Achuta Venkat Swaroop, Grym Heli, Putkonen Noora, Louhivuori Verna, Kärkkäinen Virve, Koistinaho Jari, Roybon Laurent, Castrén Maija L
Faculty of Medicine, Physiology, University of Helsinki, P.O. Box 63, Helsinki, FIN, 00014, Finland.
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, FI-70211, Finland.
Dev Neurobiol. 2017 Apr;77(4):438-453. doi: 10.1002/dneu.22419. Epub 2016 Jul 28.
Disrupted metabotropic glutamate receptor 5 (mGluR5) signaling is implicated in many neuropsychiatric disorders, including autism spectrum disorder, found in fragile X syndrome (FXS). Here we report that intracellular calcium responses to the group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG) are augmented, and calcium-dependent mGluR5-mediated mechanisms alter the differentiation of neural progenitors in neurospheres derived from human induced pluripotent FXS stem cells and the brains of mouse model of FXS. Treatment with the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) prevents an abnormal clustering of DHPG-responsive cells that are responsive to activation of ionotropic receptors in mouse FXS neurospheres. MPEP also corrects morphological defects of differentiated cells and enhanced migration of neuron-like cells in mouse FXS neurospheres. Unlike in mouse neurospheres, MPEP increases the differentiation of DHPG-responsive radial glial cells as well as the subpopulation of cells responsive to both DHPG and activation of ionotropic receptors in human neurospheres. However, MPEP normalizes the FXS-specific increase in the differentiation of cells responsive only to N-methyl-d-aspartate (NMDA) present in human neurospheres. Exposure to MPEP prevents the accumulation of intermediate basal progenitors in embryonic FXS mouse brain suggesting that rescue effects of GluR5 antagonist are progenitor type-dependent and species-specific differences of basal progenitors may modify effects of MPEP on the cortical development. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 419-437, 2017.
代谢型谷氨酸受体5（mGluR5）信号通路紊乱与许多神经精神疾病有关，包括脆性X综合征（FXS）中的自闭症谱系障碍。在此我们报告，对I组mGluR激动剂（S）-3,5-二羟基苯甘氨酸（DHPG）的细胞内钙反应增强，且钙依赖性mGluR5介导的机制改变了源自人诱导多能FXS干细胞和FXS小鼠模型大脑的神经球中神经祖细胞的分化。用mGluR5拮抗剂2-甲基-6-（苯乙炔基）吡啶（MPEP）处理可防止DHPG反应性细胞在小鼠FXS神经球中异常聚集，这些细胞对离子型受体激活有反应。MPEP还可纠正小鼠FXS神经球中分化细胞的形态缺陷，并增强神经元样细胞的迁移。与小鼠神经球不同，MPEP可增加人神经球中DHPG反应性放射状胶质细胞的分化以及对DHPG和离子型受体激活均有反应的细胞亚群。然而，MPEP可使仅对人神经球中存在的N-甲基-D-天冬氨酸（NMDA）有反应的细胞分化中FXS特异性增加恢复正常。暴露于MPEP可防止胚胎期FXS小鼠大脑中中间基底祖细胞的积累，这表明GluR5拮抗剂的挽救作用取决于祖细胞类型，且基底祖细胞的物种特异性差异可能会改变MPEP对皮质发育的影响。©2016威利期刊公司。《发育神经生物学》77:419 - 437，2017年。
