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Impact of schizophrenia GWAS loci converge onto distinct pathways in cortical interneurons vs glutamatergic neurons during development

Molecular Psychiatry volume 27, pages 4218–4233 (2022)Cite this article

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Abstract

Remarkable advances have been made in schizophrenia (SCZ) GWAS, but gleaning biological insight from these loci is challenging. Genetic influences on gene expression (e.g., eQTLs) are cell type-specific, but most studies that attempt to clarify GWAS loci’s influence on gene expression have employed tissues with mixed cell compositions that can obscure cell-specific effects. Furthermore, enriched SCZ heritability in the fetal brain underscores the need to study the impact of SCZ risk loci in specific developing neurons. MGE-derived cortical interneurons (cINs) are consistently affected in SCZ brains and show enriched SCZ heritability in human fetal brains. We identified SCZ GWAS risk genes that are dysregulated in iPSC-derived homogeneous populations of developing SCZ cINs. These SCZ GWAS loci differential expression (DE) genes converge on the PKC pathway. Their disruption results in PKC hyperactivity in developing cINs, leading to arborization deficits. We show that the fine-mapped GWAS locus in the ATP2A2 gene of the PKC pathway harbors enhancer marks by ATACseq and ChIPseq, and regulates ATP2A2 expression. We also generated developing glutamatergic neurons (GNs), another population with enriched SCZ heritability, and confirmed their functionality after transplantation into the mouse brain. Then, we identified SCZ GWAS risk genes that are dysregulated in developing SCZ GNs. GN-specific SCZ GWAS loci DE genes converge on the ion transporter pathway, distinct from those for cINs. Disruption of the pathway gene CACNA1D resulted in deficits of Ca2+ currents in developing GNs, suggesting compromised neuronal function by GWAS loci pathway deficits during development. This study allows us to identify cell type-specific and developmental stage-specific mechanisms of SCZ risk gene function, and may aid in identifying mechanism-based novel therapeutic targets.

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Fig. 1: SCZ GWAS loci DE genes converge onto PKC pathway in developing cINs.
Fig. 2: ATP2A2 and DGKI expression regulates PKC activity.
Fig. 3: SCZ risk loci regulate ATP2A2 expression.
Fig. 4: SCZ GWAS loci DE genes converge onto ion transporter pathway in developing glutamatergic neurons.
Fig. 5: CACNA1D dysregulation impairs Ca2+ currents in developing glutamatergic neurons.

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References

  1. Sullivan PF, Kendler KS, Neale MC. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry. 2003;60:1187–92.

    PubMed  Google Scholar 

  2. Weinberger DR. Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry. 1987;44:660–9.

    CAS  PubMed  Google Scholar 

  3. Carpenter WT Jr., Buchanan RW. Schizophrenia. N Engl J Med. 1994;330:681–90.

    PubMed  Google Scholar 

  4. Ripke S, Neale BM, Corvin A, Walters JTR, Farh KH, Holmans PA, et al. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421–7.

    CAS  PubMed Central  Google Scholar 

  5. Wainberg M, Sinnott-Armstrong N, Mancuso N, Barbeira AN, Knowles DA, Golan D, et al. Opportunities and challenges for transcriptome-wide association studies. Nat Genet. 2019;51:592–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 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;103:203–216.e8.

  7. Zhang K, Hocker JD, Miller M, Hou X, Chiou J, Poirion OB, et al. A single-cell atlas of chromatin accessibility in the human genome. Cell. 2021;184:5985–6001.e5919.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Finucane HK, Bulik-Sullivan B, Gusev A, Trynka G, Reshef Y, Loh PR, et al. Partitioning heritability by functional annotation using genome-wide association summary statistics. Nat Genet. 2015;47:1228–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Schork AJ, Won H, Appadurai V, Nudel R, Gandal M, Delaneau O, et al. A genome-wide association study of shared risk across psychiatric disorders implicates gene regulation during fetal neurodevelopment. Nat Neurosci. 2019;22:353–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Sey NYA, Hu B, Mah W, Fauni H, McAfee JC, Rajarajan P, et al. A computational tool (H-MAGMA) for improved prediction of brain-disorder risk genes by incorporating brain chromatin interaction profiles. Nat Neurosci. 2020;23:583–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Marin O. Interneuron dysfunction in psychiatric disorders. Nat Rev Neurosci. 2012;13:107–20.

    CAS  PubMed  Google Scholar 

  12. Kalus P, Bondzio J, Federspiel A, Muller TJ, Zuschratter W. Cell-type specific alterations of cortical interneurons in schizophrenic patients. Neuroreport. 2002;13:713–7.

    PubMed  Google Scholar 

  13. Guidotti A, Auta J, Davis JM, Di-Giorgi-Gerevini V, Dwivedi Y, Grayson DR, et al. Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study. Arch Gen Psychiatry. 2000;57:1061–9.

    CAS  PubMed  Google Scholar 

  14. Volk D, Austin M, Pierri J, Sampson A, Lewis D. GABA transporter-1 mRNA in the prefrontal cortex in schizophrenia: decreased expression in a subset of neurons. Am J Psychiatry. 2001;158:256–65.

    CAS  PubMed  Google Scholar 

  15. Reynolds GP, Abdul-Monim Z, Neill JC, Zhang ZJ. Calcium binding protein markers of GABA deficits in schizophrenia-postmortem studies and animal models. Neurotox Res. 2004;6:57–61.

