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PMID: 26524527 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Nature ·Vol. 527 ·No. 7576 ·2015-11-05 ·Pages 95-9

Mertens J, Wang QW, Kim Y, Yu DX, Pham S, Yang B, Zheng Y, Diffenderfer KE, Zhang J, Soltani S, Eames T, Schafer ST, Boyer L, Marchetto MC, Nurnberger JI, Calabrese JR, Ødegaard KJ, McCarthy MJ, Zandi PP, Alda M, Alba M, Nievergelt CM, Pharmacogenomics of Bipolar Disorder Study, Mi S, Brennand KJ, Kelsoe JR, Gage FH, Yao J

Abstract

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.

MeSH Terms
Action Potentials/drug effects Antipsychotic Agents/pharmacology Bipolar Disorder/pathology Calcium Signaling/drug effects Dentate Gyrus/drug effects,pathology Endophenotypes Humans Induced Pluripotent Stem Cells/pathology Lithium Compounds/pharmacology Male Mitochondria/pathology Neurons/drug effects,pathology Patch-Clamp Techniques
Chemicals
Antipsychotic Agents Lithium Compounds
Authors & Affiliations
28 authors, click to expand affiliations / ORCID
Mertens Jerome
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.
Wang Qiu-Wen
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.
Kim Yongsung
The Salk Institute for Biological Studies, Laboratory of Genetics, La Jolla, California 92037, USA.
Yu Diana X
The Salk Institute for Biological Studies, Laboratory of Genetics, La Jolla, California 92037, USA.
Pham Son
The Salk Institute for Biological Studies, Laboratory of Genetics, La Jolla, California 92037, USA.
Yang Bo
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.
Zheng Yi
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.
Diffenderfer Kenneth E
The Salk Institute for Biological Studies, Stem Cell Core, La Jolla, California 92037, USA.
Zhang Jian
Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
Soltani Sheila
The Salk Institute for Biological Studies, Laboratory of Genetics, La Jolla, California 92037, USA.
Eames Tameji
The Salk Institute for Biological Studies, Laboratory of Genetics, La Jolla, California 92037, USA.
Schafer Simon T
The Salk Institute for Biological Studies, Laboratory of Genetics, La Jolla, California 92037, USA.
Boyer Leah
The Salk Institute for Biological Studies, Laboratory of Genetics, La Jolla, California 92037, USA.
Marchetto Maria C
The Salk Institute for Biological Studies, Laboratory of Genetics, La Jolla, California 92037, USA.
Nurnberger John I
Department of Psychiatry, Indiana University, Indianapolis, Indiana 46202, USA.
Calabrese Joseph R
Department of Psychiatry, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Ødegaard Ketil J
Department of Psychiatry, University of Bergen, Bergen 5020, Norway.
McCarthy Michael J
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.
Zandi Peter P
Department of Psychiatry, Johns Hopkins University, Baltimore, Maryland 21218, USA.
Alda Martin
Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, B3H2E2, Canada.
Alba Martin
Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, B3H2E2, Canada.
Nievergelt Caroline M
Department of Psychiatry, University of California San Diego, La Jolla, California, 92093, USA.
Pharmacogenomics of Bipolar Disorder Study
Mi Shuangli
Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
Brennand Kristen J
Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029, USA.
Kelsoe John R
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.
Gage Fred H
The Salk Institute for Biological Studies, Laboratory of Genetics, La Jolla, California 92037, USA.
Yao Jun
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. | Jiangsu Collaborative Innovation Center for Language Ability, Jiangsu Normal University, Xuzhou 221009, China.
Investigators
17 investigators, click to expand
Kelsoe John R
Nievergelt Caroline M
Shilling Paul D
McCarthy Michael J
Buehning Laura
Nurnberger John I
Gershon Elliot S
Coryell William H
Berretini Wade H
Zandi Peter P
Calabrese Joseph R
McInnis Melvin G
Ødegaard Ketil J
Alda Martin
Frye Mark A
Gage Fred H
Craig David W
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Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/nature15526
Published
2015-11-05
Epub
2015-00-28
Pages
95-9
Language
English
Region
England
NLM ID
0410462
PMCID
PMC4742055
Subset
IM
Grants
CSRD VA · I01 CX000363 · United States
NIMH NIH HHS · U01 MH92758 · United States
NIMH NIH HHS · R01 MH106056 · United States
NIMH NIH HHS · MH106056 · United States
NIMH NIH HHS · R01 MH101454 · United States
NIMH NIH HHS · U01 MH092758 · United States
Corrections
CommentIn
-
CommentIn
PMID: 26585797
ErratumIn
PMID: 26605530
CommentIn
PMID: 26972063
External Links
PubMed source DOI: 10.1038/nature15526 PMC Full Text View journal details
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