Skip to main content
SpringerLink
Log in

Using Induced Pluripotent Stem Cells to Investigate Complex Genetic Psychiatric Disorders

  • Genetics and Neuroscience (B Maher, Section Editor)
  • Published:
Current Behavioral Neuroscience Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Induced pluripotent stem cells (iPSCs) can be generated from human patient tissue samples, differentiated into any somatic cell type, and studied under controlled culture conditions. We review how iPSCs are used to investigate genetic factors and biological mechanisms underlying psychiatric disorders, and considerations for synthesizing data across studies.

Recent Findings

Results from patient specific-iPSC studies often reveal cellular phenotypes consistent with postmortem and brain imaging studies. Unpredicted findings illustrate the power of iPSCs as a discovery tool, but may also be attributable to limitations in modeling dynamic neural networks or difficulty in identifying the most affected neural subtype or developmental stage.

Summary

Technological advances in differentiation protocols and organoid generation will enhance our ability to model the salient pathology underlying psychiatric disorders using iPSCs. The field will also benefit from context-driven interpretations of iPSC studies that recognize all potential sources of variability, including differences in patient symptomatology, genetic risk factors, and affected cellular subtype.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999;23(2):185–8. doi:10.1038/13810.

    Article  CAS  PubMed  Google Scholar 

  2. Kirov G. CNVs in neuropsychiatric disorders. Hum Mol Genet. 2015;24(R1):R45–9. doi:10.1093/hmg/ddv253.

    Article  CAS  PubMed  Google Scholar 

  3. Geschwind DH, State MW. Gene hunting in autism spectrum disorder: on the path to precision medicine. Lancet Neurol. 2015;14(11):1109–20. doi:10.1016/S1474-4422(15)00044-7.

    Article  PubMed  PubMed Central  Google Scholar 

  4. 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(7256):748–52. doi:10.1038/nature08185.

    Google Scholar 

  5. Cheng R, Juo SH, Loth JE, Nee J, Iossifov I, Blumenthal R, et al. Genome-wide linkage scan in a large bipolar disorder sample from the National Institute of Mental Health genetics initiative suggests putative loci for bipolar disorder, psychosis, suicide, and panic disorder. Mol Psychiatry. 2006;11(3):252–60. doi:10.1038/sj.mp.4001778.

    Article  CAS  PubMed  Google Scholar 

  6. Tansey KE, Rees E, Linden DE, Ripke S, Chambert KD, Moran JL, et al. Common alleles contribute to schizophrenia in CNV carriers. Mol Psychiatry. 2016;21(8):1153. doi:10.1038/mp.2015.170.

    Article  CAS  PubMed  Google Scholar 

  7. Nestler EJ, Hyman SE. Animal models of neuropsychiatric disorders. Nat Neurosci. 2010;13(10):1161–9. doi:10.1038/nn.2647.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–72. doi:10.1016/j.cell.2007.11.019.

    Article  CAS  PubMed  Google Scholar 

  9. Chambers SM, Fasano CA, Papapetrou EP, Tomishima M, Sadelain M, Studer L. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol. 2009;27(3):275–80. doi:10.1038/nbt.1529.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Brennand K, Savas JN, Kim Y, Tran N, Simone A, Hashimoto-Torii K, et al. Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia. Mol Psychiatry. 2015;20(3):361–8. doi:10.1038/mp.2014.22.

    Article  CAS  PubMed  Google Scholar 

  11. Qian X, Nguyen HN, Song MM, Hadiono C, Ogden SC, Hammack C, et al. Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure. Cell. 2016;165(5):1238–54. doi:10.1016/j.cell.2016.04.032.

