Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Expert Review
  • Published:

Cortical cellular diversity and development in schizophrenia

Molecular Psychiatry volume 26, pages 203–217 (2021)Cite this article

Subjects

Abstract

While a definitive understanding of schizophrenia etiology is far from current reality, an increasing body of evidence implicates perturbations in early development that alter the trajectory of brain maturation in this disorder, leading to abnormal function in early childhood and adulthood. This atypical development likely arises from an interaction of many brain cell types that follow distinct developmental paths. Because both cellular identity and development are governed by the transcriptome and epigenome, two levels of gene regulation that have the potential to reflect both genetic and environmental influences, mapping “omic” changes over development in diverse cells is a fruitful avenue for schizophrenia research. In this review, we provide a survey of human brain cellular composition and development, levels of genomic regulation that determine cellular identity and developmental trajectories, and what is known about how genomic regulation is dysregulated in specific cell types in schizophrenia. We also outline technical challenges and solutions to conducting cell type-specific functional genomic studies in human postmortem brain.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Developmental trajectories, delays, and molecular regulation in schizophrenia.

Similar content being viewed by others

References

  1. López-Muñoz F, Boya J, Alamo C. Neuron theory, the cornerstone of neuroscience, on the centenary of the Nobel Prize award to Santiago Ramón y Cajal. Brain Res Bull. 2006;70:391–405.

    Article  PubMed  Google Scholar 

  2. Shipp S. Structure and function of the cerebral cortex. Curr Biol. 2007;17:R443–9.

    Article  CAS  PubMed  Google Scholar 

  3. Teffer K, Semendeferi K. Human prefrontal cortex: evolution, development, and pathology. Prog Brain Res. 2012;195:191–218.

    Article  PubMed  Google Scholar 

  4. Silbereis JC, Pochareddy S, Zhu Y, Li M, Sestan N. The cellular and molecular landscapes of the developing human central nervous system. Neuron. 2016;89:248–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sherwood CC, Stimpson CD, Raghanti MA, Wildman DE, Uddin M, Grossman LI, et al. Evolution of increased glia-neuron ratios in the human frontal cortex. Proc Natl Acad Sci USA. 2006;103:13606–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Leyva-Díaz E, López-Bendito G. In and out from the cortex: development of major forebrain connections. Neuroscience. 2013;254:26–44.

    Article  PubMed  CAS  Google Scholar 

  7. Markram H, Toledo-Rodriguez M, Wang Y, Gupta A, Silberberg G, Wu C. Interneurons of the neocortical inhibitory system. Nat Rev Neurosci. 2004;5:793–807.

    Article  CAS  PubMed  Google Scholar 

  8. Rowitch DH, Kriegstein AR. Developmental genetics of vertebrate glial-cell specification. Nature. 2010;468:214–22.

    Article  CAS  PubMed  Google Scholar 

  9. Matcovitch-Natan O, Winter DR, Giladi A, Vargas Aguilar S, Spinrad A, Sarrazin S, et al. Microglia development follows a stepwise program to regulate brain homeostasis. Science. 2016;353:aad8670.

    Article  PubMed  CAS  Google Scholar 

  10. Mariani MM, Kielian T. Microglia in infectious diseases of the central nervous system. J Neuroimmune Pharm. 2009;4:448–61.

    Article  Google Scholar 

  11. Abbott NJ, Patabendige AAK, Dolman DEM, Yusof SR, Begley DJ. Structure and function of the blood-brain barrier. Neurobiol Dis. 2010;37:13–25.

    Article  CAS  PubMed  Google Scholar 

  12. Lodato S, Rouaux C, Quast KB, Jantrachotechatchawan C, Studer M, Hensch TK, et al. Excitatory projection neuron subtypes control the distribution of local inhibitory interneurons in the cerebral cortex. Neuron. 2011;69:763–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kang HJ, Kawasawa YI, Cheng F, Zhu Y, Xu X, Li M, et al. Spatio-temporal transcriptome of the human brain. Nature. 2011;478:483–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Back SA, Luo NL, Borenstein NS, Volpe JJ, Kinney HC. Arrested oligodendrocyte lineage progression during human cerebral white matter development: dissociation between the timing of progenitor differentiation and myelinogenesis. J Neuropathol Exp Neurol. 2002;61:197–211.

    Article  PubMed  Google Scholar 

  15. Holst CB, Brøchner CB, Vitting-Seerup K, Møllgård K. Astrogliogenesis in human fetal brain: complex spatiotemporal immunoreactivity patterns of GFAP, S100, AQP4 and YKL-40. J Anat. 2019;235:590–615.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Prinz M, Priller J. Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat Rev Neurosci. 2014;15:300–12.

    Article  CAS  PubMed  Google Scholar 

  17. Ajami B, Bennett JL, Krieger C, Tetzlaff W, Rossi FMV. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat Neurosci. 2007;10:1538–43.

    Article  CAS  PubMed  Google Scholar 

  18. Mildner A, Schmidt H, Nitsche M, Merkler D, Hanisch U-K, Mack M, et al. Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nat Neurosci. 2007;10:1544–53.

    Article  CAS  PubMed  Google Scholar 

  19. Hevner RF, Hodge RD, Daza RAM, Englund C. Transcription factors in glutamatergic neurogenesis: conserved programs in neocortex, cerebellum, and adult hippocampus. Neurosci Res. 2006;55:223–33.

