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

Jerome Mertens, Qiu Wen Wang, Yongsung Kim, Diana X. Yu, Son Pham, Bo Yang, Yi Zheng, Kenneth E. Diffenderfer, Jian Zhang, Sheila Soltani, Tameji Eames, Simon T. Schafer, Leah Boyer, Maria C. Marchetto, John Nurnberger, Joseph R. Calabrese, Ketil J. Ødegaard, Michael J. McCarthy, Peter P. Zandi, Martin Alba & 6 others Caroline M. Nievergelt, Shuangli Mi, Kristen J. Brennand, John R. Kelsoe, Fred H. Gage, Jun Yao

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)95-99
Number of pages5
JournalNature
Volume527
Issue number7576
DOIs
StatePublished - Nov 5 2015

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Bipolar Disorder
Lithium
Neurons
Induced Pluripotent Stem Cells
Therapeutics
Endophenotypes
RNA Sequence Analysis
Phenotype
Biological Models
Parahippocampal Gyrus
Dentate Gyrus
Cyclic AMP-Dependent Protein Kinases
Prefrontal Cortex
Synaptic Transmission
Neuroglia
Causality
Suicide
Protein Kinase C
Action Potentials
Animal Models

ASJC Scopus subject areas

  • General

Cite this

Mertens, J., Wang, Q. W., Kim, Y., Yu, D. X., Pham, S., Yang, B., ... Yao, J. (2015). Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. Nature, 527(7576), 95-99. https://doi.org/10.1038/nature15526

Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. / 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; Calabrese, Joseph R.; Ødegaard, Ketil J.; McCarthy, Michael J.; Zandi, Peter P.; Alba, Martin; Nievergelt, Caroline M.; Mi, Shuangli; Brennand, Kristen J.; Kelsoe, John R.; Gage, Fred H.; Yao, Jun.

In: Nature, Vol. 527, No. 7576, 05.11.2015, p. 95-99.

Research output: Contribution to journalArticle

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, J, Calabrese, JR, Ødegaard, KJ, McCarthy, MJ, Zandi, PP, Alba, M, Nievergelt, CM, Mi, S, Brennand, KJ, Kelsoe, JR, Gage, FH & Yao, J 2015, 'Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder', Nature, vol. 527, no. 7576, pp. 95-99. https://doi.org/10.1038/nature15526
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 ; Calabrese, Joseph R. ; Ødegaard, Ketil J. ; McCarthy, Michael J. ; Zandi, Peter P. ; Alba, Martin ; Nievergelt, Caroline M. ; Mi, Shuangli ; Brennand, Kristen J. ; Kelsoe, John R. ; Gage, Fred H. ; Yao, Jun. / Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. In: Nature. 2015 ; Vol. 527, No. 7576. pp. 95-99.
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AU - Diffenderfer, Kenneth E.

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