Neuropsychiatric disorders such as autism spectrum disorder (ASD), schizophrenia (SCZ) and bipolar disorder (BPD) are of great societal and medical importance, but the complexity of these diseases and the challenges of modeling the development and function of the human brain have made these disorders difficult to study experimentally. The recent development of 3D brain organoids derived from human pluripotent stem cells offers a promising approach for investigating the phenotypic underpinnings of these highly polygenic disorders and for understanding the contribution of individual risk variants and complex genetic background to human pathology. Here we discuss the advantages, limitations and future applications of human brain organoids as in vitro models of neuropsychiatric disease.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 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.
World Health Organization. The Global Burden of Disease: 2004 Update (WHO Press, 2008).
Collins, P.Y. et al. Grand challenges in global mental health. Nature 475, 27–30 (2011).
Hyman, S.E. Revolution stalled. Sci. Transl. Med. 4, 155cm11 (2012).
Gratten, J., Wray, N.R., Keller, M.C. & Visscher, P.M. Large-scale genomics unveils the genetic architecture of psychiatric disorders. Nat. Neurosci. 17, 782–790 (2014).
McCarroll, S.A., Feng, G. & Hyman, S.E. Genome-scale neurogenetics: methodology and meaning. Nat. Neurosci. 17, 756–763 (2014).
Doherty, J.L. & Owen, M.J. Genomic insights into the overlap between psychiatric disorders: implications for research and clinical practice. Genome Med. 6, 29 (2014).
Mouchlianitis, E., McCutcheon, R. & Howes, O.D. Brain-imaging studies of treatment-resistant schizophrenia: a systematic review. Lancet Psychiatry 3, 451–463 (2016).
Ecker, C., Bookheimer, S.Y. & Murphy, D.G. Neuroimaging in autism spectrum disorder: brain structure and function across the lifespan. Lancet Neurol. 14, 1121–1134 (2015).
Heyes, S. et al. Genetic disruption of voltage-gated calcium channels in psychiatric and neurological disorders. Prog. Neurobiol. 134, 36–54 (2015).
Moyer, C.E., Shelton, M.A. & Sweet, R.A. Dendritic spine alterations in schizophrenia. Neurosci. Lett. 601, 46–53 (2015).
Glantz, L.A. & Lewis, D.A. Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch. Gen. Psychiatry 57, 65–73 (2000).
de Bartolomeis, A., Latte, G., Tomasetti, C. & Iasevoli, F. Glutamatergic postsynaptic density protein dysfunctions in synaptic plasticity and dendritic spines morphology: relevance to schizophrenia and other behavioral disorders pathophysiology, and implications for novel therapeutic approaches. Mol. Neurobiol. 49, 484–511 (2014).
Egbujo, C.N., Sinclair, D. & Hahn, C.G. Dysregulations of synaptic vesicle trafficking in schizophrenia. Curr. Psychiatry Rep. 18, 77 (2016).
Martínez-Cerdeño, V. Dendrite and spine modifications in autism and related neurodevelopmental disorders in patients and animal models. Dev. Neurobiol. http://dx.doi.org/10.1002/dneu.22417 (2016).
Lewis, D.A., Curley, A.A., Glausier, J.R. & Volk, D.W. Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia. Trends Neurosci. 35, 57–67 (2012).
Zikopoulos, B. & Barbas, H. Altered neural connectivity in excitatory and inhibitory cortical circuits in autism. Front. Hum. Neurosci. 7, 609 (2013).
Elsayed, M. & Magistretti, P.J. A new outlook on mental illnesses: glial involvement beyond the glue. Front. Cell. Neurosci. 9, 468 (2015).
Cross-Disorder Group of the Psychiatric Genomics Consortium. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet 381, 1371–1379 (2013).
Cross-Disorder Group of the Psychiatric Genomics Consortium. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat. Genet. 45, 984–994 (2013).
Bulik-Sullivan, B. et al. An atlas of genetic correlations across human diseases and traits. Nat. Genet. 47, 1236–1241 (2015).
Kelava, I. & Lancaster, M.A. Stem cell models of human brain development. Cell Stem Cell 18, 736–748 (2016).
Wen, Z., Christian, K.M., Song, H. & Ming, G.L. Modeling psychiatric disorders with patient-derived iPSCs. Curr. Opin. Neurobiol. 36, 118–127 (2016).
Urnov, F.D. et al. Highly efficient endogenous human gene correction using designed zinc-finger nucleases. Nature 435, 646–651 (2005).