    Article  CAS  PubMed  Google Scholar 

  20. Kelsom C, Lu W. Development and specification of GABAergic cortical interneurons. Cell Biosci. 2013;3:19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hevner RF. Layer-specific markers as probes for neuron type identity in human neocortex and malformations of cortical development. J Neuropathol Exp Neurol. 2007;66:101–9.

    Article  CAS  PubMed  Google Scholar 

  22. Shibata M, Gulden FO, Sestan N. From trans to cis: transcriptional regulatory networks in neocortical development. Trends Genet. 2015;31:77–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Koenderink MJ, Uylings HB. Postnatal maturation of layer V pyramidal neurons in the human prefrontal cortex. A quantitative Golgi analysis. Brain Res. 1995;678:233–43.

    Article  PubMed  Google Scholar 

  24. Yeung MSY, Zdunek S, Bergmann O, Bernard S, Salehpour M, Alkass K, et al. Dynamics of oligodendrocyte generation and myelination in the human brain. Cell. 2014;159:766–74.

    Article  CAS  PubMed  Google Scholar 

  25. Petanjek Z, Judaš M, Šimic G, Rasin MR, Uylings HBM, Rakic P, et al. Extraordinary neoteny of synaptic spines in the human prefrontal cortex. Proc Natl Acad Sci USA. 2011;108:13281–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lambe EK, Krimer LS, Goldman-Rakic PS. Differential postnatal development of catecholamine and serotonin inputs to identified neurons in prefrontal cortex of rhesus monkey. J Neurosci. 2000;20:8780–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Gejman PV, Sanders AR, Duan J. The role of genetics in the etiology of schizophrenia. Psychiatr Clin North Am. 2010;33:35–66.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Pardiñas AF, Holmans P, Pocklington AJ, Escott-Price V, Ripke S, Carrera N, et al. Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Nat Genet 2018;50:381–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Birnbaum R, Jaffe AE, Chen Q, Hyde TM, Kleinman JE, Weinberger DR. Investigation of the prenatal expression patterns of 108 schizophrenia-associated genetic loci. Biol Psychiatry. 2015;77:e43–51.

    Article  CAS  PubMed  Google Scholar 

  30. Gulsuner S, Walsh T, Watts AC, Lee MK, Thornton AM, Casadei S, et al. Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network. Cell. 2013;154:518–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Susser ES, Lin SP. Schizophrenia after prenatal exposure to the Dutch Hunger Winter of 1944-5. Arch Gen Psychiatry. 1992;49:983–8.

    Article  CAS  PubMed  Google Scholar 

  32. Cannon M, Jones PB, Murray RM. Obstetric complications and schizophrenia: historical and meta-analytic review. Am J Psychiatry. 2002;159:1080–92.

    Article  PubMed  Google Scholar 

  33. Vassos E, Pedersen CB, Murray RM, Collier DA, Lewis CM. Meta-analysis of the association of urbanicity with schizophrenia. Schizophr Bull. 2012;38:1118–23.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Ursini G, Punzi G, Chen Q, Marenco S, Robinson JF, Porcelli A, et al. Convergence of placenta biology and genetic risk for schizophrenia. Nat Med. 2018;24:792–801.

    Article  CAS  PubMed  Google Scholar 

  35. Filatova S, Koivumaa-Honkanen H, Hirvonen N, Freeman A, Ivandic I, Hurtig T, et al. Early motor developmental milestones and schizophrenia: a systematic review and meta-analysis. Schizophr Res. 2017;188:13–20.

    Article  CAS  PubMed  Google Scholar 

  36. Reichenberg A, Caspi A, Harrington H, Houts R, Keefe RSE, Murray RM, et al. Static and dynamic cognitive deficits in childhood preceding adult schizophrenia: a 30-year study. Am J Psychiatry. 2010;167:160–9.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Jones P. Child developmental risk factors for adult schizophrenia in the British 1946 birth cohort. Lancet. 1994;344:1398–402.

    Article  CAS  PubMed  Google Scholar 

  38. Uhlhaas PJ, Singer W. Abnormal neural oscillations and synchrony in schizophrenia. Nat Rev Neurosci. 2010;11:100–13.

    Article  CAS  PubMed  Google Scholar 

  39. Lewis DA, Curley AA, Glausier JR, Volk DW. Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia. Trends Neurosci. 2012;35:57–67.

    Article  CAS  PubMed  Google Scholar 

  40. Weinberger DR, Levitt P. Neurodevelopmental origins of schizophrenia. In: Weinberger DR, Harrison PJ, editors. Schizophrenia. 3rd ed. West Sussex, UK: Blackwell Publishing Ltd; 2011. p. 393–412.

  41. Nakazawa K, Zsiros V, Jiang Z, Nakao K, Kolata S, Zhang S, et al. GABAergic interneuron origin of schizophrenia pathophysiology. Neuropharmacology. 2012;62:1574–83.

    Article  CAS  PubMed  Google Scholar 

  42. Takahashi N, Sakurai T, Davis KL, Buxbaum JD. Linking oligodendrocyte and myelin dysfunction to neurocircuitry abnormalities in schizophrenia. Prog Neurobiol. 2011;93:13–24.

