pp 1-25 | Cite as

Disease Modeling of Neuropsychiatric Brain Disorders Using Human Stem Cell-Based Neural Models

  • Johanna Kaindl
  • Beate WinnerEmail author
Part of the Current Topics in Behavioral Neurosciences book series


Human pluripotent stem (PS) cells are a relevant platform to model human-specific neurological disorders. In this chapter, we focus on human stem cell models for neuropsychiatric disorders including induced pluripotent stem (iPS) cell-derived neural precursor cells (NPCs), neurons and cerebral organoids. We discuss crucial steps for planning human disease modeling experiments. We introduce the different strategies of human disease modeling including transdifferentiation, human embryonic stem (ES) cell-based models, iPS cell-based models and genome editing options. Analysis of disease-relevant phenotypes is discussed. In more detail, we provide exemplary insight into modeling of the neurodevelopmental defects in autism spectrum disorder (ASD) and the process of neurodegeneration in Alzheimer’s disease (AD). Besides monogenic diseases, iPS cell-derived models also generated data from idiopathic and sporadic cases.


Disease modeling hiPSCs hiPSC-derived neurons Neuropsychiatric disorders Organoids 



JK is an associated member of Research Training Grant GRK2162 of the Deutsche Forschungsgemeinschaft. Funding came from the German Federal Ministry of Education and Research (BMBF, 01GQ113, 01GM1520A, 01EK1609B and 01GM1905B to B.W.); the Bavarian Ministry of Science and the Arts in the framework of ForINTER and the Interdisciplinary Center for Clinical Research (IZKF), University Hospital Erlangen (E25).


  1. Abud EM, Ramirez RN, Martinez ES, Healy LM, Nguyen CHH, Newman SA, Yeromin AV et al (2017) iPSC-derived human microglia-like cells to study neurological diseases. Neuron 94(2):278–293.e9. CrossRefGoogle Scholar
  2. Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium (2017) Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia. Mol Autism 8(1):21. CrossRefGoogle Scholar
  3. Avior Y, Lezmi E, Yanuka D, Benvenisty N (2017) Modeling developmental and tumorigenic aspects of trilateral retinoblastoma via human embryonic stem cells. Stem Cell Rep 8(5):1354–1365. CrossRefGoogle Scholar
  4. Bagley JA, Reumann D, Bian S, Lévi-Strauss J, Knoblich JA (2017) Fused cerebral organoids model interactions between brain regions. Nat Methods 14(7):743–751. CrossRefGoogle Scholar
  5. Bardy C, van den Hurk M, Kakaradov B, Erwin JA, Jaeger BN, Hernandez RV, Eames T et al (2016) Predicting the functional states of human iPSC-derived neurons with single-cell RNA-seq and electrophysiology. Mol Psychiatry 21(11):1573–1588. CrossRefGoogle Scholar
  6. Bernstein H-G, Steiner J, Guest PC, Dobrowolny H, Bogerts B (2015) Glial cells as key players in schizophrenia pathology: recent insights and concepts of therapy. Schizophr Res 161(1):4–18. CrossRefGoogle Scholar
  7. Birey F, Andersen J, Makinson CD, Islam S, Wu W, Nina H, Christina Fan H et al (2017) Assembly of functionally integrated human forebrain spheroids. Nature 545(7652):54–59. CrossRefGoogle Scholar
  8. Brennand K, Simone A, Jou J, Gelboin-Burkhart C, Tran N, Sangar S, Li Y et al (2011) Modelling schizophrenia using human induced pluripotent stem cells. Nature 473(7346):221–225. CrossRefGoogle Scholar
  9. Brennand K, Savas JN, Kim Y, Tran N, Simone A, Hashimoto-Torii K, Beaumont KG et al (2015) Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia. Mol Psychiatry 20(3):361–368. CrossRefGoogle Scholar
