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.
Subscribe to Journal
Get full journal access for 1 year
only $33.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Angst J . The emerging epidemiology of hypomania and bipolar II disorder. J Affect Disord 1998; 50: 143–151.
Hirschfeld RM, Calabrese JR, Weissman MM, Reed M, Davies MA, Frye MA et al. Screening for bipolar disorder in the community. J Clin Psychiatry 2003; 64: 53–59.
Merikangas KR, Akiskal HS, Angst J, Greenberg PE, Hirschfeld RM, Petukhova M et al. Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. Arch Gen Psychiatry 2007; 64: 543–552.
Belmaker RH . Bipolar disorder. N Engl J Med 2004; 351: 476–486.
Judd LL, Akiskal HS, Schettler PJ, Endicott J, Maser J, Solomon DA et al. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry 2002; 59: 530–537.
Vandeleur CL, Merikangas KR, Strippoli MP, Castelao E, Preisig M . Specificity of psychosis, mania and major depression in a contemporary family study. Mol Psychiatry 2014; 19: 209–213.
Baethge C, Baldessarini RJ, Freudenthal K, Streeruwitz A, Bauer M, Bschor T . Hallucinations in bipolar disorder: characteristics and comparison to unipolar depression and schizophrenia. Bipolar Disord 2005; 7: 136–145.
Harris EC, Barraclough B . Suicide as an outcome for mental disorders. A meta-analysis. Br J Psychiatry 1997; 170: 205–228.
Tondo L, Isacsson G, Baldessarini R . Suicidal behaviour in bipolar disorder: risk and prevention. CNS Drugs 2003; 17: 491–511.
Geddes JR, Burgess S, Hawton K, Jamison K, Goodwin GM . Long-term lithium therapy for bipolar disorder: systematic review and meta-analysis of randomized controlled trials. Am J Psychiatry 2004; 161: 217–222.
Burgess S, Geddes J, Hawton K, Townsend E, Jamison K, Goodwin G . Lithium for maintenance treatment of mood disorders. Cochrane Database Syst Rev 2001; (3): CD003013.
Klein PS, Melton DA . A molecular mechanism for the effect of lithium on development. Proc Natl Acad Sci USA 1996; 93: 8455–8459.
Jope RS . Anti-bipolar therapy: mechanism of action of lithium. Mol Psychiatry 1999; 4: 117–128.
Chiu CT, Wang Z, Hunsberger JG, Chuang DM . Therapeutic potential of mood stabilizers lithium and valproic acid: beyond bipolar disorder. Pharmacol Rev 2013; 65: 105–142.
Machado-Vieira R, Manji HK, Zarate CA Jr . The role of lithium in the treatment of bipolar disorder: convergent evidence for neurotrophic effects as a unifying hypothesis. Bipolar Disord 2009; 11 (Suppl. 2): 92–109.
Breen MS, White CH, Shekhtman T, Lin K, Looney D, Woelk CH et al. Lithium-responsive genes and gene networks in bipolar disorder patient-derived lymphoblastoid cell lines. Pharmacogenom J 2016; 16: 446–453.
Viguera AC, Tondo L, Baldessarini RJ . Sex differences in response to lithium treatment. Am J Psychiatry 2000; 157: 1509–1511.
Tohen M, Greil W, Calabrese JR, Sachs GS, Yatham LN, Oerlinghausen BM et al. Olanzapine versus lithium in the maintenance treatment of bipolar disorder: a 12-month, randomized, double-blind, controlled clinical trial. Am J Psychiatry 2005; 162: 1281–1290.
Smoller JW, Finn CT . Family, twin, and adoption studies of bipolar disorder. Am J Med Genet C 2003; 123C: 48–58.
McGuffin P, Rijsdijk F, Andrew M, Sham P, Katz R, Cardno A . The heritability of bipolar affective disorder and the genetic relationship to unipolar depression. Arch Gen Psychiatry 2003; 60: 497–502.
Kieseppa T, Partonen T, Haukka J, Kaprio J, Lonnqvist J . High concordance of bipolar I disorder in a nationwide sample of twins. Am J Psychiatry 2004; 161: 1814–1821.