    Article  CAS  PubMed  Google Scholar 

  43. Yu H, Bi W, Liu C, Zhao Y, Zhang D, Yue W. A hypothesis-driven pathway analysis reveals myelin-related pathways that contribute to the risk of schizophrenia and bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2014;51:140–5.

    Article  CAS  PubMed  Google Scholar 

  44. Duncan LE, Holmans PA, Lee PH, O’Dushlaine CT, Kirby AW, Smoller JW, et al. Pathway analyses implicate glial cells in schizophrenia. PLoS ONE. 2014;9:e89441.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Neniskyte U, Gross CT. Errant gardeners: glial-cell-dependent synaptic pruning and neurodevelopmental disorders. Nat Rev Neurosci. 2017;18:658–70.

    Article  CAS  PubMed  Google Scholar 

  46. Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Kamitaki N, et al. Schizophrenia risk from complex variation of complement component 4. Nature. 2016;530:177–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Sellgren CM, Gracias J, Watmuff B, Biag JD, Thanos JM, Whittredge PB, et al. Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning. Nat Neurosci. 2019;22:374–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Onwordi EC, Halff EF, Whitehurst T, Mansur A, Cotel M-C, Wells L, et al. Synaptic density marker SV2A is reduced in schizophrenia patients and unaffected by antipsychotics in rats. Nat Commun. 2020;11:246.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Geisler S, Coller J. RNA in unexpected places: long non-coding RNA functions in diverse cellular contexts. Nat Rev Mol Cell Biol. 2013;14:699–712.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Schmiedel JM, Klemm SL, Zheng Y, Sahay A, Blüthgen N, Marks DS, et al. Gene expression. MicroRNA control of protein expression noise. Science. 2015;348:128–32.

    Article  CAS  PubMed  Google Scholar 

  51. Perino M, Veenstra GJC. Chromatin control of developmental dynamics and plasticity. Dev Cell. 2016;38:610–20.

    Article  CAS  PubMed  Google Scholar 

  52. Thurman RE, Rynes E, Humbert R, Vierstra J, Maurano MT, Haugen E, et al. The accessible chromatin landscape of the human genome. Nature. 2012;489:75–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Follert P, Cremer H, Béclin C. MicroRNAs in brain development and function: a matter of flexibility and stability. Front Mol Neurosci. 2014;7:5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Derrien T, Johnson R, Bussotti G, Tanzer A, Djebali S, Tilgner H, et al. The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res. 2012;22:1775–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Andersen RE, Lim DA. Forging our understanding of lncRNAs in the brain. Cell Tissue Res. 2018;371:55–71.

    Article  CAS  PubMed  Google Scholar 

  56. Hall LL, Carone DM, Gomez AV, Kolpa HJ, Byron M, Mehta N, et al. Stable C0T-1 repeat RNA is abundant and is associated with euchromatic interphase chromosomes. Cell. 2014;156:907–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Cech TR, Steitz JA. The noncoding RNA revolution-trashing old rules to forge new ones. Cell. 2014;157:77–94.

    Article  CAS  PubMed  Google Scholar 

  58. Iijima T, Hidaka C, Iijima Y. Spatio-temporal regulations and functions of neuronal alternative RNA splicing in developing and adult brains. Neurosci Res. 2016;109:1–8.

    Article  CAS  PubMed  Google Scholar 

  59. Li S, Mason CE. The pivotal regulatory landscape of RNA modifications. Annu Rev Genom Hum Genet. 2014;15:127–50.

    Article  CAS  Google Scholar 

  60. Gerstberger S, Hafner M, Tuschl T. A census of human RNA-binding proteins. Nat Rev Genet. 2014;15:829–45.

    Article  CAS  PubMed  Google Scholar 

  61. Tilgner H, Knowles DG, Johnson R, Davis CA, Chakrabortty S, Djebali S, et al. Deep sequencing of subcellular RNA fractions shows splicing to be predominantly co-transcriptional in the human genome but inefficient for lncRNAs. Genome Res. 2012;22:1616–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A, et al. Landscape of transcription in human cells. Nature. 2012;489:101–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zaghlool A, Ameur A, Nyberg L, Halvardson J, Grabherr M, Cavelier L, et al. Efficient cellular fractionation improves RNA sequencing analysis of mature and nascent transcripts from human tissues. BMC Biotechnol. 2013;13:99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Solnestam BW, Stranneheim H, Hällman J, Käller M, Lundberg E, Lundeberg J, et al. Comparison of total and cytoplasmic mRNA reveals global regulation by nuclear retention and miRNAs. BMC Genom. 2012;13:574.

    Article  CAS  Google Scholar 

  65. Pandya-Jones A, Bhatt DM, Lin C-H, Tong A-J, Smale ST, Black DL. Splicing kinetics and transcript release from the chromatin compartment limit the rate of lipid A-induced gene expression. RNA. 2013;19:811–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Prasanth KV, Prasanth SG, Xuan Z, Hearn S, Freier SM, Bennett CF, et al. Regulating gene expression through RNA nuclear retention. Cell. 2005;123:249–63.

