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Nature. 2015 Nov 5;527(7576):95-9. doi: 10.1038/nature15526. Epub 2015 Oct 28.

Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder.

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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.
The Salk Institute for Biological Studies, Laboratory of Genetics, La Jolla, California 92037, USA.
The Salk Institute for Biological Studies, Stem Cell Core, La Jolla, California 92037, USA.
Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
Department of Psychiatry, Indiana University, Indianapolis, Indiana 46202, USA.
Department of Psychiatry, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Department of Psychiatry, University of Bergen, Bergen 5020, Norway.
Department of Psychiatry, VA San Diego Healthcare System, La Jolla, California 92151, USA.
Department of Psychiatry, University of California San Diego, La Jolla, California, 92093, USA.
Department of Psychiatry, Johns Hopkins University, Baltimore, Maryland 21218, USA.
Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, B3H2E2, Canada.
Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029, USA.
Jiangsu Collaborative Innovation Center for Language Ability, Jiangsu Normal University, Xuzhou 221009, China.


Bipolar disorder is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression; without treatment, 15% of patients commit suicide. Hence, it has been ranked by the World Health Organization as a top disorder of morbidity and lost productivity. Previous neuropathological studies have revealed a series of alterations in the brains of patients with bipolar disorder or animal models, such as reduced glial cell number in the prefrontal cortex of patients, upregulated activities of the protein kinase A and C pathways and changes in neurotransmission. 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 Ca(2+) 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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