    Article  CAS  PubMed  Google Scholar 

  12. Zeng H, Guo M, Martins-Taylor K, Wang X, Zhang Z, Park JW, et al. Specification of region-specific neurons including forebrain glutamatergic neurons from human induced pluripotent stem cells. PLoS One. 2010;5(7):e11853. doi:10.1371/journal.pone.0011853.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Liu Y, Liu H, Sauvey C, Yao L, Zarnowska ED, Zhang SC. Directed differentiation of forebrain GABA interneurons from human pluripotent stem cells. Nat Protoc. 2013;8(9):1670–9. doi:10.1038/nprot.2013.106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Boyer LF, Campbell B, Larkin S, Mu Y, Gage FH. Dopaminergic differentiation of human pluripotent cells. Curr Protoc Stem Cell Biol. 2012; Chapter 1:Unit1H 6. doi:10.1002/9780470151808.sc01h06s22.

    PubMed  Google Scholar 

  15. Williams EC, Zhong X, Mohamed A, Li R, Liu Y, Dong Q, et al. Mutant astrocytes differentiated from Rett syndrome patients-specific iPSCs have adverse effects on wild-type neurons. Hum Mol Genet. 2014;23(11):2968–80. doi:10.1093/hmg/ddu008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 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(7576):95–9. doi:10.1038/nature15526.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Akbarian S, Kim JJ, Potkin SG, Hagman JO, Tafazzoli A, Bunney Jr WE, et al. Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics. Arch Gen Psychiatry. 1995;52(4):258–66.

    Article  CAS  PubMed  Google Scholar 

  18. Egbujo CN, Sinclair D, Hahn CG. Dysregulations of synaptic vesicle trafficking in schizophrenia. Curr Psychiatry Rep. 2016;18(8):77. doi:10.1007/s11920-016-0710-5.

    Article  PubMed  Google Scholar 

  19. Volk DW, Sampson AR, Zhang Y, Edelson JR, Lewis DA. Cortical GABA markers identify a molecular subtype of psychotic and bipolar disorders. Psychol Med. 2016;46(12):2501–12. doi:10.1017/S0033291716001446.

    Article  CAS  PubMed  Google Scholar 

  20. Murai K, Sun G, Ye P, Tian E, Yang S, Cui Q, et al. The TLX-miR-219 cascade regulates neural stem cell proliferation in neurodevelopment and schizophrenia iPSC model. Nat Commun. 2016;7:10965. doi:10.1038/ncomms10965.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wen Z, Nguyen HN, Guo Z, Lalli MA, Wang X, Su Y, et al. Synaptic dysregulation in a human iPS cell model of mental disorders. Nature. 2014;515(7527):414–8. doi:10.1038/nature13716.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ananiev G, Williams EC, Li H, Chang Q. Isogenic pairs of wild type and mutant induced pluripotent stem cell (iPSC) lines from Rett syndrome patients as in vitro disease model. PLoS One. 2011;6(9):e25255. doi:10.1371/journal.pone.0025255.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Cheung AY, Horvath LM, Grafodatskaya D, Pasceri P, Weksberg R, Hotta A, et al. Isolation of MECP2-null Rett syndrome patient hiPS cells and isogenic controls through X-chromosome inactivation. Hum Mol Genet. 2011;20(11):2103–15. doi:10.1093/hmg/ddr093.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Larimore J, Ryder PV, Kim KY, Ambrose LA, Chapleau C, Calfa G, et al. MeCP2 regulates the synaptic expression of a Dysbindin-BLOC-1 network component in mouse brain and human induced pluripotent stem cell-derived neurons. PLoS One. 2013;8(6):e65069. doi:10.1371/journal.pone.0065069.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Marchetto MC, Carromeu C, Acab A, Yu D, Yeo GW, Mu Y, et al. A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell. 2010;143(4):527–39. doi:10.1016/j.cell.2010.10.016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Belinsky GS, Rich MT, Sirois CL, Short SM, Pedrosa E, Lachman HM, et al. Patch-clamp recordings and calcium imaging followed by single-cell PCR reveal the developmental profile of 13 genes in iPSC-derived human neurons. Stem Cell Res. 2014;12(1):101–18. doi:10.1016/j.scr.2013.09.014.

    Article  CAS  PubMed  Google Scholar 

  27. Bundo M, Toyoshima M, Okada Y, Akamatsu W, Ueda J, Nemoto-Miyauchi T, et al. Increased l1 retrotransposition in the neuronal genome in schizophrenia. Neuron. 2014;81(2):306–13. doi:10.1016/j.neuron.2013.10.053.

