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Characterization of bipolar disorder patient-specific induced pluripotent stem cells from a family reveals neurodevelopmental and mRNA expression abnormalities

Molecular Psychiatry volume 20, pages 703–717 (2015)Cite this article

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Abstract

Bipolar disorder (BD) is a common neuropsychiatric disorder characterized by chronic recurrent episodes of depression and mania. Despite evidence for high heritability of BD, little is known about its underlying pathophysiology. To develop new tools for investigating the molecular and cellular basis of BD, we applied a family-based paradigm to derive and characterize a set of 12 induced pluripotent stem cell (iPSC) lines from a quartet consisting of two BD-affected brothers and their two unaffected parents. Initially, no significant phenotypic differences were observed between iPSCs derived from the different family members. However, upon directed neural differentiation, we observed that CXCR4 (CXC chemokine receptor-4) expressing central nervous system (CNS) neural progenitor cells (NPCs) from both BD patients compared with their unaffected parents exhibited multiple phenotypic differences at the level of neurogenesis and expression of genes critical for neuroplasticity, including WNT pathway components and ion channel subunits. Treatment of the CXCR4+ NPCs with a pharmacological inhibitor of glycogen synthase kinase 3, a known regulator of WNT signaling, was found to rescue a progenitor proliferation deficit in the BD patient NPCs. Taken together, these studies provide new cellular tools for dissecting the pathophysiology of BD and evidence for dysregulation of key pathways involved in neurodevelopment and neuroplasticity. Future generation of additional iPSCs following a family-based paradigm for modeling complex neuropsychiatric disorders in conjunction with in-depth phenotyping holds promise for providing insights into the pathophysiological substrates of BD and is likely to inform the development of targeted therapeutics for its treatment and ideally prevention.

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Acknowledgements

This work was supported through funding from the National Institute of Mental Health (R21MH093958, R33MH087896) and the Stanley Medical Research Institute. We thank members of the MGH CHGR iModels Group for helpful feedback and comments along with other members of the Perlis and Haggarty Laboratories, and Drs Casey Gifford and Alexander Meissner for carrying out the NanoString Scorecard Assays. We also thank members of the Genomics Platform for their assistance with genomic analysis. Dr Eliot Gershon is thanked for providing details on the BD family fibroblast sample collection.

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Author notes

  1. F H Lau

    Present address: 11Current address: Department of Surgery, Louisiana State University Health Sciences Center, New Orleans, LA, USA.,

  2. J M Madison and F Zhou: These authors contributed equally to this work.

Authors and Affiliations

  1. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    J M Madison, F Zhou, A Nigam, A Hussain, D D Barker, R Nehme, J Hsu, P Wolf, M Fleishman, C O'Dushlaine, S Rose, K Chambert, E H Rueckert, D M Fass, J Nemesh, T E Mullen, S McCarroll, R H Perlis & S J Haggarty

  2. Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA, USA

    J M Madison, F Zhou, A Hussain, K van der Ven, J Hsu, P Wolf, M Fleishman, E H Rueckert, R H Perlis & S J Haggarty

  3. Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA

    J M Madison, A Nigam, R H Perlis & S J Haggarty

  4. Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA

    R Nehme, F H Lau, T Ahfeldt & L Daheron

  5. Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    P Wolf, D M Fass & S J Haggarty

  6. Chemical Neurobiology Laboratory, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA

    E H Rueckert, S D Sheridan, D M Fass, R H Perlis & S J Haggarty

  7. Department of Genetics, Harvard Medical School, Boston, MA, USA

    J Nemesh, T E Mullen & S McCarroll

  8. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    P Sklar

  9. Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    P Sklar

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  1. J M Madison
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Correspondence to J M Madison or S J Haggarty.

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Madison, J., Zhou, F., Nigam, A. et al. Characterization of bipolar disorder patient-specific induced pluripotent stem cells from a family reveals neurodevelopmental and mRNA expression abnormalities. Mol Psychiatry 20, 703–717 (2015). https://doi.org/10.1038/mp.2015.7

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