  10. Camp JG, Badsha F, Florio M, Kanton S, Gerber T, Wilsch-Bräuninger M, Lewitus E et al (2015) Human cerebral organoids recapitulate gene expression programs of fetal neocortex development. Proc Natl Acad Sci 112(51):201520760. CrossRefGoogle Scholar
  11. Chambers SM, Fasano CA, Papapetrou EP, Tomishima M, Sadelain M, Studer L (2009) Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol 27(3):275–280. CrossRefGoogle Scholar
  12. Chen JS, Dagdas YS, Kleinstiver BP, Welch MM, Sousa AA, Harrington LB, Sternberg SH, Keith Joung J, Yildiz A, Doudna JA (2017) Enhanced proofreading governs CRISPR–Cas9 targeting accuracy. Nature 550:407. CrossRefGoogle Scholar
  13. Cheung AYL, Horvath LM, Grafodatskaya D, Pasceri P, Weksberg R, Hotta A, Carrel L, Ellis J (2011) Isolation of MECP2-null rett syndrome patient hiPS cells and isogenic controls through X-chromosome inactivation. Hum Mol Genet 20(11):2103–2115. CrossRefGoogle Scholar
  14. Choi SH, Kim YH, Hebisch M, Sliwinski C, Lee S, D’Avanzo C, Chen H et al (2014) A three-dimensional human neural cell culture model of Alzheimer’s disease. Nature 515(7526):274–278. CrossRefGoogle Scholar
  15. Colasante G, Lignani G, Rubio A, Medrihan L, Yekhlef L, Sessa A, Massimino L et al (2015) Rapid conversion of fibroblasts into functional forebrain GABAergic interneurons by direct genetic reprogramming. Cell Stem Cell 17(6):719–734. CrossRefGoogle Scholar
  16. Cotter DR, Pariante CM, Everall IP, Cotter DR, Pariante CM, Everall IP (2001) Glial cell abnormalities in major psychiatric disorders: the evidence and implications. Brain Res Bull 55(5):585–595. Google Scholar
  17. Davis RL, Weintraub H, Lassar AB, Davis RL, Weintraub H, Lassar AB (1987) Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell 51(6):987–1000. Google Scholar
  18. Derecki NC, Cronk JC, Lu Z, Xu E, Abbott SBG, Guyenet PG, Kipnis J (2012) Wild-type microglia arrest pathology in a mouse model of rett syndrome. Nature 484(7392):105–109. CrossRefGoogle Scholar
  19. Dever DP, Bak RO, Reinisch A, Camarena J, Washington G, Nicolas CE, Pavel-Dinu M et al (2016) CRISPR/Cas9 β-globin gene targeting in human haematopoietic stem cells. Nature 539(7629):384–389. CrossRefGoogle Scholar
  20. Doers ME, Musser MT, Nichol R, Berndt ER, Baker M, Gomez TM, Zhang S-C, Abbeduto L, Bhattacharyya A (2014) iPSC-derived forebrain neurons from FXS individuals show defects in initial Neurite outgrowth. Stem Cells Dev 23(15):1777–1787. CrossRefGoogle Scholar
  21. Douvaras P, Sun B, Wang M, Kruglikov I, Lallos G, Zimmer M, Terrenoire C et al (2017) Directed differentiation of human pluripotent stem cells to microglia. Stem Cell Rep 8:1516–1524. CrossRefGoogle Scholar
  22. Eiges R, Urbach A, Malcov M, Frumkin T, Schwartz T, Amit A, Yaron Y et al (2007) Developmental study of fragile X syndrome using human embryonic stem cells derived from Preimplantation genetically diagnosed embryos. Cell Stem Cell 1(5):568–577. CrossRefGoogle Scholar
  23. Etemad S, Zamin RM, Ruitenberg MJ, Filgueira L (2012) A novel in vitro human microglia model: characterization of human monocyte-derived microglia. J Neurosci Methods 209(1):79–89. CrossRefGoogle Scholar
  24. Fogarty NME, McCarthy A, Snijders KE, Powell BE, Kubikova N, Blakeley P, Lea R et al (2017) Genome editing reveals a role for OCT4 in human embryogenesis. Nature 550(7674):67–73. CrossRefGoogle Scholar
  25. Gascón S, Masserdotti G, Russo GL, Götz M (2017) Direct neuronal reprogramming: achievements, hurdles, and new roads to success. Cell Stem Cell 21(1):18–34. CrossRefGoogle Scholar
  26. Gratten J, Wray NR, Keller MC, Visscher PM (2014) Large-scale genomics unveils the genetic architecture of psychiatric disorders. Nat Neurosci 17(6):782–790. CrossRefGoogle Scholar