    Article  CAS  PubMed  Google Scholar 

  28. Pedrosa E, Sandler V, Shah A, Carroll R, Chang C, Rockowitz S, et al. Development of patient-specific neurons in schizophrenia using induced pluripotent stem cells. J Neurogenet. 2011;25(3):88–103. doi:10.3109/01677063.2011.597908.

    Article  CAS  PubMed  Google Scholar 

  29. Doers ME, Musser MT, Nichol R, Berndt ER, Baker M, Gomez TM, et al. iPSC-derived forebrain neurons from FXS individuals show defects in initial neurite outgrowth. Stem Cells Dev. 2014;23(15):1777–87. doi:10.1089/scd.2014.0030.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Liu J, Koscielska KA, Cao Z, Hulsizer S, Grace N, Mitchell G, et al. Signaling defects in iPSC-derived fragile X premutation neurons. Hum Mol Genet. 2012;21(17):3795–805. doi:10.1093/hmg/dds207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sheridan SD, Theriault KM, Reis SA, Zhou F, Madison JM, Daheron L, et al. Epigenetic characterization of the FMR1 gene and aberrant neurodevelopment in human induced pluripotent stem cell models of fragile X syndrome. PLoS One. 2011;6(10):e26203. doi:10.1371/journal.pone.0026203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Das DK, Tapias V, D'Aiuto L, Chowdari KV, Francis L, Zhi Y, et al. Genetic and morphological features of human iPSC-derived neurons with chromosome 15q11.2 (BP1-BP2) deletions. Mol Neuropsychiatry. 2015;1(2):116–23. doi:10.1159/000430916.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Germain ND, Chen PF, Plocik AM, Glatt-Deeley H, Brown J, Fink JJ, et al. Gene expression analysis of human induced pluripotent stem cell-derived neurons carrying copy number variants of chromosome 15q11-q13.1. Mol Autism. 2014;5:44. doi:10.1186/2040-2392-5-44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Yoon KJ, Nguyen HN, Ursini G, Zhang F, Kim NS, Wen Z, et al. Modeling a genetic risk for schizophrenia in iPSCs and mice reveals neural stem cell deficits associated with adherens junctions and polarity. Cell Stem Cell. 2014;15(1):79–91. doi:10.1016/j.stem.2014.05.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Griesi-Oliveira K, Acab A, Gupta AR, Sunaga DY, Chailangkarn T, Nicol X, et al. Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons. Mol Psychiatry. 2015;20(11):1350–65. doi:10.1038/mp.2014.141.

    Article  CAS  PubMed  Google Scholar 

  36. Krey JF, Pasca SP, Shcheglovitov A, Yazawa M, Schwemberger R, Rasmusson R, et al. Timothy syndrome is associated with activity-dependent dendritic retraction in rodent and human neurons. Nat Neurosci. 2013;16(2):201–9. doi:10.1038/nn.3307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Pasca SP, Portmann T, Voineagu I, Yazawa M, Shcheglovitov A, Pasca AM, et al. Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nat Med. 2011;17(12):1657–62. doi:10.1038/nm.2576.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Roussos P, Mitchell AC, Voloudakis G, Fullard JF, Pothula VM, Tsang J, et al. A role for noncoding variation in schizophrenia. Cell Rep. 2014;9(4):1417–29. doi:10.1016/j.celrep.2014.10.015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Tian Y, Voineagu I, Pasca SP, Won H, Chandran V, Horvath S, et al. Alteration in basal and depolarization induced transcriptional network in iPSC derived neurons from Timothy syndrome. Genome Med. 2014;6(10):75. doi:10.1186/s13073-014-0075-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Shcheglovitov A, Shcheglovitova O, Yazawa M, Portmann T, Shu R, Sebastiano V, et al. SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients. Nature. 2013;503(7475):267–71. doi:10.1038/nature12618.

