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Patient-Derived In Vitro Models of Microglial Function and Synaptic Engulfment in Schizophrenia

  • Steven D. Sheridan
    Affiliations
    Center for Genomic Medicine and Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts

    Department of Psychiatry, Harvard Medical School, Boston, Massachusetts
    Search for articles by this author
  • Joy E. Horng
    Affiliations
    Center for Genomic Medicine and Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts

    Department of Psychiatry, Harvard Medical School, Boston, Massachusetts
    Search for articles by this author
  • Roy H. Perlis
    Correspondence
    Address correspondence to Roy H. Perlis, M.D.
    Affiliations
    Center for Genomic Medicine and Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts

    Department of Psychiatry, Harvard Medical School, Boston, Massachusetts
    Search for articles by this author

      Abstract

      Multiple lines of evidence implicate dysregulated microglia-mediated synaptic pruning in the pathophysiology of schizophrenia. In vitro human cellular studies represent a promising means of pursuing this hypothesis, complementing efforts with animal models and postmortem human data while addressing their limitations. The challenges in culturing homogeneous populations of cells derived from postmortem or surgical biopsy brain material from patients, and their limited availability, has led to a focus on differentiation of induced pluripotent stem cells. These methods too have limitations, in that they disrupt the epigenome and can demonstrate line-to-line variability due in part to extended time in culture, partial reprogramming, and/or residual epigenetic memory from the cell source, yielding large technical artifacts. Yet another strategy uses direct transdifferentiation of peripheral mononuclear blood cells, or umbilical cord blood cells, to microglia-like cells. Any of these approaches can be paired with patient-derived synaptosomes from differentiated neurons as a simpler alternative to co-culture. Patient-derived microglia models may facilitate identification of novel modulators of synaptic pruning and identification of biomarkers that may allow more targeted early interventions.

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