  27. Hockemeyer D, Wang H, Kiani S, Lai CS, Gao Q, Cassady JP, Cost GJ et al (2017) Genetic engineering of human pluripotent cells using TALE nucleases. Nat Biotechnol 29:731. CrossRefGoogle Scholar
  28. Hollingsworth EW, Vaughn JE, Orack JC, Skinner C, Khouri J, Lizarraga SB, Hester ME, Watanabe F, Kosik KS, Imitola J (2017) iPhemap: an Atlas of phenotype to genotype relationships of human iPSC models of neurological diseases. EMBO Mol Med 9(12):1742–1762. CrossRefGoogle Scholar
  29. Honda M, Minami I, Tooi N, Morone N, Nishioka H, Uemura K, Kinoshita A, Heuser JE, Nakatsuji N, Aiba K (2016) The modeling of Alzheimer’s disease by the overexpression of mutant presenilin 1 in human embryonic stem cells. Biochem Biophys Res Commun 469(3):587–592. CrossRefGoogle Scholar
  30. Hook V, Brennand KJ, Kim Y, Toneff T, Funkelstein L, Lee KC, Ziegler M, Gage FH (2014) Human iPSC neurons display activity-dependent neurotransmitter secretion: aberrant catecholamine levels in Schizophrenia neurons. Stem Cell Rep 3(4):531–538. CrossRefGoogle Scholar
  31. Hu W, Qiu B, Guan W, Wang Q, Wang M, Li W, Gao L et al (2015) Direct conversion of normal and Alzheimer’s disease human fibroblasts into neuronal cells by small molecules. Cell Stem Cell 17(2):204–212. CrossRefGoogle Scholar
  32. Illes S, Jakab M, Beyer F, Gelfert R, Couillard-Despres S, Schnitzler A, Ritter M, Aigner L (2014) Intrinsically active and pacemaker neurons in pluripotent stem cell-derived neuronal populations. Stem Cell Rep 2(3):323–336. CrossRefGoogle Scholar
  33. Israel MA, Yuan SH, Bardy C, Reyna SM, Mu Y, Herrera C, Hefferan MP et al (2012) Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells. Nature 482(7384):216–220. CrossRefGoogle Scholar
  34. Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E (2012) A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337(6096):816–821. CrossRefGoogle Scholar
  35. Jo J, Xiao Y, Sun AX, Cukuroglu E, Tran H-D, Göke J, Tan ZY et al (2016) Midbrain-like organoids from human pluripotent stem cells contain functional dopaminergic and neuromelanin-producing neurons. Cell Stem Cell 19(2):248–257. CrossRefGoogle Scholar
  36. Kim K, Doi A, Wen B, Ng K, Zhao R, Cahan P, Kim J et al (2010) Epigenetic memory in induced pluripotent stem cells. Nature 467(7313):285–290. CrossRefGoogle Scholar
  37. Koch P, Tamboli IY, Mertens J, Wunderlich P, Ladewig J, Stüber K, Esselmann H, Wiltfang J, Brüstle O, Walter J (2012) Presenilin-1 L166P mutant human pluripotent stem cell–derived neurons exhibit partial loss of γ-secretase activity in endogenous amyloid-β generation. Am J Pathol 180(6):2404–2416. CrossRefGoogle Scholar
  38. Kondo T, Asai M, Tsukita K, Kutoku Y, Ohsawa Y, Sunada Y, Imamura K et al (2013) Modeling Alzheimer’s disease with iPSCs reveals stress phenotypes associated with intracellular Aβ and differential drug responsiveness. Cell Stem Cell 12:487–496. CrossRefGoogle Scholar
  39. Krencik R, Weick JP, Liu Y, Zhang Z-J, Zhang S-C (2011) Specification of transplantable astroglial subtypes from human pluripotent stem cells. Nat Biotechnol 29(6):528–534. CrossRefGoogle Scholar
  40. Kriks S, Shim J-W, Piao J, Ganat YM, Wakeman DR, Xie Z, Carrillo-Reid L et al (2011) Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease. Nature 480(7378):547–551. CrossRefGoogle Scholar
  41. Lancaster MA, Renner M, Martin C-A, Wenzel D, Bicknell LS, Hurles ME, Homfray T, Penninger JM, Jackson AP, Knoblich JA (2013) Cerebral organoids model human brain development and microcephaly. Nature 501(7467):373–379. CrossRefGoogle Scholar
