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

• Published in: Nature (London) Vol. 527; no. 7576; pp. 95 - 99
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.11.2015; Nature Publishing Group
• Subjects: 631/378/1689; 631/532/2064/2158; Action Potentials - drug effects; Antipsychotic Agents - pharmacology; Bipolar disorder; Bipolar Disorder - pathology; Calcium Signaling - drug effects; Dentate Gyrus - drug effects; Dentate Gyrus - pathology; Dosage and administration; Drug therapy; Endophenotypes; Fibroblasts; Gene expression; Genotype & phenotype; Health aspects; Humanities and Social Sciences; Humans; Hyperactivity; Induced Pluripotent Stem Cells - pathology; Kinases; letter; Lithium; Lithium Compounds - pharmacology; Male; Mitochondria; Mitochondria - pathology; multidisciplinary; Neural networks; Neurons; Neurons - drug effects; Neurons - pathology; Patch-Clamp Techniques; Patient outcomes; Patients; Science; Studies
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature15526

A neuronal model of bipolar disorder based on induced pluripotent stem cell (iPSC) technology finds hyperactive action-potential firing and differential responsiveness to lithium in iPSC-derived neurons from patients with bipolar disorder. Efficacy of lithium in bipolar disorder Lithium is widely used as a mood stabilizer in bipolar disorder, but not all patients respond favourably. In this paper, Fred Gage and colleagues generated hippocampal dentate gyrus-like neurons from induced pluripotent stem cells (iPSCs) obtained from lithium-responsive and lithium-non-responsive patients with bipolar disorder in order to assess differences in cellular phenotypes. They found mitochondrial abnormalities and hyperexcitability in young iPSC-derived neurons from bipolar disorder patients. Hyperexcitability was reversed by lithium treatment only in neurons derived from lithium-responsive individuals. This suggests that hyperexcitability may be an early endophenotype of bipolar disorder and that iPSC models may be useful for the development of new therapies. Bipolar disorder is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression; without treatment, 15% of patients commit suicide 1 . Hence, it has been ranked by the World Health Organization as a top disorder of morbidity and lost productivity 2 . Previous neuropathological studies have revealed a series of alterations in the brains of patients with bipolar disorder or animal models 3 , such as reduced glial cell number in the prefrontal cortex of patients 4 , upregulated activities of the protein kinase A and C pathways 5 , 6 , 7 and changes in neurotransmission 8 , 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 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.