    Article  CAS  PubMed  Google Scholar 

  67. Mauger O, Lemoine F, Scheiffele P. Targeted intron retention and excision for rapid gene regulation in response to neuronal activity. Neuron. 2016;92:1266–78.

    Article  CAS  PubMed  Google Scholar 

  68. Bahar Halpern K, Caspi I, Lemze D, Levy M, Landen S, Elinav E, et al. Nuclear retention of mRNA in mammalian tissues. Cell Rep. 2015;13:2653–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Battich N, Stoeger T, Pelkmans L. Control of transcript variability in single mammalian cells. Cell. 2015;163:1596–610.

    Article  CAS  PubMed  Google Scholar 

  70. Medioni C, Mowry K, Besse F. Principles and roles of mRNA localization in animal development. Development. 2012;139:3263–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Price AJ, Hwang T, Tao R, Burke EE, Rajpurohit A, Shin JH, et al. Characterizing the nuclear and cytoplasmic transcriptomes in developing and mature human cortex uncovers new insight into psychiatric disease gene regulation. Genome Res. 2020;30:1–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Jaffe AE, Shin J, Collado-Torres L, Leek JT, Tao R, Li C, et al. Developmental regulation of human cortex transcription and its clinical relevance at single base resolution. Nat Neurosci. 2015;18:154–61.

    Article  CAS  PubMed  Google Scholar 

  73. Beveridge NJ, Santarelli DM, Wang X, Tooney PA, Webster MJ, Weickert CS, et al. Maturation of the human dorsolateral prefrontal cortex coincides with a dynamic shift in microRNA expression. Schizophr Bull. 2014;40:399–409.

    Article  PubMed  Google Scholar 

  74. Zhang X, Chen MH, Wu X, Kodani A, Fan J, Doan R, et al. Cell-type-specific alternative splicing governs cell fate in the developing cerebral cortex. Cell. 2016;166:1147–62.e15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Hwang T, Park C-K, Leung AKL, Gao Y, Hyde TM, Kleinman JE, et al. Dynamic regulation of RNA editing in human brain development and disease. Nat Neurosci. 2016;19:1093–9.

    Article  CAS  PubMed  Google Scholar 

  76. Boutz PL, Bhutkar A, Sharp PA. Detained introns are a novel, widespread class of post-transcriptionally spliced introns. Genes Dev. 2015;29:63–80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Wong JJ-L, Ritchie W, Ebner OA, Selbach M, Wong JWH, Huang Y, et al. Orchestrated intron retention regulates normal granulocyte differentiation. Cell. 2013;154:583–95.

    Article  CAS  PubMed  Google Scholar 

  78. Yap K, Lim ZQ, Khandelia P, Friedman B, Makeyev EV. Coordinated regulation of neuronal mRNA steady-state levels through developmentally controlled intron retention. Genes Dev. 2012;26:1209–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Braunschweig U, Gueroussov S, Plocik AM, Graveley BR, Blencowe BJ. Dynamic integration of splicing within gene regulatory pathways. Cell. 2013;152:1252–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Chen L. Characterization and comparison of human nuclear and cytosolic editomes. Proc Natl Acad Sci USA. 2013;110:E2741–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Mariño-Ramírez L, Kann MG, Shoemaker BA, Landsman D. Histone structure and nucleosome stability. Expert Rev Proteom. 2005;2:719–29.

    Article  Google Scholar 

  82. Chen T, Dent SYR. Chromatin modifiers and remodellers: regulators of cellular differentiation. Nat Rev Genet. 2014;15:93–106.

    Article  CAS  PubMed  Google Scholar 

  83. Hota SK, Bruneau BG. ATP-dependent chromatin remodeling during mammalian development. Development. 2016;143:2882–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Jenuwein T, Allis CD. Translating the histone code. Science. 2001;293:1074–80.

    Article  CAS  PubMed  Google Scholar 

  85. Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Res. 2011;21:381–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Lachner M, O’Carroll D, Rea S, Mechtler K, Jenuwein T. Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature. 2001;410:116–20.

    Article  CAS  PubMed  Google Scholar 

  87. Delaneau O, Zazhytska M, Borel C, Giannuzzi G, Rey G, Howald C, et al. Chromatin three-dimensional interactions mediate genetic effects on gene expression. Science. 2019;364. https://doi.org/10.1126/science.aat8266.

  88. Cheung I, Shulha HP, Jiang Y, Matevossian A, Wang J, Weng Z, et al. Developmental regulation and individual differences of neuronal H3K4me3 epigenomes in the prefrontal cortex. Proc Natl Acad Sci USA. 2010;107:8824–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Won H, de la Torre-Ubieta L, Stein JL, Parikshak NN, Huang J, Opland CK, et al. Chromosome conformation elucidates regulatory relationships in developing human brain. Nature. 2016;538:523–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Su Y, Shin J, Zhong C, Wang S, Roychowdhury P, Lim J, et al. Neuronal activity modifies the chromatin accessibility landscape in the adult brain. Nat Neurosci. 2017;20:476–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Zhu J, Adli M, Zou JY, Verstappen G, Coyne M, Zhang X, et al. Genome-wide chromatin state transitions associated with developmental and environmental cues. Cell. 2013;152:642–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Rodenhiser D, Mann M. Epigenetics and human disease: translating basic biology into clinical applications. CMAJ. 2006;174:341–8.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Smith ZD, Meissner A. DNA methylation: roles in mammalian development. Nat Rev Genet. 2013;14:204–20.