  42. Lee SH, Ripke S, Neale BM, Faraone SV, Purcell SM, Perlis RH, Mowry BJ et al (2013) Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat Genet 45(9):984–994. CrossRefGoogle Scholar
  43. Li Y, Wang H, Muffat J, Cheng AW, Orlando DA, Lovén J, Kwok S-m et al (2013) Global transcriptional and translational repression in human-embryonic-stem-cell-derived rett syndrome neurons. Cell Stem Cell 13(4):446–458. CrossRefGoogle Scholar
  44. Li ZM, Shi M, Malty RH, Aoki H, Minic Z, Phanse S et al (2015) Identification of human neuronal protein complexes reveals biochemical activities and convergent mechanisms of action in autism spectrum disorders. Cell Syst 1(5):361–374. CrossRefGoogle Scholar
  45. Liao J, Karnik R, Hongcang G, Ziller MJ, Clement K, Tsankov AM, Akopian V et al (2015) Targeted disruption of DNMT1, DNMT3A and DNMT3B in human embryonic stem cells. Nat Genet 47(5):469–478. CrossRefGoogle Scholar
  46. Lin M, Zhao D, Hrabovsky A, Pedrosa E, Zheng D, Lachman HM (2014) Heat shock alters the expression of Schizophrenia and autism candidate genes in an induced pluripotent stem cell model of the human telencephalon. PloS One 9(4):e94968. CrossRefGoogle Scholar
  47. Lister R, Pelizzola M, Kida YS, David Hawkins R, Nery JR, Hon G, Antosiewicz-Bourget J et al (2011) Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature 471(7336):68–73. CrossRefGoogle Scholar
  48. Liu Q, Waltz S, Woodruff G, Ouyang J, Israel MA, Herrera C, Sarsoza F et al (2014) Effect of potent γ-secretase modulator in human neurons derived from multiple presenilin 1-induced pluripotent stem cell mutant carriers. JAMA Neurol 71(12):1481–1489. CrossRefGoogle Scholar
  49. Madison JM, Zhou F, Nigam A, Hussain A, Barker DD, Nehme R, van der Ven K et al (2015) Characterization of bipolar disorder patient-specific induced pluripotent stem cells from a family reveals neurodevelopmental and mRNA expression abnormalities. Mol Psychiatry 20(6):703–717. CrossRefGoogle Scholar
  50. Mali P, Yang L, Esvelt KM, Aach J, Guell M, DiCarlo JE, Norville JE, Church GM (2013) RNA-guided human genome engineering via Cas9. Science 339(6121):823–826. CrossRefGoogle Scholar
  51. Marchetto CC, Acab A, Yu D, Yeo GW, Mu Y, Chen G, Gage FH, Muotri AR (2010) A model for neural development and treatment of rett syndrome using human induced pluripotent stem cells. Cell 143(4):527–539. CrossRefGoogle Scholar
  52. Marchetto MC, Belinson H, Tian Y, Freitas BC, Fu C, Vadodaria K, Beltrao-Braga P et al (2017) Altered proliferation and networks in neural cells derived from idiopathic autistic individuals. Mol Psychiatry 22(6):820–835. CrossRefGoogle Scholar
  53. Mariani J, Coppola G, Zhang P, Abyzov A, Provini L, Tomasini L, Amenduni M et al (2015) FOXG1-dependent dysregulation of GABA/glutamate neuron differentiation in autism spectrum disorders. Cell 162(2):375–390. CrossRefGoogle Scholar
  54. Maroof AM, Keros S, Tyson JA, Ying S-W, Ganat YM, Merkle FT, Liu B et al (2013) Directed differentiation and functional maturation of cortical interneurons from human embryonic stem cells. Cell Stem Cell 12(5):559–572. CrossRefGoogle Scholar
  55. Mertens J, Paquola ACM, Manching K, Hatch E, Böhnke L, Ladjevardi S, McGrath S et al (2015a) Directly reprogrammed human neurons retain aging-associated Transcriptomic signatures and reveal age-related Nucleocytoplasmic defects. Cell Stem Cell 17(6):705–718. CrossRefGoogle Scholar
  56. Mertens J, Wang Q-W, Kim Y, Yu DX, Pham S, Yang B, Zheng Y et al (2015b) Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. Nature 527(7576):95–99. CrossRefGoogle Scholar
