Cited by 562Bipolar Disorder and TreatmentPluripotent Stem Cells ResearchNeuroscience and Neuropharmacology Research

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

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The Pharmacogenomics of Bipolar Disorder Study, Mertens, Jerome, Wang, Qiu-Wen, Kim, Yongsung, Yu, Diana X., Pham, Son, Yang, Bo, Zheng, Yi, Diffenderfer, Kenneth E., Zhang, Jian, Soltani, Sheila, Eames, Tameji, Schafer, Simon T., Boyer, Leah, Marchetto, Maria C., Nurnberger, John I., Calabrese, Joseph R., Oedegaard, Ketil J., McCarthy, Michael J., Zandi, Peter P., Alda, Martin, Nievergelt, Caroline M., Mi, Shuangli, Brennand, Kristen J., Kelsoe, John R., Gage, Fred H., Yao, Jun·2015·Nature

DOI 10.1038/nature15526PMC PMC4742055

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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.

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Authors: Study, T. P. O. B. D., Mertens, J., Wang, Q.-W., Kim, Y., Yu, D. X., Pham, S., Yang, B., Zheng, Y., Diffenderfer, K. E., Zhang, J., Soltani, S., Eames, T., Schafer, S. T., Boyer, L., Marchetto, M. C., Nurnberger, J. I., Calabrese, J. R., Oedegaard, K. J., McCarthy, M. J., Zandi, P. P., Alda, M., Nievergelt, C. M., Mi, S., Brennand, K. J., Kelsoe, J. R., Gage, F. H., & Yao, J.
Affiliations: Center for Life Sciences (CN)
Salk Institute for Biological Studies (US)
Chinese Academy of Sciences (CN)
Case Western Reserve University (US)
Haukeland University Hospital (NO)
University of California San Diego (US)
Johns Hopkins University (US)
Dalhousie University (CA)
Icahn School of Medicine at Mount Sinai (US)
Jiangsu Normal University (CN)
Corresponding author: Kelsoe, John R.
Gage, Fred H.
Yao, Jun
ORCID: Yu, Diana X.
Pham, Son
Yang, Bo
Zheng, Yi
Zhang, Jian
Schafer, Simon T.
Boyer, Leah
Marchetto, Maria C.
Calabrese, Joseph R.
McCarthy, Michael J.
Zandi, Peter P.
Alda, Martin
Nievergelt, Caroline M.
Mi, Shuangli
Brennand, Kristen J.
Kelsoe, John R.
Gage, Fred H.
Yao, Jun
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2015-10-28
Volume: 527
Issue: 7576
Pages: 95-99
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature15526
PMC: PMC4742055
OpenAlex: W2139372806
Cited by: 562
References: 30
Citations by year: 2026: 20 · 2025: 50 · 2024: 45 · 2023: 37 · 2022: 54 · 2021: 60 · 2020: 58 · 2019: 68 · 2018: 50 · 2017: 54 · 2016: 58 · 2015: 5
FWCI: 45.23
Type: journal article
Language: en
Update notices: erratum (2015-11-25)
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
eScholarship (California Digital Library) (submittedVersion)
IUScholarWorks (Indiana University) (submittedVersion)
Purdue University Indianapolis (Indiana University) (submittedVersion)
PMC
Funders: U.S. Department of Veterans Affairs (I01CX000363)
National Institute of Mental Health (R01MH106056, U01 MH92758, R01MH101454, MH106056, U01MH092758)
Topics: Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: bipolar disorder, lithium response, lithium resistance, neuronal hyperexcitability, iPSC-derived neurons, mitochondrial abnormalities, action potential firing, endophenotypes, iPSC disease models, mood stabilizers, calcium imaging, patch-clamp electrophysiology, drug response prediction, personalized medicine, mania
MeSH terms: Action Potentials, Bipolar Disorder, Humans, Male, Mitochondria, Neurons, Antipsychotic Agents, Lithium Compounds, Patch-Clamp Techniques, Dentate Gyrus, Calcium Signaling, Induced Pluripotent Stem Cells, Endophenotypes

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

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