    CAS  PubMed  Google Scholar 

  41. Wang P, Lin M, Pedrosa E, Hrabovsky A, Zhang Z, Guo W, et al. CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in neurodevelopment. Mol Autism. 2015;6:55. doi:10.1186/s13229-015-0048-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lee IS, Carvalho CM, Douvaras P, Ho SM, Hartley BJ, Zuccherato LW, et al. Characterization of molecular and cellular phenotypes associated with a heterozygous CNTNAP2 deletion using patient-derived hiPSC neural cells. NPJ Schizophr. 2015;1.

  43. Hu BY, Weick JP, Yu J, Ma LX, Zhang XQ, Thomson JA, et al. Neural differentiation of human induced pluripotent stem cells follows developmental principles but with variable potency. Proc Natl Acad Sci U S A. 2010;107(9):4335–40. doi:10.1073/pnas.0910012107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Jones JR, Zhang SC. Engineering human cells and tissues through pluripotent stem cells. Curr Opin Biotechnol. 2016;40:133–8. doi:10.1016/j.copbio.2016.03.010.

    Article  CAS  PubMed  Google Scholar 

  45. Poulin JF, Tasic B, Hjerling-Leffler J, Trimarchi JM, Awatramani R. Disentangling neural cell diversity using single-cell transcriptomics. Nat Neurosci. 2016;19(9):1131–41. doi:10.1038/nn.4366.

    Article  CAS  PubMed  Google Scholar 

  46. Garey LJ, Ong WY, Patel TS, Kanani M, Davis A, Mortimer AM, et al. Reduced dendritic spine density on cerebral cortical pyramidal neurons in schizophrenia. J Neurol Neurosurg Psychiatry. 1998;65(4):446–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Hutsler JJ, Zhang H. Increased dendritic spine densities on cortical projection neurons in autism spectrum disorders. Brain Res. 2010;1309:83–94. doi:10.1016/j.brainres.2009.09.120.

    Article  CAS  PubMed  Google Scholar 

  48. Herbert MR, Ziegler DA, Makris N, Filipek PA, Kemper TL, Normandin JJ, et al. Localization of white matter volume increase in autism and developmental language disorder. Ann Neurol. 2004;55(4):530–40. doi:10.1002/ana.20032.

    Article  PubMed  Google Scholar 

  49. Shenton ME, Dickey CC, Frumin M, McCarley RW. A review of MRI findings in schizophrenia. Schizophr Res. 2001;49(1–2):1–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Cocchi E, Drago A, Serretti A. Hippocampal pruning as a new theory of schizophrenia Etiopathogenesis. Mol Neurobiol. 2016;53(3):2065–81. doi:10.1007/s12035-015-9174-6.

    Article  CAS  PubMed  Google Scholar 

  51. Pocklington AJ, O'Donovan M, Owen MJ. The synapse in schizophrenia. Eur J Neurosci. 2014;39(7):1059–67. doi:10.1111/ejn.12489.

    Article  PubMed  Google Scholar 

  52. Gai X, Xie HM, Perin JC, Takahashi N, Murphy K, Wenocur AS, et al. Rare structural variation of synapse and neurotransmission genes in autism. Mol Psychiatry. 2012;17(4):402–11. doi:10.1038/mp.2011.10.

    Article  CAS  PubMed  Google Scholar 

  53. Millar JK, Wilson-Annan JC, Anderson S, Christie S, Taylor MS, Semple CA, et al. Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet. 2000;9(9):1415–23.

    Article  CAS  PubMed  Google Scholar 

  54. Sachs NA, Sawa A, Holmes SE, Ross CA, DeLisi LE, Margolis RL. A frameshift mutation in disrupted in schizophrenia 1 in an American family with schizophrenia and schizoaffective disorder. Mol Psychiatry. 2005;10(8):758–64. doi:10.1038/sj.mp.4001667.

    Article  CAS  PubMed  Google Scholar 

  55. Brandon NJ, Millar JK, Korth C, Sive H, Singh KK, Sawa A. Understanding the role of DISC1 in psychiatric disease and during normal development. J Neurosci. 2009;29(41):12768–75. doi:10.1523/JNEUROSCI.3355-09.2009.