  57. Mertens J, Marchetto MC, Bardy C, Gage FH (2016) Evaluating cell reprogramming, differentiation and conversion technologies in neuroscience. Nat Rev Neurosci 17(7):424–437. CrossRefGoogle Scholar
  58. Miller JD, Ganat YM, Kishinevsky S, Bowman RL, Liu B, Tu EY, Mandal P et al (2017) Human iPSC-based modeling of late-onset disease via progerin-induced aging. Cell Stem Cell 13:691–705. CrossRefGoogle Scholar
  59. Muffat J, Li Y, Yuan B, Mitalipova M, Omer A, Corcoran S, Bakiasi G et al (2016) Efficient derivation of microglia-like cells from human pluripotent stem cells. Nat Med 22(11):1358–1367. CrossRefGoogle Scholar
  60. Muguruma K, Nishiyama A, Kawakami H, Hashimoto K, Sasai Y (2015) Self-organization of polarized cerebellar tissue in 3D culture of human pluripotent stem cells. Cell Rep 10(4):537–550. CrossRefGoogle Scholar
  61. Muratore CR, Rice HC, Srikanth P, Callahan DG, Shin T, Benjamin LNP, Walsh DM, Selkoe DJ, Young-Pearse TL (2014) The familial Alzheimer’s disease APPV717I mutation alters APP processing and Tau expression in iPSC-derived neurons. Hum Mol Genet 23(13):3523–3536. CrossRefGoogle Scholar
  62. Nicholas CR, Chen J, Tang Y, Southwell DG, Chalmers N, Vogt D, Arnold CM et al (2013) Functional maturation of hPSC-derived forebrain interneurons requires an extended timeline and mimics human neural development. Cell Stem Cell 12(5):573–586. CrossRefGoogle Scholar
  63. Niclis JC, Pinar A, Haynes JM, Alsanie W, Jenny R, Dottori M, Cram DS (2013) Characterization of forebrain neurons derived from late-onset Huntington’s disease human embryonic stem cell lines. Front Cell Neurosci 7:37. CrossRefGoogle Scholar
  64. Nishino K, Toyoda M, Yamazaki-Inoue M, Fukawatase Y, Chikazawa E, Sakaguchi H, Akutsu H, Umezawa A (2011) DNA methylation dynamics in human induced pluripotent stem cells over time. PLoS Genet 7(5):e1002085. CrossRefGoogle Scholar
  65. Ochalek A, Mihalik B, Avci HX, Chandrasekaran A, Téglási A, Bock I, Giudice ML et al (2017) Neurons derived from sporadic Alzheimer’s disease iPSCs reveal elevated TAU hyperphosphorylation, increased amyloid levels, and GSK3B activation. Alzheimer’s Res Ther 9(1):90. CrossRefGoogle Scholar
  66. Ohgidani M, Kato TA, Setoyama D, Sagata N, Hashimoto R, Shigenobu K, Yoshida T et al (2017) Direct induction of ramified microglia-like cells from human monocytes: dynamic microglial dysfunction in Nasu-Hakola disease. Sci Rep 4:4957. CrossRefGoogle Scholar
  67. Oksanen M, Petersen AJ, Naumenko N, Puttonen K, Lehtonen Š, Olivé MG, Shakirzyanova A et al (2017) PSEN1 mutant iPSC-derived model reveals severe astrocyte pathology in Alzheimer’s disease. Stem Cell Rep 9(6):1885–1897. CrossRefGoogle Scholar
  68. Pandya H, Shen MJ, Ichikawa DM, Sedlock AB, Choi Y, Johnson KR, Kim G et al (2017) Differentiation of human and murine induced pluripotent stem cells to microglia-like cells. Nat Neurosci 20(5):753–759. CrossRefGoogle Scholar
  69. Pang ZP, Yang N, Vierbuchen T, Ostermeier A, Fuentes DR, Yang TQ, Citri A et al (2011) Induction of human neuronal cells by defined transcription factors. Nature 476(7359):220–223. CrossRefGoogle Scholar
  70. Park I-H, Arora N, Huo H, Maherali N, Ahfeldt T, Shimamura A, Lensch MW, Cowan C, Hochedlinger K, Daley GQ (2008) Disease-specific induced pluripotent stem cells. Cell 134(5):877–886. CrossRefGoogle Scholar
  71. Paşca SP, Portmann T, Voineagu I, Yazawa M, Shcheglovitov A, Paşca AM, Cord B et al (2011) Using iPSC-derived neurons to uncover cellular phenotypes associated with timothy syndrome. Nat Med 17(12):1657–1662. CrossRefGoogle Scholar