Miller, J.C. et al. A TALE nuclease architecture for efficient genome editing. Nat. Biotechnol. 29, 143–148 (2011).
Cong, L. et al. Multiplex genome engineering using CRISPR/Cas systems. Science 339, 819–823 (2013).
Mali, P. et al. RNA-guided human genome engineering via Cas9. Science 339, 823–826 (2013).
González, F. et al. An iCRISPR platform for rapid, multiplexable, and inducible genome editing in human pluripotent stem cells. Cell Stem Cell 15, 215–226 (2014).
Hockemeyer, D. & Jaenisch, R. Induced pluripotent stem cells meet genome editing. Cell Stem Cell 18, 573–586 (2016).
Zhang, S.C., Wernig, M., Duncan, I.D., Brüstle, O. & Thomson, J.A. In vitro differentiation of transplantable neural precursors from human embryonic stem cells. Nat. Biotechnol. 19, 1129–1133 (2001).
Chambers, S.M. et al. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat. Biotechnol. 27, 275–280 (2009).
Shi, Y., Kirwan, P., Smith, J., Robinson, H.P.C. & Livesey, F.J. Human cerebral cortex development from pluripotent stem cells to functional excitatory synapses. Nat. Neurosci. 15, 477–486 (2012).
Elkabetz, Y. et al. Human ES cell-derived neural rosettes reveal a functionally distinct early neural stem cell stage. Genes Dev. 22, 152–165 (2008).
Lancaster, M.A. et al. Cerebral organoids model human brain development and microcephaly. Nature 501, 373–379 (2013).
Qian, X. et al. Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure. Cell 165, 1238–1254 (2016).
Kadoshima, T. et al. Self-organization of axial polarity, inside-out layer pattern, and species-specific progenitor dynamics in human ES cell-derived neocortex. Proc. Natl. Acad. Sci. USA 110, 20284–20289 (2013).
Otani, T., Marchetto, M.C., Gage, F.H., Simons, B.D. & Livesey, F.J. 2D and 3D stem cell models of primate cortical development identify species-specific differences in progenitor behavior contributing to brain size. Cell Stem Cell 18, 467–480 (2016).
Cugola, F.R. et al. The Brazilian Zika virus strain causes birth defects in experimental models. Nature 534, 267–271 (2016).
Dang, J. et al. Zika virus depletes neural progenitors in human cerebral organoids through activation of the innate immune receptor TLR3. Cell Stem Cell 19, 258–265 (2016).
Garcez, P.P. et al. Zika virus impairs growth in human neurospheres and brain organoids. Science 352, 816–818 (2016).
Watanabe, K. et al. Directed differentiation of telencephalic precursors from embryonic stem cells. Nat. Neurosci. 8, 288–296 (2005).
Eiraku, M. et al. Self-organized formation of polarized cortical tissues from ESCs and its active manipulation by extrinsic signals. Cell Stem Cell 3, 519–532 (2008).
Ying, Q.L., Stavridis, M., Griffiths, D., Li, M. & Smith, A. Conversion of embryonic stem cells into neuroectodermal precursors in adherent monoculture. Nat. Biotechnol. 21, 183–186 (2003).
Pas¸ca, A.M. et al. Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nat. Methods 12, 671–678 (2015).
Rigamonti, A. et al. Large-scale production of mature neurons from human pluripotent stem cells in a three-dimensional suspension culture system. Stem Cell Reports 6, 993–1008 (2016).
Sakaguchi, H. et al. Generation of functional hippocampal neurons from self-organizing human embryonic stem cell-derived dorsomedial telencephalic tissue. Nat. Commun. 6, 8896 (2015).
Jo, J. et al. Midbrain-like organoids from human pluripotent stem cells contain functional dopaminergic and neuromelanin-producing neurons. Cell Stem Cell 19, 248–257 (2016).
Muguruma, K., Nishiyama, A., Kawakami, H., Hashimoto, K. & Sasai, Y. Self-organization of polarized cerebellar tissue in 3D culture of human pluripotent stem cells. Cell Rep. 10, 537–550 (2015).
Woodhams, P.L. & Atkinson, D.J. Regeneration of entorhino-dentate projections in organotypic slice cultures: mode of axonal regrowth and effects of growth factors. Exp. Neurol. 140, 68–78 (1996).
Eiraku, M. et al. Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature 472, 51–56 (2011).
Camp, J.G. et al. Human cerebral organoids recapitulate gene expression programs of fetal neocortex development. Proc. Natl. Acad. Sci. USA 112, 15672–15677 (2015).