    Article  CAS  PubMed  Google Scholar 

  94. Feng J, Zhou Y, Campbell SL, Le T, Li E, Sweatt JD, et al. Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons. Nat Neurosci. 2010;13:423–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Stadler MB, Murr R, Burger L, Ivanek R, Lienert F, Schöler A, et al. DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature. 2011;480:490–5.

    Article  CAS  PubMed  Google Scholar 

  96. Lister R, Pelizzola M, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J, et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature. 2009;462:315–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Xie W, Schultz MD, Lister R, Hou Z, Rajagopal N, Ray P, et al. Epigenomic analysis of multilineage differentiation of human embryonic stem cells. Cell. 2013;153:1134–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Yin Y, Morgunova E, Jolma A, Kaasinen E, Sahu B, Khund-Sayeed S, et al. Impact of cytosine methylation on DNA binding specificities of human transcription factors. Science. 2017;356. https://doi.org/10.1126/science.aaj2239.

  99. Laurent L, Wong E, Li G, Huynh T, Tsirigos A, Ong CT, et al. Dynamic changes in the human methylome during differentiation. Genome Res. 2010;20:320–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Maurano MT, Wang H, John S, Shafer A, Canfield T, Lee K, et al. Role of DNA methylation in modulating transcription factor occupancy. Cell Rep. 2015;12:1184–95.

    Article  CAS  PubMed  Google Scholar 

  101. Lister R, Mukamel EA, Nery JR, Urich M, Puddifoot CA, Johnson ND, et al. Global epigenomic reconfiguration during mammalian brain development. Science. 2013;341:1237905.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. He Y, Ecker JR. Non-CG methylation in the human genome. Annu Rev Genom Hum Genet. 2015;16:55–77.

    Article  CAS  Google Scholar 

  103. Guo W, Zhang MQ, Wu H. Mammalian non-CG methylations are conserved and cell-type specific and may have been involved in the evolution of transposon elements. Sci Rep. 2016;6:32207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Perzel Mandell KA, Price AJ, Wilton R, Collado Torres L, Tao R, Eagles NJ, et al. Characterizing the dynamic and functional DNA methylation landscape in the developing human cortex. Epigenetics. 2020 (In Press).

  105. Price AJ, Collado-Torres L, Ivanov NA, Xia W, Burke EE, Shin JH, et al. Divergent neuronal DNA methylation patterns across human cortical development reveal critical periods and a unique role of CpH methylation. Genome Biol. 2019;20:196.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Guo JU, Ma DK, Mo H, Ball MP, Jang M-H, Bonaguidi MA, et al. Neuronal activity modifies the DNA methylation landscape in the adult brain. Nat Neurosci. 2011;14:1345–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Halder R, Hennion M, Vidal RO, Shomroni O, Rahman R-U, Rajput A, et al. DNA methylation changes in plasticity genes accompany the formation and maintenance of memory. Nat Neurosci. 2016;19:102–10.

    Article  CAS  PubMed  Google Scholar 

  108. Fromer M, Roussos P, Sieberts SK, Johnson JS, Kavanagh DH, Perumal TM, et al. Gene expression elucidates functional impact of polygenic risk for schizophrenia. Nat Neurosci. 2016;19:1442–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Collado-Torres L, Burke EE, Peterson A, Shin J, Straub RE, Rajpurohit A, et al. Regional heterogeneity in gene expression, regulation, and coherence in the frontal cortex and hippocampus across development and schizophrenia. Neuron. 2019;103:203–16.e8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Gandal MJ, Zhang P, Hadjimichael E, Walker RL, Chen C, Liu S, et al. Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder. Science. 2018;362. https://doi.org/10.1126/science.aat8127.

  111. Jaffe AE, Hoeppner DJ, Saito T, Blanpain L, Ukaigwe J, Burke EE, et al. Profiling gene expression in the human dentate gyrus granule cell layer reveals insights into schizophrenia and its genetic risk. Nat Neurosci. 2020. https://doi.org/10.1038/s41593-020-0604-z.

  112. Li M, Jaffe AE, Straub RE, Tao R, Shin JH, Wang Y, et al. A human-specific AS3MT isoform and BORCS7 are molecular risk factors in the 10q24.32 schizophrenia-associated locus. Nat Med. 2016;22:649–56.

    Article  CAS  PubMed  Google Scholar 

  113. Jaffe AE, Straub RE, Shin JH, Tao R, Gao Y, Collado-Torres L, et al. Developmental and genetic regulation of the human cortex transcriptome illuminate schizophrenia pathogenesis. Nat Neurosci. 2018;21:1117–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Geaghan M, Cairns MJ. Microrna and posttranscriptional dysregulation in psychiatry. Biol Psychiatry. 2015;78:231–9.

    Article  CAS  PubMed  Google Scholar 

  115. Mahmoudi E, Cairns MJ. MiR-137: an important player in neural development and neoplastic transformation. Mol Psychiatry. 2017;22:44–55.