  72. Paulsen BDa S, De Moraes Maciel R, Galina A, Souza Da Silveira M, Dos Santos Souza C, Drummond H, Nascimento Pozzatto E et al (2012) Altered oxygen metabolism associated to neurogenesis of induced pluripotent stem cells derived from a schizophrenic patient. Cell Transplant 21(7):1547–1559. CrossRefGoogle Scholar
  73. Perrier AL, Tabar V, Barberi T, Rubio ME, Bruses J, Topf N, Harrison NL, Studer L (2004) Derivation of midbrain dopamine neurons from human embryonic stem cells. Proc Natl Acad Sci 101(34):12543–12548. CrossRefGoogle Scholar
  74. Persico AM, Bourgeron T, Persico AM, Bourgeron T, Persico AM, Bourgeron T (2006) Searching for ways out of the autism maze: genetic, epigenetic and environmental clues. Trends Neurosci 29(7):349–358. CrossRefGoogle Scholar
  75. Pfisterer U, Kirkeby A, Torper O, Wood J, Nelander J, Dufour A, Björklund A, Lindvall O, Jakobsson J, Parmar M (2011) Direct conversion of human fibroblasts to dopaminergic neurons. Proc Natl Acad Sci U S A 108(25):10343–10348. CrossRefGoogle Scholar
  76. Purcell SM, Moran JL, Fromer M, Ruderfer D, Solovieff N, Roussos P, O’Dushlaine C et al (2014) A polygenic burden of rare disruptive mutations in schizophrenia. Nature 506(7487):185–190. CrossRefGoogle Scholar
  77. Qian X, Nguyen HN, Song MM, Hadiono C, Ogden SC, Hammack C, Yao B et al (2016) Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure. Cell 165(5):1238–1254. CrossRefGoogle Scholar
  78. Qin H, Zhao A, Zhang C, Xiaobing F (2016) Epigenetic control of reprogramming and transdifferentiation by histone modifications. Stem Cell Rev 12(6):708–720. CrossRefGoogle Scholar
  79. Quadrato G, Nguyen T, Macosko EZ, Sherwood JL, Yang SM, Berger DR, Maria N et al (2017) Cell diversity and network dynamics in photosensitive human brain organoids. Nature 545(7652):48–53. CrossRefGoogle Scholar
  80. Rackham OJL, Firas J, Fang H, Oates ME, Holmes ML, Knaupp AS, Harukazu FANTOM Consortium et al (2016) A predictive computational framework for direct reprogramming between human cell types. Nat Genet 48(3):331–335. CrossRefGoogle Scholar
  81. Raja WK, Mungenast AE, Lin Y-T, Ko T, Abdurrob F, Seo J, Tsai L-H (2016) Self-organizing 3D human neural tissue derived from induced pluripotent stem cells recapitulate Alzheimer’s disease phenotypes. PloS One 11(9):e0161969. CrossRefGoogle Scholar
  82. Ripke S, O’Dushlaine C, Chambert K, Moran JL, Kähler AK, Akterin S, Bergen SE et al (2013) Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet 45(10):1150–1159. CrossRefGoogle Scholar
  83. Ripke S, Neale BM, Corvin A, Walters JTR, Farh K-H, Holmans PA, Lee P et al (2014) Biological insights from 108 schizophrenia-associated genetic loci. Nature 511(7510):421–427. CrossRefGoogle Scholar
  84. Robicsek O, Karry R, Petit I, Salman-Kesner N, Müller F-J, Klein E, Aberdam D, Ben-Shachar D (2013) Abnormal neuronal differentiation and mitochondrial dysfunction in hair follicle-derived induced pluripotent stem cells of schizophrenia patients. Mol Psychiatry 18(10):1067–1076. CrossRefGoogle Scholar
  85. Russo FB, Freitas BC, Pignatari GC, Fernandes IR, Sebat J, Muotri AR, Beltrão-Braga PCB (2017) Modeling the interplay between neurons and astrocytes in autism using human induced pluripotent stem cells. Biol Psychiatry 83:569. CrossRefGoogle Scholar
  86. Sakaguchi H, Kadoshima T, Soen M, Narii N, Ishida Y, Ohgushi M, Takahashi J, Eiraku M, Sasai Y (2015) Generation of functional hippocampal neurons from self-organizing human embryonic stem cell-derived dorsomedial telencephalic tissue. Nat Commun 6:8896. CrossRefGoogle Scholar