    Article  CAS  PubMed  Google Scholar 

  56. Maher BJ, LoTurco JJ. Disrupted-in-schizophrenia (DISC1) functions presynaptically at glutamatergic synapses. PLoS One. 2012;7(3):e34053. doi:10.1371/journal.pone.0034053.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ming GL, Song H. Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron. 2011;70(4):687–702. doi:10.1016/j.neuron.2011.05.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Chiang CH, Su Y, Wen Z, Yoritomo N, Ross CA, Margolis RL, et al. Integration-free induced pluripotent stem cells derived from schizophrenia patients with a DISC1 mutation. Mol Psychiatry. 2011;16(4):358–60. doi:10.1038/mp.2011.13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Barbosa AC, Kim MS, Ertunc M, Adachi M, Nelson ED, McAnally J, et al. MEF2C, a transcription factor that facilitates learning and memory by negative regulation of synapse numbers and function. Proc Natl Acad Sci U S A. 2008;105(27):9391–6. doi:10.1073/pnas.0802679105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Brennand KJ, Simone A, Jou J, Gelboin-Burkhart C, Tran N, Sangar S, et al. Modelling schizophrenia using human induced pluripotent stem cells. Nature. 2011;473(7346):221–5. doi:10.1038/nature09915.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Topol A, Zhu S, Tran N, Simone A, Fang G, Brennand KJ. Altered WNT signaling in human induced pluripotent stem cell neural progenitor cells derived from four schizophrenia patients. Biol Psychiatry. 2015;78(6):e29–34. doi:10.1016/j.biopsych.2014.12.028.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Hook V, Brennand KJ, Kim Y, Toneff T, Funkelstein L, Lee KC, et al. Human iPSC neurons display activity-dependent neurotransmitter secretion: aberrant catecholamine levels in schizophrenia neurons. Stem Cell Reports. 2014;3(4):531–8. doi:10.1016/j.stemcr.2014.08.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Tai Y, Feng S, Ge R, Du W, Zhang X, He Z, et al. TRPC6 channels promote dendritic growth via the CaMKIV-CREB pathway. J Cell Sci. 2008;121(Pt 14):2301–7. doi:10.1242/jcs.026906.

    Article  CAS  PubMed  Google Scholar 

  64. Zhou J, Du W, Zhou K, Tai Y, Yao H, Jia Y, et al. Critical role of TRPC6 channels in the formation of excitatory synapses. Nat Neurosci. 2008;11(7):741–3. doi:10.1038/nn.2127.

    Article  CAS  PubMed  Google Scholar 

  65. Marfella CG, Imbalzano AN. The Chd family of chromatin remodelers. Mutat Res. 2007;618(1–2):30–40. doi:10.1016/j.mrfmmm.2006.07.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Stefansson H, Ophoff RA, Steinberg S, Andreassen OA, Cichon S, Rujescu D, et al. Common variants conferring risk of schizophrenia. Nature. 2009;460(7256):744–7. doi:10.1038/nature08186.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Lambert D, Middle F, Hamshere ML, Segurado R, Raybould R, Corvin A, et al. Stage 2 of the Wellcome Trust UK-Irish bipolar affective disorder sibling-pair genome screen: evidence for linkage on chromosomes 6q16-q21, 4q12-q21, 9p21, 10p14-p12 and 18q22. Mol Psychiatry. 2005;10(9):831–41. doi:10.1038/sj.mp.4001684.

    Article  CAS  PubMed  Google Scholar 

  68. Iossifov I, Ronemus M, Levy D, Wang Z, Hakker I, Rosenbaum J, et al. De novo gene disruptions in children on the autistic spectrum. Neuron. 2012;74(2):285–99. doi:10.1016/j.neuron.2012.04.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Lancaster MA, Renner M, Martin CA, Wenzel D, Bicknell LS, Hurles ME, et al. Cerebral organoids model human brain development and microcephaly. Nature. 2013;501(7467):373–9. doi:10.1038/nature12517.