    Article  CAS  PubMed  Google Scholar 

  116. Wright C, Gupta CN, Chen J, Patel V, Calhoun VD, Ehrlich S, et al. Polymorphisms in MIR137HG and microRNA-137-regulated genes influence gray matter structure in schizophrenia. Transl Psychiatry. 2016;6:e724.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Wright C, Calhoun VD, Ehrlich S, Wang L, Turner JA, Bizzozero NIP-. Meta gene set enrichment analyses link miR-137-regulated pathways with schizophrenia risk. Front Genet. 2015;6:147.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Walker RL, Ramaswami G, Hartl C, Mancuso N, Gandal MJ, de la Torre-Ubieta L, et al. Genetic control of expression and splicing in developing human brain informs disease mechanisms. Cell. 2019;179:750–71.e22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. O’Brien HE, Hannon E, Hill MJ, Toste CC, Robertson MJ, Morgan JE, et al. Expression quantitative trait loci in the developing human brain and their enrichment in neuropsychiatric disorders. Genome Biol. 2018;19:194.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Finucane HK, Reshef YA, Anttila V, Slowikowski K, Gusev A, Byrnes A, et al. Heritability enrichment of specifically expressed genes identifies disease-relevant tissues and cell types. Nat Genet. 2018;50:621–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Calderon D, Bhaskar A, Knowles DA, Golan D, Raj T, Fu AQ, et al. Inferring relevant cell types for complex traits by using single-cell gene expression. Am J Hum Genet. 2017;101:686–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Skene NG, Bryois J, Bakken TE, Breen G, Crowley JJ, Gaspar HA, et al. Genetic identification of brain cell types underlying schizophrenia. Nat Genet. 2018;50:825–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Montano C, Taub MA, Jaffe A, Briem E, Feinberg JI, Trygvadottir R, et al. Association of DNA methylation differences with schizophrenia in an epigenome-wide association study. JAMA Psychiatry. 2016;73:506–14.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Jaffe AE, Gao Y, Deep-Soboslay A, Tao R, Hyde TM, Weinberger DR, et al. Mapping DNA methylation across development, genotype and schizophrenia in the human frontal cortex. Nat Neurosci. 2016;19:40–47.

    Article  CAS  PubMed  Google Scholar 

  125. Viana J, Hannon E, Dempster E, Pidsley R, Macdonald R, Knox O, et al. Schizophrenia-associated methylomic variation: molecular signatures of disease and polygenic risk burden across multiple brain regions. Hum Mol Genet. 2017;26:210–25.

    CAS  PubMed  Google Scholar 

  126. Hannon E, Dempster E, Viana J, Burrage J, Smith AR, Macdonald R, et al. An integrated genetic-epigenetic analysis of schizophrenia: evidence for co-localization of genetic associations and differential DNA methylation. Genome Biol. 2016;17:176.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Bryois J, Garrett ME, Song L, Safi A, Giusti-Rodriguez P, Johnson GD, et al. Evaluation of chromatin accessibility in prefrontal cortex of individuals with schizophrenia. Nat Commun. 2018;9:3121.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Jaffe AE, Irizarry RA. Accounting for cellular heterogeneity is critical in epigenome-wide association studies. Genome Biol. 2014;15:R31.

    Article  PubMed  PubMed Central  Google Scholar 

  129. Li M, Santpere G, Imamura Kawasawa Y, Evgrafov OV, Gulden FO, Pochareddy S, et al. Integrative functional genomic analysis of human brain development and neuropsychiatric risks. Science. 2018;362. https://doi.org/10.1126/science.aat7615.

  130. Rajarajan P, Borrman T, Liao W, Schrode N, Flaherty E, Casiño C, et al. Neuron-specific signatures in the chromosomal connectome associated with schizophrenia risk. Science. 2018;362. https://doi.org/10.1126/science.aat4311.

  131. Hannon E, Spiers H, Viana J, Pidsley R, Burrage J, Murphy TM, et al. Methylation QTLs in the developing brain and their enrichment in schizophrenia risk loci. Nat Neurosci. 2016;19:48–54.

