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eNeuro. 2019 Oct 17;6(5). pii: ENEURO.0403-18.2019. doi: 10.1523/ENEURO.0403-18.2019. Print 2019 Sep/Oct.

In Vitro Modeling of the Bipolar Disorder and Schizophrenia Using Patient-Derived Induced Pluripotent Stem Cells with Copy Number Variations of PCDH15 and RELN.

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Department of Physiology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
iPS Cell-Based Drug Discovery, Drug Research Division, Sumitomo Dainippon Pharma. Co., Ltd, Osaka, Osaka 554-0022, Japan.
Department of Psychiatry, Nagoya University Graduate School of Medicine, Aichi, Nagoya 466-8550, Japan.
Institute for Advanced Research, Nagoya University, Aichi, Nagoya 466-8550, Japan.
Medical Genomics Center, Nagoya University Hospital, Aichi, Nagoya 466-8550, Japan.
Department of Systems Medicine, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
Department of Neuropsychiatry, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan.
Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University School of Medicine, Stanford, California 94305.
Department of Neuroscience, Friedman Brian Institute, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York 10029.
Department of Physiology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan


Bipolar disorder (BP) and schizophrenia (SCZ) are major psychiatric disorders, but the molecular mechanisms underlying the complicated pathologies of these disorders remain unclear. It is difficult to establish adequate in vitro models for pathological analysis because of the heterogeneity of these disorders. In the present study, to recapitulate the pathologies of these disorders in vitro, we established in vitro models by differentiating mature neurons from human induced pluripotent stem cells (hiPSCs) derived from BP and SCZ patient with contributive copy number variations, as follows: two BP patients with PCDH15 deletion and one SCZ patient with RELN deletion. Glutamatergic neurons and GABAergic neurons were induced from hiPSCs under optimized conditions. Both types of induced neurons from both hiPSCs exhibited similar phenotypes of MAP2 (microtubule-associated protein 2)-positive dendrite shortening and decreasing synapse numbers. Additionally, we analyzed isogenic PCDH15- or RELN-deleted cells. The dendrite and synapse phenotypes of isogenic neurons were partially similar to those of patient-derived neurons. These results suggest that the observed phenotypes are general phenotypes of psychiatric disorders, and our in vitro models using hiPSC-based technology may be suitable for analysis of the pathologies of psychiatric disorders.


GABAergic neurons; bipolar disorder; copy number variations; glutamatergic neurons; induced pluripotent stem cells; schizophrenia

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