  87. Shaltouki A, Peng J, Liu Q, Rao MS, Zeng X (2013) Efficient generation of astrocytes from human pluripotent stem cells in defined conditions. Stem Cells 31(5):941–952. CrossRefGoogle Scholar
  88. Shcheglovitov A, Shcheglovitova O, Yazawa M, Portmann T, Shu R, Sebastiano V, Krawisz A et al (2013) SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients. Nature 503(7475):267–271. CrossRefGoogle Scholar
  89. Sheridan SD, Theriault KM, Reis SA, Zhou F, Madison JM, Daheron L, Loring JF, Haggarty SJ (2011) Epigenetic characterization of the FMR1 gene and aberrant neurodevelopment in human induced pluripotent stem cell models of fragile X syndrome. PLoS One 6(10):e26203. CrossRefGoogle Scholar
  90. Shi Y, Kirwan P, Smith J, MacLean G, Orkin SH, Livesey FJ (2012) A human stem cell model of early Alzheimer’s disease pathology in down syndrome. Sci Trans Med 4(124):124ra29. CrossRefGoogle Scholar
  91. Slaymaker IM, Gao L, Zetsche B, Scott DA, Yan WX, Zhang F (2016) Rationally engineered Cas9 nucleases with improved specificity. Science 351(6268):84–88. CrossRefGoogle Scholar
  92. Soldner F, Laganière J, Cheng AW, Hockemeyer D, Gao Q, Alagappan R, Khurana V et al (2011) Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations. Cell 146(2):318–331. CrossRefGoogle Scholar
  93. Soldner F, Stelzer Y, Shivalila CS, Abraham BJ, Latourelle JC, Barrasa MI, Goldmann J, Myers RH, Young RA, Jaenisch R (2016) Parkinson-associated risk variant in distal enhancer of α-synuclein modulates target gene expression. Nature 533(7601):95–99. CrossRefGoogle Scholar
  94. Soliman MA, Aboharb F, Zeltner N, Studer L (2017) Pluripotent stem cells in neuropsychiatric disorders. Mol Psychiatry 22(10):1241–1249. CrossRefGoogle Scholar
  95. Son EY, Ichida JK, Wainger BJ, Toma JS, Rafuse VF, Woolf CJ, Eggan K (2011) Conversion of mouse and human fibroblasts into functional spinal motor neurons. Cell Stem Cell 9(3):205–218. CrossRefGoogle Scholar
  96. Sproul AA, Jacob S, Pre D, Kim SH, Nestor MW, Navarro-Sobrino M, Santa-Maria I et al (2014) Characterization and molecular profiling of PSEN1 familial Alzheimer’s disease iPSC-derived neural progenitors. PloS One 9(1):e84547. CrossRefGoogle Scholar
  97. Sugathan A, Biagioli M, Golzio C, Erdin S, Blumenthal I, Manavalan P, Ragavendran A et al (2014) CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors. Proc Natl Acad Sci U S A 111(42):E4468–E4477. CrossRefGoogle Scholar
  98. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131(5):861–872. CrossRefGoogle Scholar
  99. Tcw J, Wang M, Pimenova AA, Bowles KR, Hartley BJ, Lacin E, Machlovi SI et al (2017) An efficient platform for astrocyte differentiation from human induced pluripotent stem cells. Stem Cell Rep 9(2):600–614. CrossRefGoogle Scholar
  100. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM (1998) Embryonic stem cell lines derived from human blastocysts. Science 282(5391):1145–1147. Google Scholar
  101. Tobe BTD, Crain AM, Winquist AM, Calabrese B, Makihara H, Zhao W-N, Lalonde J et al (2017) Probing the lithium-response pathway in hiPSCs implicates the phosphoregulatory set-point for a cytoskeletal modulator in bipolar pathogenesis. Proc Natl Acad Sci U S A 114(22):E4462–E4471. CrossRefGoogle Scholar
  102. Urbach MS, Nissim B, Urbach A, Schuldiner M, Benvenisty N (2004) Modeling for Lesch-Nyhan disease by gene targeting in human embryonic stem cells. Stem Cells 22(4):635–641. CrossRefGoogle Scholar
  103. Urbach A, Benvenisty N, Urbach A, Benvenisty N (2009) Studying early lethality of 45,XO (Turner’s syndrome) embryos using human embryonic stem cells. PLoS One 4(1):e4175. CrossRefGoogle Scholar