    Article  CAS  PubMed  Google Scholar 

  132. Rizzardi LF, Hickey PF, Rodriguez DiBlasi V, Tryggvadóttir R, Callahan CM, Idrizi A, et al. Neuronal brain-region-specific DNA methylation and chromatin accessibility are associated with neuropsychiatric trait heritability. Nat Neurosci. 2019;22:307–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Girdhar K, Hoffman GE, Jiang Y, Brown L, Kundakovic M, Hauberg ME, et al. Cell-specific histone modification maps in the human frontal lobe link schizophrenia risk to the neuronal epigenome. Nat Neurosci. 2018;21:1126–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. de la Torre-Ubieta L, Stein JL, Won H, Opland CK, Liang D, Lu D, et al. The dynamic landscape of open chromatin during human cortical neurogenesis. Cell. 2018;172:289–304.e18.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Polioudakis D, de la Torre-Ubieta L, Langerman J, Elkins AG, Shi X, Stein JL, et al. A Single-Cell Transcriptomic Atlas of Human Neocortical Development during Mid-gestation. Neuron. 2019;103:785–801.e8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Braun PR, Han S, Hing B, Nagahama Y, Gaul LN, Heinzman JT, et al. Genome-wide DNA methylation comparison between live human brain and peripheral tissues within individuals. Transl Psychiatry. 2019;9:47.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Shin J, Ming G, Song H. Decoding neural transcriptomes and epigenomes via high-throughput sequencing. Nat Neurosci. 2014;17:1463–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. McGregor K, Bernatsky S, Colmegna I, Hudson M, Pastinen T, Labbe A, et al. An evaluation of methods correcting for cell-type heterogeneity in DNA methylation studies. Genome Biol. 2016;17:84.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Guintivano J, Aryee MJ, Kaminsky ZA. A cell epigenotype specific model for the correction of brain cellular heterogeneity bias and its application to age, brain region and major depression. Epigenetics. 2013;8:290–302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, et al. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015;12:453–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Rossner MJ, Hirrlinger J, Wichert SP, Boehm C, Newrzella D, Hiemisch H, et al. Global transcriptome analysis of genetically identified neurons in the adult cortex. J Neurosci. 2006;26:9956–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Dong X, Liao Z, Gritsch D, Hadzhiev Y, Bai Y, Locascio JJ, et al. Enhancers active in dopamine neurons are a primary link between genetic variation and neuropsychiatric disease. Nat Neurosci. 2018;21:1482–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Matevossian A, Akbarian S. Neuronal nuclei isolation from human postmortem brain tissue. J Vis Exp. 2008. https://doi.org/10.3791/914.

  144. Kozlenkov A, Wang M, Roussos P, Rudchenko S, Barbu M, Bibikova M, et al. Substantial DNA methylation differences between two major neuronal subtypes in human brain. Nucleic Acids Res. 2016;44:2593–612.

    Article  PubMed  Google Scholar 

  145. Okada S, Saiwai H, Kumamaru H, Kubota K, Harada A, Yamaguchi M, et al. Flow cytometric sorting of neuronal and glial nuclei from central nervous system tissue. J Cell Physiol. 2011;226:552–8.

    Article  CAS  PubMed  Google Scholar 

  146. Ernst A, Alkass K, Bernard S, Salehpour M, Perl S, Tisdale J, et al. Neurogenesis in the striatum of the adult human brain. Cell. 2014;156:1072–83.

    Article  CAS  PubMed  Google Scholar 

  147. Sarnat HB, Nochlin D, Born DE. Neuronal nuclear antigen (NeuN): a marker of neuronal maturation in early human fetal nervous system. Brain Dev. 1998;20:88–94.

    Article  CAS  PubMed  Google Scholar 

  148. Dent MAR, Segura-Anaya E, Alva-Medina J, Aranda-Anzaldo A. NeuN/Fox-3 is an intrinsic component of the neuronal nuclear matrix. FEBS Lett. 2010;584:2767–71.

    Article  CAS  PubMed  Google Scholar 

  149. Kim KK, Adelstein RS, Kawamoto S. Identification of neuronal nuclei (NeuN) as Fox-3, a new member of the Fox-1 gene family of splicing factors. J Biol Chem. 2009;284:31052–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Unal-Cevik I, Kilinç M, Gürsoy-Ozdemir Y, Gurer G, Dalkara T. Loss of NeuN immunoreactivity after cerebral ischemia does not indicate neuronal cell loss: a cautionary note. Brain Res. 2004;1015:169–74.

    Article  CAS  PubMed  Google Scholar 

  151. Portiansky EL, Barbeito CG, Gimeno EJ, Zuccolilli GO, Goya RG. Loss of NeuN immunoreactivity in rat spinal cord neurons during aging. Exp Neurol. 2006;202:519–21.

    Article  CAS  PubMed  Google Scholar 

  152. Bakken TE, Hodge RD, Miller JA, Yao Z, Nguyen TN, Aevermann B, et al. Single-nucleus and single-cell transcriptomes compared in matched cortical cell types. PLoS ONE. 2018;13:e0209648.

    Article  PubMed  PubMed Central  Google Scholar 

  153. Svensson V, Vento-Tormo R, Teichmann SA. Exponential scaling of single-cell RNA-seq in the past decade. Nat Protoc. 2018;13:599–604.

    Article  CAS  PubMed  Google Scholar 

  154. Schwartzman O, Tanay A. Single-cell epigenomics: techniques and emerging applications. Nat Rev Genet. 2015;16:716–26.

    Article  CAS  PubMed  Google Scholar 

  155. Picelli S, Faridani OR, Björklund AK, Winberg G, Sagasser S, Sandberg R. Full-length RNA-seq from single cells using Smart-seq2. Nat Protoc. 2014;9:171–81.

    Article  CAS  PubMed  Google Scholar 

  156. Macosko EZ, Basu A, Satija R, Nemesh J, Shekhar K, Goldman M, et al. Highly parallel genome-wide expression profiling of individual cells using nanoliter droplets. Cell. 2015;161:1202–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Gupta I, Collier PG, Haase B, Mahfouz A, Joglekar A, Floyd T, et al. Single-cell isoform RNA sequencing characterizes isoforms in thousands of cerebellar cells. Nat Biotechnol. 2018. https://doi.org/10.1038/nbt.4259.

