Zhao Lingyu, Jiao Qian, Huang Chen, Hou Ni, Chen Xinlin, Zhang Jianshui, Yang Pengbo, Xu Xi, Song Tusheng, Liu Yong
aInstitute of Neurobiology bDepartment of Genetics and Cell Biology, Environment and Genes Related to Diseases Key Laboratory of Education Ministry, Xi'an Jiaotong University College of Medicine cDepartment of Anatomy, Xi'an Medical University, Xi'an, People's Republic of China.
Neuroreport. 2014 Apr 16;25(6):427-34. doi: 10.1097/WNR.0000000000000134.
Metabotropic glutamate receptors (mGluRs) regulate neurogenesis in the mammalian central nervous system during development and throughout adulthood. However, the mechanisms remain unknown. The present study was aimed at investigating the effect of mGluR5 on the differentiation of rat neural progenitor cells (NPCs) into neurons as well as the underlying molecular mechanisms. NPCs were treated with mGluR5 agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), mGluR5 siRNA, and antagonist 6-methyl-2-(phenylethynyl) pyridine hydrochloride (MPEP), respectively. Three different subtypes of neurons (cholinergic, GABAergic, and dopaminergic neurons) were evaluated, and the activation of signaling pathways of mitogen-activated protein kinases was determined. Results showed that CHPG caused rat NPCs to differentiate into neurons, whereas mGluR5 siRNA and MPEP inhibited the cell differentiation. The proportion of cholinergic neurons increased with CHPG treatment and decreased after siRNA or MPEP treatment, whereas there were no significant changes in the proportions of GABAergic and dopaminergic neurons after treatment. The phosphorylated ERK1/2 levels increased after CHPG treatment and decreased after siRNA or MPEP treatment. In conclusion, our findings showed that mGluR5 caused rat NPCs to differentiate into cholinergic neurons by activating ERKs, suggesting that mGluR5 may play a significant role in the mechanism and treatment of degenerative diseases such as Alzheimer's disease.
代谢型谷氨酸受体（mGluRs）在哺乳动物中枢神经系统发育过程及成年期均调控神经发生。然而，其机制尚不清楚。本研究旨在探究mGluR5对大鼠神经祖细胞（NPCs）向神经元分化的影响及其潜在分子机制。分别用mGluR5激动剂（RS）-2-氯-5-羟基苯甘氨酸（CHPG）、mGluR5小干扰RNA（siRNA）和拮抗剂6-甲基-2-（苯乙炔基）吡啶盐酸盐（MPEP）处理NPCs。评估了三种不同亚型的神经元（胆碱能、γ-氨基丁酸能和多巴胺能神经元），并测定了丝裂原活化蛋白激酶信号通路的激活情况。结果显示，CHPG促使大鼠NPCs分化为神经元，而mGluR5 siRNA和MPEP抑制细胞分化。胆碱能神经元比例在CHPG处理后增加，在siRNA或MPEP处理后降低，而处理后γ-氨基丁酸能和多巴胺能神经元比例无显著变化。CHPG处理后磷酸化ERK1/2水平升高，siRNA或MPEP处理后降低。总之，我们的研究结果表明，mGluR5通过激活细胞外信号调节激酶（ERKs）促使大鼠NPCs分化为胆碱能神经元，提示mGluR5可能在阿尔茨海默病等退行性疾病的机制及治疗中发挥重要作用。
