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Neurons derived from patients with bipolar disorder divide into intrinsically different sub-populations of neurons, predicting the patients’ responsiveness to lithium

Abstract

Bipolar disorder (BD) is a progressive psychiatric disorder with more than 3% prevalence worldwide. Affected individuals experience recurrent episodes of depression and mania, disrupting normal life and increasing the risk of suicide greatly. The complexity and genetic heterogeneity of psychiatric disorders have challenged the development of animal and cellular models. We recently reported that hippocampal dentate gyrus (DG) neurons differentiated from induced pluripotent stem cell (iPSC)-derived fibroblasts of BD patients are electrophysiologically hyperexcitable. Here we used iPSCs derived from Epstein–Barr virus-immortalized B-lymphocytes to verify that the hyperexcitability of DG-like neurons is reproduced in this different cohort of patients and cells. Lymphocytes are readily available for research with a large number of banked lines with associated patient clinical description. We used whole-cell patch-clamp recordings of over 460 neurons to characterize neurons derived from control individuals and BD patients. Extensive functional analysis showed that intrinsic cell parameters are very different between the two groups of BD neurons, those derived from lithium (Li)-responsive (LR) patients and those derived from Li-non-responsive (NR) patients, which led us to partition our BD neurons into two sub-populations of cells and suggested two different subdisorders. Training a Naïve Bayes classifier with the electrophysiological features of patients whose responses to Li are known allows for accurate classification with more than 92% success rate for a new patient whose response to Li is unknown. Despite their very different functional profiles, both populations of neurons share a large, fast after-hyperpolarization (AHP). We therefore suggest that the large, fast AHP is a key feature of BD and a main contributor to the fast, sustained spiking abilities of BD neurons. Confirming our previous report with fibroblast-derived DG neurons, chronic Li treatment reduced the hyperexcitability in the lymphoblast-derived LR group but not in the NR group, strengthening the validity and utility of this new human cellular model of BD.

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Acknowledgements

We thank Mary Lynn Gage for help with editing the article, Elisha Moses and Menahem Segal for very helpful discussions and L Moore, E Mejia and B Miller for technical assistance. SBP thanks Haowen Zhou for technical assistance, Drs Michael Jackson, Ian Pass, Guang Chen, Evan Snyder, Andrew Crane and Brian Tobe for discussion of line selection, and Drs Dongmei Wu and Yang Liu at the SBP Stem Cell Core. SBP acknowledges support from the Viterbi Family Foundation of the Jewish Community Foundation San Diego. For the production of the iPSCs, SBP would like to acknowledge financial support from Janssen Pharmaceuticals. The production of neural progenitor cells and electrophysiological measurements were also supported by Janssen Pharmaceuticals. The collection of clinical data and lymphoblasts was supported by the Grant No. 64410 from the Canadian Institutes of Health Research (CIHR) (to MA). This work was also supported by the Paul G Allen Family Foundation, Bob and Mary Jane Engman, The Leona M and Harry B Helmsley Charitable Trust Grant No. 2012-PG-MED002, Annette C Merle-Smith, R01 MH095741 (to FHG), U19MH106434 (to FHG) and by The G Harold and Leila Y Mathers Foundation.

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Correspondence to F H Gage.

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Stern, S., Santos, R., Marchetto, M. et al. Neurons derived from patients with bipolar disorder divide into intrinsically different sub-populations of neurons, predicting the patients’ responsiveness to lithium. Mol Psychiatry 23, 1453–1465 (2018). https://doi.org/10.1038/mp.2016.260

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