  158. Lake BB, Ai R, Kaeser GE, Salathia NS, Yung YC, Liu R, et al. Neuronal subtypes and diversity revealed by single-nucleus RNA sequencing of the human brain. Science. 2016;352:1586–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Lacar B, Linker SB, Jaeger BN, Krishnaswami SR, Barron JJ, Kelder MJE, et al. Nuclear RNA-seq of single neurons reveals molecular signatures of activation. Nat Commun. 2016;7:11022.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Krishnaswami SR, Grindberg RV, Novotny M, Venepally P, Lacar B, Bhutani K, et al. Using single nuclei for RNA-seq to capture the transcriptome of postmortem neurons. Nat Protoc. 2016;11:499–524.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Darmanis S, Sloan SA, Zhang Y, Enge M, Caneda C, Shuer LM, et al. A survey of human brain transcriptome diversity at the single cell level. Proc Natl Acad Sci USA. 2015;112:7285–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Habib N, Avraham-Davidi I, Basu A, Burks T, Shekhar K, Hofree M, et al. Massively parallel single-nucleus RNA-seq with DroNc-seq. Nat Methods. 2017;14:955–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Luo C, Keown CL, Kurihara L, Zhou J, He Y, Li J, et al. Single-cell methylomes identify neuronal subtypes and regulatory elements in mammalian cortex. Science. 2017;357:600–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Pollen AA, Nowakowski TJ, Shuga J, Wang X, Leyrat AA, Lui JH, et al. Low-coverage single-cell mRNA sequencing reveals cellular heterogeneity and activated signaling pathways in developing cerebral cortex. Nat Biotechnol. 2014;32:1053–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Fan X, Dong J, Zhong S, Wei Y, Wu Q, Yan L, et al. Spatial transcriptomic survey of human embryonic cerebral cortex by single-cell RNA-seq analysis. Cell Res. 2018;28:730–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Zhong S, Zhang S, Fan X, Wu Q, Yan L, Dong J, et al. A single-cell RNA-seq survey of the developmental landscape of the human prefrontal cortex. Nature. 2018;555:524–8.

    Article  CAS  PubMed  Google Scholar 

  167. Eng C-HL, Lawson M, Zhu Q, Dries R, Koulena N, Takei Y, et al. Transcriptome-scale super-resolved imaging in tissues by RNA seqFISH. Nature. 2019;568:235–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Rodriques SG, Stickels RR, Goeva A, Martin CA, Murray E, Vanderburg CR, et al. Slide-seq: a scalable technology for measuring genome-wide expression at high spatial resolution. Science. 2019;363:1463–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Maynard KR, Jaffe AE, Martinowich K. Spatial transcriptomics: putting genome-wide expression on the map. Neuropsychopharmacology. 2020;45:232–3.

    Article  CAS  PubMed  Google Scholar 

  170. Fullard JF, Charney AW, Voloudakis G, Uzilov AV, Haroutunian V, Roussos P. Assessment of somatic single-nucleotide variation in brain tissue of cases with schizophrenia. Transl Psychiatry. 2019;9:21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  171. Birnbaum R, Weinberger DR. Genetic insights into the neurodevelopmental origins of schizophrenia. Nat Rev Neurosci. 2017;18:727–40.

    Article  CAS  PubMed  Google Scholar 

  172. WHO Multicentre Growth Reference Study Group. WHO Child Growth Standards based on length/height, weight and age. Acta Paediatr Suppl. 2006;450:76–85.

    Google Scholar 

  173. Johnson JS, Newport EL. Critical period effects in second language learning: The influence of maturational state on the acquisition of English as a second language. Cogn Psychol. 1989;21:60–99.

    Article  CAS  PubMed  Google Scholar 

  174. Catts VS, Fung SJ, Long LE, Joshi D, Vercammen A, Allen KM, et al. Rethinking schizophrenia in the context of normal neurodevelopment. Front Cell Neurosci. 2013;7:60.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank Emily E. Burke for contributing to the figure in this publication.

Funding

This work is supported by the generous donations of the Lieber and Maltz families. In addition, AJP was supported by R21MH105853, R01MH112751, and U01MH106893; AEJ was supported by R21MH105853 and R01MH112751; and DRW was supported by R21MH105853 and U01MH106893.

Author information

Authors and Affiliations

  1. Lieber Institute for Brain Development, Baltimore, MD, USA

    Amanda J. Price, Andrew E. Jaffe & Daniel R. Weinberger

  2. Department of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Amanda J. Price, Andrew E. Jaffe & Daniel R. Weinberger

  3. Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Andrew E. Jaffe & Daniel R. Weinberger

  4. Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Andrew E. Jaffe & Daniel R. Weinberger

  5. Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    Andrew E. Jaffe

  6. Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    Andrew E. Jaffe

  7. Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Daniel R. Weinberger

Authors
  1. Amanda J. Price
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrew E. Jaffe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daniel R. Weinberger
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AJP: conceptualization and writing—original draft preparation, writing—review and editing. DRW: writing—review and editing. AEJ: writing—review and editing.

Corresponding author

Correspondence to Daniel R. Weinberger.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Price, A.J., Jaffe, A.E. & Weinberger, D.R. Cortical cellular diversity and development in schizophrenia. Mol Psychiatry 26, 203–217 (2021). https://doi.org/10.1038/s41380-020-0775-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-020-0775-8

This article is cited by

Search

Advanced search

Quick links