Yin, X. et al. Engineering stem cell organoids. Cell Stem Cell 18, 25–38 (2016).
Flaherty, E.K. & Brennand, K.J. Using hiPSCs to model neuropsychiatric copy number variations (CNVs) has potential to reveal underlying disease mechanisms. Brain Res. http://dx.doi.org/10.1016/j.brainres.2015.11.009 (2015).
Brennand, K.J. et al. Modelling schizophrenia using human induced pluripotent stem cells. Nature 473, 221–225 (2011).
Marchetto, M.C. et al. A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell 143, 527–539 (2010).
Chen, H.M. et al. Transcripts involved in calcium signaling and telencephalic neuronal fate are altered in induced pluripotent stem cells from bipolar disorder patients. Transl. Psychiatry 4, e375 (2014).
Madison, J.M. et al. Characterization of bipolar disorder patient-specific induced pluripotent stem cells from a family reveals neurodevelopmental and mRNA expression abnormalities. Mol. Psychiatry 20, 703–717 (2015).
Mertens, J. et al. Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. Nature 527, 95–99 (2015).
Wen, Z. et al. Synaptic dysregulation in a human iPS cell model of mental disorders. Nature 515, 414–418 (2014).
Yoon, K.J. 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 15, 79–91 (2014).
Shcheglovitov, A. et al. SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients. Nature 503, 267–271 (2013).
Adamo, A. et al. 7q11.23 dosage-dependent dysregulation in human pluripotent stem cells affects transcriptional programs in disease-relevant lineages. Nat. Genet. 47, 132–141 (2015).
Mariani, J. et al. FOXG1-dependent dysregulation of GABA/glutamate neuron differentiation in autism spectrum disorders. Cell 162, 375–390 (2015).
Robicsek, O. et al. Abnormal neuronal differentiation and mitochondrial dysfunction in hair follicle-derived induced pluripotent stem cells of schizophrenia patients. Mol. Psychiatry 18, 1067–1076 (2013).
Hashimoto-Torii, K. et al. Roles of heat shock factor 1 in neuronal response to fetal environmental risks and its relevance to brain disorders. Neuron 82, 560–572 (2014).
Griesi-Oliveira, K. et al. Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons. Mol. Psychiatry 20, 1350–1365 (2015).
Muotri, A.R. et al. L1 retrotransposition in neurons is modulated by MeCP2. Nature 468, 443–446 (2010).
Larimore, J. 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 8, e65069 (2013).
Liu, J. et al. Signaling defects in iPSC-derived fragile X premutation neurons. Hum. Mol. Genet. 21, 3795–3805 (2012).
Pas¸ca, S.P. et al. Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nat. Med. 17, 1657–1662 (2011).
Tian, Y. et al. Alteration in basal and depolarization induced transcriptional network in iPSC derived neurons from Timothy syndrome. Genome Med. 6, 75 (2014).
Ananiev, G., Williams, E.C., 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 6, e25255 (2011).
Cheung, A.Y. et al. Isolation of MECP2-null Rett Syndrome patient hiPS cells and isogenic controls through X-chromosome inactivation. Hum. Mol. Genet. 20, 2103–2115 (2011).
Ricciardi, S. et al. CDKL5 ensures excitatory synapse stability by reinforcing NGL-1-PSD95 interaction in the postsynaptic compartment and is impaired in patient iPSC-derived neurons. Nat. Cell Biol. 14, 911–923 (2012).
Macosko, E.Z. et al. Highly parallel genome-wide expression profiling of individual cells using nanoliter droplets. Cell 161, 1202–1214 (2015).
Klein, A.M. et al. Droplet barcoding for single-cell transcriptomics applied to embryonic stem cells. Cell 161, 1187–1201 (2015).
Lee, J.H. et al. Highly multiplexed subcellular RNA sequencing in situ. Science 343, 1360–1363 (2014).
Tieng, V. et al. Engineering of midbrain organoids containing long-lived dopaminergic neurons. Stem Cells Dev. 23, 1535–1547 (2014).
Falk, A. et al. Modeling psychiatric disorders: from genomic findings to cellular phenotypes. Mol. Psychiatry 21, 1167–1179 (2016).
Tomassy, G.S., Dershowitz, L.B. & Arlotta, P. Diversity matters: a revised guide to myelination. Trends Cell Biol. 26, 135–147 (2016).
