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

TitleDifferential responses to lithium in hyperexcitable neurons from patients with bipolar disorder.
Publication TypeJournal Article
Year of Publication2015
AuthorsMertens J, Wang Q-W, 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, degaard KJØ, McCarthy MJ, Zandi PP, Alda M, Alba M, Nievergelt CM, Mi S, Brennand KJ, Kelsoe JR, Gage FH, Yao J
Corporate AuthorsPharmacogenomics of Bipolar Disorder Study
Date Published2015 Nov 5
KeywordsAction Potentials, Antipsychotic Agents, Bipolar Disorder, Calcium Signaling, Dentate Gyrus, Endophenotypes, Humans, Induced Pluripotent Stem Cells, Lithium Compounds, Male, Mitochondria, Neurons, Patch-Clamp Techniques

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.

Alternate JournalNature
PubMed ID26524527
PubMed Central IDPMC4742055
Grant ListMH106056 / MH / NIMH NIH HHS / United States
R01 MH101454 / MH / NIMH NIH HHS / United States
R01 MH106056 / MH / NIMH NIH HHS / United States
U01 MH092758 / MH / NIMH NIH HHS / United States
U01 MH92758 / MH / NIMH NIH HHS / United States
Gage Laboratory