International Schizophrenia C, Purcell SM, Wray NR, Stone JL, Visscher PM, O'Donovan MC et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 2009; 460: 748–752.
Craddock N, Sklar P . Genetics of bipolar disorder. Lancet 2013; 381: 1654–1662.
Psychiatric GCBDWG. Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat Genet 2011; 43: 977–983.
Ferreira MA, O'Donovan MC, Meng YA, Jones IR, Ruderfer DM, Jones L et al. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet 2008; 40: 1056–1058.
Carter CJ . Multiple genes and factors associated with bipolar disorder converge on growth factor and stress activated kinase pathways controlling translation initiation: implications for oligodendrocyte viability. Neurochem Int 2007; 50: 461–490.
Ogden CA, Rich ME, Schork NJ, Paulus MP, Geyer MA, Lohr JB et al. Candidate genes, pathways and mechanisms for bipolar (manic-depressive) and related disorders: an expanded convergent functional genomics approach. Mol Psychiatry 2004; 9: 1007–1029.
Nestler EJ, Hyman SE . Animal models of neuropsychiatric disorders. Nat Neurosci 2010; 13: 1161–1169.
Einat H, Manji HK . Cellular plasticity cascades: genes-to-behavior pathways in animal models of bipolar disorder. Biol Psychiatry 2006; 59: 1160–1171.
Rajkowska G, Halaris A, Selemon LD . Reductions in neuronal and glial density characterize the dorsolateral prefrontal cortex in bipolar disorder. Biol Psychiatry 2001; 49: 741–752.
Bertolino A, Frye M, Callicott JH, Mattay VS, Rakow R, Shelton-Repella J et al. Neuronal pathology in the hippocampal area of patients with bipolar disorder: a study with proton magnetic resonance spectroscopic imaging. Biol Psychiatry 2003; 53: 906–913.
Bouras C, Kovari E, Hof PR, Riederer BM, Giannakopoulos P . Anterior cingulate cortex pathology in schizophrenia and bipolar disorder. Acta Neuropathol 2001; 102: 373–379.
Rajkowska G . Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells. Biol Psychiatry 2000; 48: 766–777.
Cotter D, Mackay D, Landau S, Kerwin R, Everall I . Reduced glial cell density and neuronal size in the anterior cingulate cortex in major depressive disorder. Arch Gen Psychiatry 2001; 58: 545–553.
Askland K, Read C, Moore J . Pathways-based analyses of whole-genome association study data in bipolar disorder reveal genes mediating ion channel activity and synaptic neurotransmission. Hum Genet 2009; 125: 63–79.
Mahmood T, Silverstone T . Serotonin and bipolar disorder. J Affect Disord 2001; 66: 1–11.
Scarr E, Pavey G, Sundram S, MacKinnon A, Dean B . Decreased hippocampal NMDA, but not kainate or AMPA receptors in bipolar disorder. Bipolar Disord 2003; 5: 257–264.
Benes FM, Berretta S . GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology 2001; 25: 1–27.
Guidotti A, Auta J, Davis JM, Di-Giorgi-Gerevini V, Dwivedi Y, Grayson DR et al. Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study. Arch Gen Psychiatry 2000; 57: 1061–1069.
Fattal O, Link J, Quinn K, Cohen BH, Franco K . Psychiatric comorbidity in 36 adults with mitochondrial cytopathies. CNS Spectrums 2007; 12: 429–438.
Marazziti D, Baroni S, Picchetti M, Landi P, Silvestri S, Vatteroni E et al. Psychiatric disorders and mitochondrial dysfunctions. Eur Rev Med Pharmacol Sci 2012; 16: 270–275.
Mertens J, Wang QW, Kim Y, Yu DX, Pham S, Yang B et al. Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. Nature 2015; 527: 95–99.
Harrison PJ, Cader MZ, Geddes JR . Reprogramming psychiatry: stem cells and bipolar disorder. Lancet 2016; 387: 823–825.
Choi SM, Liu H, Chaudhari P, Kim Y, Cheng L, Feng J et al. Reprogramming of EBV-immortalized B-lymphocyte cell lines into induced pluripotent stem cells. Blood 2011; 118: 1801–1805.
