 pathways by cytokines and determine the effect of cytokine alteration on autism-like behavior in mice and mouse neural cell migration, development, apoptosis and synaptic plasticity. The importance of this application is that completion of the proposed studies will give us a clearer answer regarding the role of cytokines, ERK1/2 and ERK5 signaling pathways in the pathogenesis of autism and lead to the finding of a potentially effective treatment of autism.

孤独症是一种严重的神经发育障碍性疾病，其发病机制尚不明确。我们的前期研究发现ERK1/2和ERK5信号通路在孤独症患者和BTBR孤独症模型小鼠的大脑皮质中都存在异常激活的现象，并对神经元的迁移、发育、突触传递功能以及树突棘的成熟产生了影响，但是其激活机制仍不清楚。大量研究表明，免疫功能紊乱和多种细胞因子表达升高与孤独症的发生密切相关，提示我们ERK1/2和ERK5通路的激活可能与这些细胞因子有关。本项目拟在现有研究成果的基础上，以BTBR小鼠和B6小鼠作为研究对象，利用过表达和RNA干扰慢病毒从体内和体外两方面深入探讨细胞因子对ERK1/2和ERK5通路在孤独症中的调控机制，同时观察对小鼠孤独症相关行为学以及小鼠大脑皮质神经元的发育、凋亡、突触可塑性的调节作用，为进一步明确孤独症的发病机理，探索新的治疗方法提供理论基础和实验依据。

孤独症是一种严重的神经发育障碍性疾病，其致病机制尚不明确。研究表明，机体免疫系统紊乱和细胞因子表达失调是导致孤独症发生的重要原因，而IL-6的高表达在其中发挥了极为重要的作用。我们的前期研究发现ERK1/2和ERK5信号通路在孤独症患者和BTBR孤独症模型小鼠的大脑皮质中都存在异常激活的现象，但是其激活机制仍不清楚。. 本课题在前期研究的基础上，应用分子生物学、细胞生物学和动物行为学等手段，分别从细胞和动物两个水平上首次发现了：（1）IL-6可以通过激活大脑皮层神经元中ERK5信号通路促进神经元的迁移能力，并通过增强Bcl-2基因的表达抑制神经元的凋亡。（2）IL-6激活ERK5信号通路抑制了大脑皮层神经元兴奋性突触的形成，导致兴奋性/抑制性神经元比例失调，并且抑制了神经元树突棘的形成和发育，突触结构和功能受到影响。（3）IL-6通过上调大脑皮层神经元中ERK5信号通路的活性使小鼠产生社交障碍、学习和记忆能力下降以及焦虑情绪增强等孤独症样行为特征。这些研究结果揭示了细胞因子IL-6与ERK5信号通路在孤独症发生、发展过程中所发挥的作用，以及其相互之间的调控机制，为进一步明确孤独症的发病机理，探索新的治疗方法提供了理论基础和实验依据。.