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. Access through your institution Buy or subscribe This

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ACUTE IMPACT OF THERAPEUTICALLY EFFECTIVE AND OVERDOSE CONCENTRATIONS OF LITHIUM ON HUMAN NEURONAL SINGLE CELL AND NETWORK FUNCTION Article Open access 12 May 2021 DEFICIENT _LEF1_

EXPRESSION IS ASSOCIATED WITH LITHIUM RESISTANCE AND HYPEREXCITABILITY IN NEURONS DERIVED FROM BIPOLAR DISORDER PATIENTS Article 04 January 2021 LITHIUM TREATMENT AND HUMAN HIPPOCAMPAL

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Scholar  Download references 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. AUTHOR INFORMATION Author notes * S Stern and R Santos: These authors contributed

equally to this work. AUTHORS AND AFFILIATIONS * Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA S Stern, R Santos, M C Marchetto, A P D Mendes & F

H Gage * Ecole Normale Supérieure, PSL Research University, CNRS, Inserm, Institut de Biologie de l’Ecole Normale Supérieure (IBENS), Paris, France R Santos & P Charnay * Department of

Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada G A Rouleau * Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical

Discovery Institute, La Jolla, CA, USA S Biesmans & A G Bang * State Key Laboratory of Membrane Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences,

IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing, China Q-W Wang & J Yao * Department of Psychiatry, Dalhousie University, Halifax, NS, Canada M Alda Authors * S

Stern View author publications You can also search for this author inPubMed Google Scholar * R Santos View author publications You can also search for this author inPubMed Google Scholar * M

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ARTICLE 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 Download citation * Received: 12 September 2016 * Revised: 04 November 2016 *

Accepted: 06 December 2016 * Published: 28 February 2017 * Issue Date: June 2018 * DOI: https://doi.org/10.1038/mp.2016.260 SHARE THIS ARTICLE Anyone you share the following link with will

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