• An Erratum to this article was published on 25 November 2015

Abstract

Bipolar disorder is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression; without treatment, 15% of patients commit suicide1. Hence, it has been ranked by the World Health Organization as a top disorder of morbidity and lost productivity2. Previous neuropathological studies have revealed a series of alterations in the brains of patients with bipolar disorder or animal models3, such as reduced glial cell number in the prefrontal cortex of patients4, upregulated activities of the protein kinase A and C pathways5,6,7 and changes in neurotransmission8,9,10,11. However, the roles and causation of these changes in bipolar disorder have been too complex to exactly determine the pathology of the disease. Furthermore, although some patients show remarkable improvement with lithium treatment for yet unknown reasons, others are refractory to lithium treatment. Therefore, developing an accurate and powerful biological model for bipolar disorder has been a challenge. The introduction of induced pluripotent stem-cell (iPSC) technology has provided a new approach. Here we have developed an iPSC model for human bipolar disorder and investigated the cellular phenotypes of hippocampal dentate gyrus-like neurons derived from iPSCs of patients with bipolar disorder. Guided by RNA sequencing expression profiling, we have detected mitochondrial abnormalities in young neurons from patients with bipolar disorder by using mitochondrial assays; in addition, using both patch-clamp recording and somatic Ca2+ imaging, we have observed hyperactive action-potential firing. This hyperexcitability phenotype of young neurons in bipolar disorder was selectively reversed by lithium treatment only in neurons derived from patients who also responded to lithium treatment. Therefore, hyperexcitability is one early endophenotype of bipolar disorder, and our model of iPSCs in this disease might be useful in developing new therapies and drugs aimed at its clinical treatment.

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Acknowledgements

We thank the patients who participated in this study. We thank M. Ku for help in the RNA-seq analysis, and L. McHenry, D. Lisuk and C. Bardy for help with the somatic Ca2+ imaging experiments. We thank L. Moore, E. Mejia, B. Miller, R. Wright, T. Berggren and S. Lu for technical assistance. We also thank C. O’Connor for help on flow cytometry. This work was supported by the National Natural Science Foundation of China (grant numbers 31471020, 31161120358, 31123004), the National Basic Research Program of China (2015CB910603, 2011CB510106), the Open Project of Key Laboratory of Genomic and Precision Medicine, Chinese Academy of Sciences, by the Engmann Foundation, the JPB Foundation, the Helmsley Trust, the Mather’s Foundation, the Glenn Foundation for Aging Research, by National Institute of Health grant MH106056 (K.J.B.), New York Stem Cell Foundation – Robertson Award (K.J.B.), and by grants/contracts to J.R.K. from the National Institute of Mental Health (U01 MH92758) supporting the Pharmacogenomics of Bipolar Disorder Study and from the Department of Veterans Affairs (5I01CX000363). K.J.B. is a New York Stem Cell Foundation - Robertson Investigator. J.Y. is an Investigator of the Young Thousand Talents Program of China.

Author information

Author notes

    • Jerome Mertens
    •  & Qiu-Wen Wang

    These authors contributed equally to this work.

Affiliations

  1. State Key Laboratory of Membrane Biology, Tsinghua-Peking Joint Center for Life Sciences, McGovern Institute for Brain Research, School of Life Sciences, Tsinghua University, Beijing 100084, China

    • Jerome Mertens
    • , Qiu-Wen Wang
    • , Bo Yang
    • , Yi Zheng
    •  & Jun Yao
  2. The Salk Institute for Biological Studies, Laboratory of Genetics, La Jolla, California 92037, USA

    • Jerome Mertens
    • , Yongsung Kim
    • , Diana X. Yu
    • , Son Pham
    • , Sheila Soltani
    • , Tameji Eames
    • , Simon T. Schafer
    • , Leah Boyer
    • , Maria C. Marchetto
    • , Fred H. Gage
    •  & Jun Yao
  3. The Salk Institute for Biological Studies, Stem Cell Core, La Jolla, California 92037, USA

    • Kenneth E. Diffenderfer
  4. Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China

    • Jian Zhang
    •  & Shuangli Mi
  5. Department of Psychiatry, Indiana University, Indianapolis, Indiana 46202, USA

    • John I. Nurnberger
  6. Department of Psychiatry, Case Western Reserve University, Cleveland, Ohio 44106, USA

    • Joseph R. Calabrese
  7. Department of Psychiatry, Haukeland University Hospital and Department of Clinical Medicine, Section for Psychiatry, University of Bergen and K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, 5021 Bergen, Norway

    • Ketil J. Oedegaard
  8. Department of Psychiatry, VA San Diego Healthcare System, La Jolla, California 92151, USA

    • Michael J. McCarthy
    •  & John R. Kelsoe
  9. Department of Psychiatry, University of California San Diego, La Jolla, California, 92093, USA

    • Michael J. McCarthy
    • , Caroline M. Nievergelt
    •  & John R. Kelsoe
  10. Department of Psychiatry, Johns Hopkins University, Baltimore, Maryland 21218, USA

    • Peter P. Zandi
  11. Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, B3H2E2, Canada

    • Martin Alda
  12. Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029, USA

    • Kristen J. Brennand
  13. Jiangsu Collaborative Innovation Center for Language Ability, Jiangsu Normal University, Xuzhou 221009, China

    • Jun Yao

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  1. The Pharmacogenomics of Bipolar Disorder Study

    Lists of participants and their affiliations appear in the Supplementary Information.

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Contributions

J.M., Q.W.W., K.E.D., L.B., K.J.B., T.J.E. and J.Y. conducted the iPSC reprogramming and differentiation experiments. Q.W.W., B.Y. and J.Y. conducted the electrophysiological recording experiments. J.M., Q.W.W., Y.Z., S.S. and J.Y. conducted immunostaining experiments. D.X.Y., J.M., Q.W.W., B.Y. S.T.S. and J.Y. conducted Ca2+ imaging experiments. Y.K., Q.W.W. and J.Y. performed mitochondrial assays. J.M., S.P., B.Y., J.Z., Y.Z., S.M. and J.Y. conducted RNA-seq and qRT-PCR analysis. J.R.K., J.I.N., J.R.C., K.J.O., M.J.M., P.P.Z., M.A., C.M.N. and the Pharmacogenomics of Bipolar Disorder Study designed and conducted the clinical trial and provided samples from patients. J.Y. designed the experiments with F.H.G. and wrote the manuscript with J.M. and Q.W.W.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to John R. Kelsoe or Fred H. Gage or Jun Yao.

Extended data

Supplementary information

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    Supplementary Information

    This file contains Supplementary Tables 1-7 and full RT-PCR gels for Extended Data Figure 1.

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https://doi.org/10.1038/nature15526

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