title: Metabotropic glutamate receptor 5 responses dictate differentiation of neural progenitors to NMDA-responsive cells in fragile X syndrome.
abstract: 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.
authors.affiliation: Faculty of Medicine, Physiology, University of Helsinki, P.O. Box 63, Helsinki, FIN, 00014, Finland.
authors.forename: Venkat Swaroop
authors.initials: VS
authors.lastname: Achuta
authors.affiliation: Faculty of Medicine, Physiology, University of Helsinki, P.O. Box 63, Helsinki, FIN, 00014, Finland.
authors.forename: Heli
authors.initials: H
authors.lastname: Grym
authors.affiliation: Faculty of Medicine, Physiology, University of Helsinki, P.O. Box 63, Helsinki, FIN, 00014, Finland.
authors.forename: Noora
authors.initials: N
authors.lastname: Putkonen
authors.affiliation: Faculty of Medicine, Physiology, University of Helsinki, P.O. Box 63, Helsinki, FIN, 00014, Finland.
authors.forename: Verna
authors.initials: V
authors.lastname: Louhivuori
authors.affiliation: A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, FI-70211, Finland.
authors.forename: Virve
authors.initials: V
authors.lastname: Kärkkäinen
authors.affiliation: A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, FI-70211, Finland.
authors.forename: Jari
authors.initials: J
authors.lastname: Koistinaho
authors.affiliation: Stem Cell Laboratory for CNS Disease Modeling, Department of Experimental Medical Science, Lund University, BMC A10, Sölvegatan 19, Lund, SE-221 84, Sweden.
authors.forename: Laurent
authors.initials: L
authors.lastname: Roybon
authors.affiliation: Faculty of Medicine, Physiology, University of Helsinki, P.O. Box 63, Helsinki, FIN, 00014, Finland.|Autism Foundation, Kuortaneenkatu 7B, Helsinki, FI-00520, Finland.
authors.forename: Maija L
authors.initials: ML
authors.lastname: Castrén
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002540:Cerebral Cortex / Q000196:embryology* / Q000378:metabolism*; D004195:Disease Models, Animal; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D005600:Fragile X Syndrome / Q000378:metabolism*; D006801:Humans; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016202:N-Methylaspartate / Q000378:metabolism*; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*
chemical_list: D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C578936:Grm5 protein, mouse; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D008734:Methoxyhydroxyphenylglycol; D016202:N-Methylaspartate; C121465:6-methyl-2-(phenylethynyl)pyridine; C010117:3,4-dihydroxyphenylglycol
keywords: 2-methyl-6-(phenylethynyl)-pyridine; fragile X syndrome; glutamatergic neurons; induced pluripotent stem cells; metabotropic glutamate receptor 5