Rajesh D, Dickerson SJ, Yu J, Brown ME, Thomson JA, Seay NJ . Human lymphoblastoid B-cell lines reprogrammed to EBV-free induced pluripotent stem cells. Blood 2011; 118: 1797–1800.
Mamdani F, Alda M, Grof P, Young LT, Rouleau G, Turecki G . Lithium response and genetic variation in the CREB family of genes. Am J Med Genet B 2008; 147B: 500–504.
Spitzer RL, Endicott J, Robins E . Research diagnostic criteria: rationale and reliability. Arch Gen Psychiatry 1978; 35: 773–782.
Endicott J, Spitzer RL . A diagnostic interview: the schedule for affective disorders and schizophrenia. Arch Gen Psychiatry 1978; 35: 837–844.
Lopez de Lara C, Jaitovich-Groisman I, Cruceanu C, Mamdani F, Lebel V, Yerko V et al. Implication of synapse-related genes in bipolar disorder by linkage and gene expression analyses. Int J Neuropsychopharmacol 2010; 13: 1397–1410.
Manchia M, Adli M, Akula N, Ardau R, Aubry JM, Backlund L et al. Assessment of response to lithium maintenance treatment in bipolar disorder: a Consortium On Lithium Genetics (ConLiGen) Report. PLoS One 2013; 8: e65636.
Garnham J, Munro A, Slaney C, Macdougall M, Passmore M, Duffy A et al. Prophylactic treatment response in bipolar disorder: results of a naturalistic observation study. J affect Disord 2007; 104: 185–190.
Grof P, Cavazzoni P, Grof E, Garnham J, MacDougall M, O'Donovan C, Alda M . Is response to prophylactic lithium a familial trait? J Clin Psychiatry 2002; 63: 942–947.
Okita K, Matsumura Y, Sato Y, Okada A, Morizane A, Okamoto S et al. A more efficient method to generate integration-free human iPS cells. Nat Methods 2011; 8: 409–412.
Rudy B . Diversity and ubiquity of K channels. Neuroscience 1988; 25: 729–749.
Yu DX, Di Giorgio FP, Yao J, Marchetto MC, Brennand K, Wright R et al. Modeling hippocampal neurogenesis using human pluripotent stem cells. Stem Cell Rep 2014; 2: 295–310.
Stern S, Segal M, Moses E . Involvement of potassium and cation channels in hippocampal abnormalities of embryonic Ts65Dn and Tc1 trisomic mice. EBioMedicine 2015; 2: 1048–1062.
Jan LY, Jan YN . Voltage-gated and inwardly rectifying potassium channels. J Physiol 1997; 505 (Part 2): 267–282.
Erisir A, Lau D, Rudy B, Leonard CS . Function of specific K(+) channels in sustained high-frequency firing of fast-spiking neocortical interneurons. J Neurophysiol 1999; 82: 2476–2489.
Connors BW, Gutnick MJ . Intrinsic firing patterns of diverse neocortical neurons. Trends Neurosci 1990; 13: 99–104.
Martina M, Schultz JH, Ehmke H, Monyer H, Jonas P . Functional and molecular differences between voltage-gated K+ channels of fast-spiking interneurons and pyramidal neurons of rat hippocampus. J Neurosci 1998; 18: 8111–8125.
Rudy B, Chow A, Lau D, Amarillo Y, Ozaita A, Saganich M et al. Contributions of Kv3 channels to neuronal excitability. Ann NY Acad Sci 1999; 868: 304–343.
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.
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on the Molecular Psychiatry website
About this article
Cite this 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
Scientific Reports (2021)
Posttranslational modifications & lithium’s therapeutic effect—Potential biomarkers for clinical responses in psychiatric & neurodegenerative disorders
Neuroscience & Biobehavioral Reviews (2021)
Differential acute impact of therapeutically effective and overdose concentrations of lithium on human neuronal single cell and network function
Translational Psychiatry (2021)
Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients
Molecular Psychiatry (2021)
Molecular Psychiatry (2021)