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Human iPSC Glial Mouse Chimeras Reveal Glial Contributions to Schizophrenia.

Cell stem cell | Aug 3, 2017

In this study, we investigated whether intrinsic glial dysfunction contributes to the pathogenesis of schizophrenia (SCZ). Our approach was to establish humanized glial chimeric mice using glial progenitor cells (GPCs) produced from induced pluripotent stem cells derived from patients with childhood-onset SCZ. After neonatal implantation into myelin-deficient shiverer mice, SCZ GPCs showed premature migration into the cortex, leading to reduced white matter expansion and hypomyelination relative to controls. The SCZ glial chimeras also showed delayed astrocytic differentiation and abnormal astrocytic morphologies. When established in myelin wild-type hosts, SCZ glial mice showed reduced prepulse inhibition and abnormal behavior, including excessive anxiety, antisocial traits, and disturbed sleep. RNA-seq of cultured SCZ human glial progenitor cells (hGPCs) revealed disrupted glial differentiation-associated and synaptic gene expression, indicating that glial pathology was cell autonomous. Our data therefore suggest a causal role for impaired glial maturation in the development of schizophrenia and provide a humanized model for its in vivo assessment.

Pubmed ID: 28736215 RIS Download

Mesh terms: Animals | Astrocytes | Behavior | Cell Differentiation | Chimera | Gene Expression Regulation | Humans | Induced Pluripotent Stem Cells | Mice | Myelin Sheath | Neuroglia | Phenotype | Schizophrenia

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Associated grants

  • Agency: NIA NIH HHS, Id: R01 AG048769
  • Agency: NINDS NIH HHS, Id: R01 NS078304
  • Agency: NIMH NIH HHS, Id: R01 MH104701
  • Agency: NINDS NIH HHS, Id: R01 NS075345
  • Agency: NIMH NIH HHS, Id: R01 MH099578
  • Agency: NINDS NIH HHS, Id: R01 NS100366

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dbGaP at NCBI

Database to archive and distribute the results of studies that have investigated the interaction of genotype and phenotype, including genome-wide association studies, medical sequencing, molecular diagnostic assays, and association between genotype and non-clinical traits. dbGaP provides two types of access for users, open and controlled. Summaries of studies and the contents of measured variables as well as original study document text are generally available to the public, while access to individual-level data including phenotypic data tables and genotypes require varying levels of authorization. The data in dbGaP will be pre-competitive, and will not be protected by intellectual property patents. Investigators who agree to the terms of dbGaP data use may not restrict other investigators' use of primary dbGaP data by filing intellectual property patents on it. However, the use of primary data from dbGaP to develop commercial products and tests to meet public health needs is encouraged. Submitters who are not Federally-funded and affiliated with an NIH IC will need to work with an NIH DAC so that proposed submission can be reviewed for consistency with appropriate policies to protect the privacy of research participants and confidentiality of their data. Submissions to dbGaP will not be accepted without assurance that the submitting institution approves the submission and has verified that the data submission is consistent with all applicable laws and regulations, as well as institutional policies. Submitters must also identify any limits on research uses of the data that are specifically set by individual research participants, e.g., through their informed consent. Open-access data can be browsed online or downloaded from dbGaP without prior permission or authorization.

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