Bipolar disorder is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression; without treatment, approximately 15% of patients commit suicide. It has been ranked by the World Health Organization as a top disorder of morbidity and lost productivity. Although some patients show improvement with lithium treatment for reasons which are still unclear, others are refractory to lithium treatment. Therefore, developing an accurate and powerful biological model for bipolar disorder has been a challenge. In this study Mertens and colleagues developed an induced pluripotent stem-cell (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, they 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, they 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. The authors suggest that hyperexcitability is one early endophenotype of bipolar disorder, and the model of iPSCs in this disease might be useful in developing new therapies and drugs for clinical treatment.
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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, Alba M, Nievergelt CM, Pharmacogenomics of Bipolar Disorder Study, Mi S, Brennand KJ, Kelsoe JR, Gage FH and Yao J: Defferential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. Nature 527(7576): 95-99 (2015).
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http://www.ncbi.nlm.nih.gov/pubmed/26524527