Hong, S., Dissing-Olesen, L. & Stevens, B. New insights on the role of microglia in synaptic pruning in health and disease. Curr. Opin. Neurobiol. 36, 128–134 (2016).
Bilimoria, P.M. & Stevens, B. Microglia function during brain development: New insights from animal models. Brain Res. 1617, 7–17 (2015).
Ginhoux, F. & Prinz, M. Origin of microglia: current concepts and past controversies. Cold Spring Harb. Perspect. Biol. 7, a020537 (2015).
Young-Pearse, T.L. & Morrow, E.M. Modeling developmental neuropsychiatric disorders with iPSC technology: challenges and opportunities. Curr. Opin. Neurobiol. 36, 66–73 (2016).
Muffat, J. et al. Efficient derivation of microglia-1 like cells from human pluripotent stem cells. Nat. Med. 22, http://dx.doi.org/10.1038/nm.4189 (2016).
Schwartz, M.P. et al. Human pluripotent stem cell-derived neural constructs for predicting neural toxicity. Proc. Natl. Acad. Sci. USA 112, 12516–12521 (2015).
Hochbaum, D.R. et al. All-optical electrophysiology in mammalian neurons using engineered microbial rhodopsins. Nat. Methods 11, 825–833 (2014).
Tsien, R.Y. New calcium indicators and buffers with high selectivity against magnesium and protons: design, synthesis, and properties of prototype structures. Biochemistry 19, 2396–2404 (1980).
Scholvin, J. et al. Close-packed silicon microelectrodes for scalable spatially oversampled neural recording. IEEE Trans. Biomed. Eng. 63, 120–130 (2016).
Sullivan, P.F., Daly, M.J. & O'Donovan, M. Genetic architectures of psychiatric disorders: the emerging picture and its implications. Nat. Rev. Genet. 13, 537–551 (2012).
Polderman, T.J. et al. Meta-analysis of the heritability of human traits based on fifty years of twin studies. Nat. Genet. 47, 702–709 (2015).
Sanders, S.J. et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485, 237–241 (2012).
He, X. et al. Integrated model of de novo and inherited genetic variants yields greater power to identify risk genes. PLoS Genet. 9, e1003671 (2013).
Stefansson, H. et al. CNVs conferring risk of autism or schizophrenia affect cognition in controls. Nature 505, 361–366 (2014).
Lencz, T. et al. Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: a report from the Cognitive Genomics consorTium (COGENT). Mol. Psychiatry 19, 168–174 (2014).
Robinson, E.B. et al. Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population. Nat. Genet. 48, 552–555 (2016).
Moreno-De-Luca, A. et al. Developmental brain dysfunction: revival and expansion of old concepts based on new genetic evidence. Lancet Neurol. 12, 406–414 (2013).
Moreno-De-Luca, D., Moreno-De-Luca, A., Cubells, J.F. & Sanders, S.J. Cross-disorder comparison of four neuropsychiatric CNV loci. Curr. Genet. Med. Rep. 2, 151–161 (2014).
Malhotra, D. & Sebat, J. CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell 148, 1223–1241 (2012).
Sekar, A. et al. Schizophrenia risk from complex variation of complement component 4. Nature 530, 177–183 (2016).
We thank S. Hyman, L. Rubin, E. Robinson and K. Lilliehook for their critical discussion and suggestions for this manuscript. We are grateful to N. Maria and J. Nguyen for editing of the manuscript, and D. Sun for creating the illustrations for this article. P.A. is a NYSC Robertson Investigator. Work in the Arlotta lab is supported by grants to P.A. the US National Institutes of Health (NS078164 and MH101268), the Stanley Center for Psychiatric Disease of the Broad Institute of MIT and Harvard, and the Harvard Brain Initiative. We apologize to colleagues whose work we could not cite because of space limitations.
The authors declare no competing financial interests.
About this article
Cite this article
Quadrato, G., Brown, J. & Arlotta, P. The promises and challenges of human brain organoids as models of neuropsychiatric disease. Nat Med 22, 1220–1228 (2016). https://doi.org/10.1038/nm.4214
Journal of Biomedical Science (2021)
Mind the translational gap: using iPS cell models to bridge from genetic discoveries to perturbed pathways and therapeutic targets
Molecular Autism (2021)
Human sensorimotor organoids derived from healthy and amyotrophic lateral sclerosis stem cells form neuromuscular junctions
Nature Communications (2021)
Journal of Medical and Biological Engineering (2021)
Cell and Tissue Banking (2021)