Human iPSC Glial Mouse Chimeras Reveal Glial Contributions to Schizophrenia

Publication date: Available online 20 July 2017
Source:Cell Stem Cell
Author(s): Martha S. Windrem, Mikhail Osipovitch, Zhengshan Liu, Janna Bates, Devin Chandler-Militello, Lisa Zou, Jared Munir, Steven Schanz, Katherine McCoy, Robert H. Miller, Su Wang, Maiken Nedergaard, Robert L. Findling, Paul J. Tesar, Steven A. Goldman
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.

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Teaser

Goldman and colleagues use mice chimerized with human patient-derived glial progenitor cells to find out whether glia contribute to childhood-onset schizophrenia. The defects in cell differentiation, myelination, and behavior they see strongly suggest that glial cells do, in fact, have a previously unappreciated role in the pathogenesis of this disease.


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