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Functional changes of AMPA responses in human induced pluripotent stem cell-derived neural progenitors in fragile X syndrome.
Achuta, Venkat Swaroop; Möykkynen, Tommi; Peteri, Ulla-Kaisa; Turconi, Giorgio; Rivera, Claudio; Keinänen, Kari; Castrén, Maija L.
Afiliación
  • Achuta VS; Department of Physiology, Faculty of Medicine, University of Helsinki, P.O. Box 63, FIN-00014 Helsinki, Finland.
  • Möykkynen T; Division of Biochemistry and Biotechnology, Department of Biosciences, University of Helsinki, P.O. Box 56, FIN-00014, Helsinki, Finland.
  • Peteri UK; Department of Physiology, Faculty of Medicine, University of Helsinki, P.O. Box 63, FIN-00014 Helsinki, Finland.
  • Turconi G; Department of Physiology, Faculty of Medicine, University of Helsinki, P.O. Box 63, FIN-00014 Helsinki, Finland.
  • Rivera C; Neuroscience Center, University of Helsinki, P.O. Box 56, FIN-00014 Helsinki, Finland.
  • Keinänen K; Institut de Neurobiologie de la Méditerranée, INSERM, Unité 901, 13009 Marseille, France.
  • Castrén ML; Aix-Marseille Université, Unité Mixte de Recherche 901, 13273 Marseille, France.
Sci Signal ; 11(513)2018 01 16.
Article en En | MEDLINE | ID: mdl-29339535
Altered neuronal network formation and function involving dysregulated excitatory and inhibitory circuits are associated with fragile X syndrome (FXS). We examined functional maturation of the excitatory transmission system in FXS by investigating the response of FXS patient-derived neural progenitor cells to the glutamate analog (AMPA). Neural progenitors derived from induced pluripotent stem cell (iPSC) lines generated from boys with FXS had augmented intracellular Ca2+ responses to AMPA and kainate that were mediated by Ca2+-permeable AMPA receptors (CP-AMPARs) lacking the GluA2 subunit. Together with the enhanced differentiation of glutamate-responsive cells, the proportion of CP-AMPAR and N-methyl-d-aspartate (NMDA) receptor-coexpressing cells was increased in human FXS progenitors. Differentiation of cells lacking GluA2 was also increased and paralleled the increased inward rectification in neural progenitors derived from Fmr1-knockout mice (the FXS mouse model). Human FXS progenitors had increased the expression of the precursor and mature forms of miR-181a, a microRNA that represses translation of the transcript encoding GluA2. Blocking GluA2-lacking, CP-AMPARs reduced the neurite length of human iPSC-derived control progenitors and further reduced the shortened length of neurites in human FXS progenitors, supporting the contribution of CP-AMPARs to the regulation of progenitor differentiation. Furthermore, we observed reduced expression of Gria2 (the GluA2-encoding gene) in the frontal lobe of FXS mice, consistent with functional changes of AMPARs in FXS. Increased Ca2+ influx through CP-AMPARs may increase the vulnerability and affect the differentiation and migration of distinct cell populations, which may interfere with normal circuit formation in FXS.
Asunto(s)

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Receptores AMPA / Células Madre Pluripotentes Inducidas / Síndrome del Cromosoma X Frágil / Neuronas Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: Sci Signal Asunto de la revista: CIENCIA / FISIOLOGIA Año: 2018 Tipo del documento: Article País de afiliación: Finlandia

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Receptores AMPA / Células Madre Pluripotentes Inducidas / Síndrome del Cromosoma X Frágil / Neuronas Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: Sci Signal Asunto de la revista: CIENCIA / FISIOLOGIA Año: 2018 Tipo del documento: Article País de afiliación: Finlandia