  104. Urbach A, Bar-Nur O, Daley GQ, Benvenisty N (2010) Differential modeling of fragile X syndrome by human embryonic stem cells and induced-pluripotent stem cells. Cell Stem Cell 6:407–411. CrossRefGoogle Scholar
  105. Vadodaria KC, Mertens J, Paquola A, Bardy C, Li X, Jappelli R, Fung L et al (2016) Generation of functional human serotonergic neurons from fibroblasts. Mol Psychiatry 21(1):49–61. CrossRefGoogle Scholar
  106. Vera E, Bosco N, Studer L, Byrd W, Shay JW, Gu Y, Alt FW et al (2016) Generating late-onset human iPSC-based disease models by inducing neuronal age-related phenotypes through telomerase manipulation. Cell Rep 17(4):1184–1192. CrossRefGoogle Scholar
  107. Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Südhof TC, Wernig M (2010) Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463(7284):1035–1041. CrossRefGoogle Scholar
  108. Wang P, Lin M, Pedrosa E, Hrabovsky A, Zheng Z, Guo W, Lachman HM, Zheng D (2015) CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in neurodevelopment. Mol Autism 6:55. CrossRefGoogle Scholar
  109. Wang P, Mokhtari R, Pedrosa E, Kirschenbaum M, Bayrak C, Zheng D, Lachman HM (2017) CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in cerebral organoids derived from iPS cells. Mol Autism 8(1):11. CrossRefGoogle Scholar
  110. Wen Z, Nguyen HN, Guo Z, Lalli MA, Wang X, Su Y, Kim N-S et al (2014) Synaptic dysregulation in a human iPS cell model of mental disorders. Nature 515(7527):414–418. CrossRefGoogle Scholar
  111. Wen Z, Christian KM, Song H, Ming G-L (2016) Modeling psychiatric disorders with patient-derived iPSCs. Curr Opin Neurobiol 36:118–127. CrossRefGoogle Scholar
  112. Whiteford HA, Ferrari AJ, Degenhardt L, Feigin V, Vos T (2017) The global burden of mental, neurological and substance use disorders: an analysis from the global burden of disease study 2010. PloS One 10(2):e0116820. CrossRefGoogle Scholar
  113. WHO (2014) The global burden of disease: 2004 update. WHO, Geneva. Google Scholar
  114. Williams EC, Zhong X, Mohamed A, Li R, Liu Y, Dong Q, Ananiev GE et al (2014) Mutant astrocytes differentiated from rett syndrome patients-specific iPSCs have adverse effects on wild-type neurons. Hum Mol Genet 23(11):2968–2980. CrossRefGoogle Scholar
  115. Xu X, Radulescu C, Utami K, Pouladi M (2017) Obtaining multi-electrode array recordings from human induced pluripotent stem cell-derived neurons. Bio-Protocol 7(22).
  116. Yagi T, Ito D, Okada Y, Akamatsu W, Nihei Y, Yoshizaki T, Yamanaka S, Okano H, Suzuki N (2011) Modeling familial Alzheimer’s disease with induced pluripotent stem cells. Hum Mol Genet 20(23):4530–4539. CrossRefGoogle Scholar
  117. Yamamuro K, Kimoto S, Rosen KM, Kishimoto T, Makinodan M (2015) Potential primary roles of glial cells in the mechanisms of psychiatric disorders. Front Cell Neurosci 9:154. CrossRefGoogle Scholar
  118. Yoon K-J, Nguyen HN, Ursini G, Zhang F, Kim N-S, Wen Z, Makri G et al (2014) Modeling a genetic risk for schizophrenia in iPSCs and mice reveals neural stem cell deficits associated with adherens junctions and polarity. Cell Stem Cell 15(1):79–91. CrossRefGoogle Scholar
  119. Yu DX, Paolo F, Giorgio D, Yao J, Marchetto MC, Brennand K, Wright R et al (2014) Stem cell reports modeling hippocampal neurogenesis using human pluripotent stem cells. Stem Cell Rep 2:295–310. CrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Stem Cell BiologyFriedrich-Alexander-University (FAU) Erlangen-NürnbergErlangenGermany

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