    Article  CAS  PubMed  Google Scholar 

  70. Mariani J, Coppola G, Zhang P, Abyzov A, Provini L, Tomasini L, et al. FOXG1-dependent dysregulation of GABA/glutamate neuron differentiation in autism Spectrum disorders. Cell. 2015;162(2):375–90. doi:10.1016/j.cell.2015.06.034.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Rubenstein JL. Three hypotheses for developmental defects that may underlie some forms of autism spectrum disorder. Curr Opin Neurol. 2010;23(2):118–23. doi:10.1097/WCO.0b013e328336eb13.

    Article  PubMed  Google Scholar 

  72. Ariani F, Hayek G, Rondinella D, Artuso R, Mencarelli MA, Spanhol-Rosseto A, et al. FOXG1 is responsible for the congenital variant of Rett syndrome. Am J Hum Genet. 2008;83(1):89–93. doi:10.1016/j.ajhg.2008.05.015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Tang X, Kim J, Zhou L, Wengert E, Zhang L, Wu Z, et al. KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome. Proc Natl Acad Sci U S A. 2016;113(3):751–6. doi:10.1073/pnas.1524013113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Craddock N, Sklar P. Genetics of bipolar disorder. Lancet. 2013;381(9878):1654–62. doi:10.1016/S0140-6736(13)60855-7.

    Article  CAS  PubMed  Google Scholar 

  75. Muhleisen TW, Leber M, Schulze TG, Strohmaier J, Degenhardt F, Treutlein J, et al. Genome-wide association study reveals two new risk loci for bipolar disorder. Nat Commun. 2014;5:3339. doi:10.1038/ncomms4339.

    Article  CAS  PubMed  Google Scholar 

  76. O'Shea KS, McInnis MG. Neurodevelopmental origins of bipolar disorder: iPSC models. Mol Cell Neurosci. 2016;73:63–83. doi:10.1016/j.mcn.2015.11.006.

    Article  CAS  PubMed  Google Scholar 

  77. Chen HM, DeLong CJ, Bame M, Rajapakse I, Herron TJ, McInnis MG, et al. Transcripts involved in calcium signaling and telencephalic neuronal fate are altered in induced pluripotent stem cells from bipolar disorder patients. Transl Psychiatry. 2014;4:e375. doi:10.1038/tp.2014.12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Madison JM, Zhou F, Nigam A, Hussain A, Barker DD, Nehme R, et al. Characterization of bipolar disorder patient-specific induced pluripotent stem cells from a family reveals neurodevelopmental and mRNA expression abnormalities. Mol Psychiatry. 2015;20(6):703–17. doi:10.1038/mp.2015.7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Chen Y, Xiong M, Dong Y, Haberman A, Cao J, Liu H, et al. Chemical control of grafted human PSC-derived neurons in a mouse model of Parkinson's disease. Cell Stem Cell. 2016;18(6):817–26. doi:10.1016/j.stem.2016.03.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

B.J.M. was partially supported by NIH (R01MH110487), the Pitt Hopkins Research Foundation, and the Brace Cove Foundation. K.M.C. was partially supported by NIH grants NS093772, NS097206, and MH106434.

Author information

Authors and Affiliations

  1. Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Stephanie J. Temme & Kimberly M. Christian

  2. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Stephanie J. Temme & Kimberly M. Christian

  3. Lieber Institute for Brain Development, Baltimore, MD, 21205, USA

    Stephanie J. Temme & Brady J. Maher

  4. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Brady J. Maher

  5. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Brady J. Maher

Authors
  1. Stephanie J. Temme
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brady J. Maher
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kimberly M. Christian
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kimberly M. Christian.

Ethics declarations

Conflict of Interest

Stephanie J. Temme, Brady J. Maher, and Dr. Kimberly M. Christian declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Genetics and Neuroscience

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Temme, S.J., Maher, B.J. & Christian, K.M. Using Induced Pluripotent Stem Cells to Investigate Complex Genetic Psychiatric Disorders. Curr Behav Neurosci Rep 3, 275–284 (2016). https://doi.org/10.1007/s40473-016-0100-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40473-016-0100-7

Keywords

Search

Navigation