    PubMed  Google Scholar 

  16. Fung SJ, Webster MJ, Sivagnanasundaram S, Duncan C, Elashoff M, Weickert CS. Expression of interneuron markers in the dorsolateral prefrontal cortex of the developing human and in schizophrenia. Am J Psychiatry. 2010;167:1479–88.

    PubMed  Google Scholar 

  17. Hashimoto T, Arion D, Unger T, Maldonado-Aviles JG, Morris HM, Volk DW, et al. Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia. Mol Psychiatry. 2008;13:147–61.

    CAS  PubMed  Google Scholar 

  18. Hoftman GD, Volk DW, Bazmi HH, Li S, Sampson AR, Lewis DA. Altered cortical expression of GABA-related genes in schizophrenia: illness progression vs developmental disturbance. Schizophrenia Bull. 2013;41:180–91.

  19. Wang AY, Lohmann KM, Yang CK, Zimmerman EI, Pantazopoulos H, Herring N, et al. Bipolar disorder type 1 and schizophrenia are accompanied by decreased density of parvalbumin- and somatostatin-positive interneurons in the parahippocampal region. Acta Neuropathol. 2011;122:615–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Morris HM, Hashimoto T, Lewis DA. Alterations in somatostatin mRNA expression in the dorsolateral prefrontal cortex of subjects with schizophrenia or schizoaffective disorder. Cereb Cortex. 2008;18:1575–87.

    PubMed  Google Scholar 

  21. Meyer-Lindenberg A. From maps to mechanisms through neuroimaging of schizophrenia. Nature. 2010;468:194–202.

    CAS  PubMed  Google Scholar 

  22. Jaaro-Peled H, Ayhan Y, Pletnikov MV, Sawa A. Review of pathological hallmarks of schizophrenia: comparison of genetic models with patients and nongenetic models. Schizophrenia Bull. 2010;36:301–13.

    Google Scholar 

  23. Lewis DA, Hashimoto T, Volk DW. Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci. 2005;6:312–24.

    CAS  PubMed  Google Scholar 

  24. Fuchs EC, Zivkovic AR, Cunningham MO, Middleton S, Lebeau FE, Bannerman DM, et al. Recruitment of parvalbumin-positive interneurons determines hippocampal function and associated behavior. Neuron. 2007;53:591–604.

    CAS  PubMed  Google Scholar 

  25. Sohal VS, Zhang F, Yizhar O, Deisseroth K. Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Nature. 2009;459:698–702.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Williams S, Boksa P. Gamma oscillations and schizophrenia. J Psychiatry Neurosci. 2010;35:75–77.

    PubMed  PubMed Central  Google Scholar 

  27. Dienel SJ, Lewis DA. Alterations in cortical interneurons and cognitive function in schizophrenia. Neurobiol Dis. 2019;131:104208.

    PubMed  Google Scholar 

  28. Lewis DA, Glantz LA, Pierri JN, Sweet RA. Altered cortical glutamate neurotransmission in schizophrenia: evidence from morphological studies of pyramidal neurons. Ann N Y Acad Sci. 2003;1003:102–12.

    CAS  PubMed  Google Scholar 

  29. 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.e788.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Song M, Pebworth M-P, Yang X, Abnousi A, Fan C, Wen J et al. Cell-type-specific 3D epigenomes in the developing human cortex. Nature 2020;587:644–9.

  31. Trevino AE, Sinnott-Armstrong N, Andersen J, Yoon S-J, Huber N, Pritchard JK, et al. Chromatin accessibility dynamics in a model of human forebrain development. Science. 2020;367:eaay1645.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Ziffra RS, Kim CN, Ross JM, Wilfert A, Turner TN, Haeussler M et al. Single-cell epigenomics reveals mechanisms of human cortical development. Nature 2021;598:205–13.

  33. Benson CA, Powell HR, Liput M, Dinham S, Freedman DA, Ignatowski TA, et al. Immune factor, TNFα, disrupts human brain organoid development similar to schizophrenia-schizophrenia increases developmental vulnerability to TNFα. Front Cell Neurosci. 2020;14:233.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Brennand KJ, Simone A, Jou J, Gelboin-Burkhart C, Tran N, Sangar S, et al. Modelling schizophrenia using human induced pluripotent stem cells. Nature. 2011;473:221–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Forrest MP, Zhang H, Moy W, McGowan H, Leites C, Dionisio LE, et al. Open chromatin profiling in hiPSC-derived neurons prioritizes functional noncoding psychiatric risk variants and highlights neurodevelopmental loci. Cell Stem Cell. 2017;21:305–31.e308.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Robicsek O, Karry R, Petit I, Salman-Kesner N, Müller FJ, Klein E, et al. Abnormal neuronal differentiation and mitochondrial dysfunction in hair follicle-derived induced pluripotent stem cells of schizophrenia patients. Mol Psychiatry. 2013;18:1067–76.

    CAS  PubMed  Google Scholar 

  37. Li J, Tran OT, Crowley TB, Moore TM, Zackai EH, Emanuel BS, et al. Association of mitochondrial biogenesis with variable penetrance of schizophrenia. JAMA Psychiatry. 2021;78:911–21.

    PubMed  Google Scholar 

  38. Linaro D, Vermaercke B, Iwata R, Ramaswamy A, Libé-Philippot B, Boubakar L et al. Xenotransplanted human cortical neurons reveal species-specific development and functional integration into mouse visual circuits. Neuron. 2019;104:972–86.e6.

  39. Camp JG, Badsha F, Florio M, Kanton S, Gerber T, Wilsch-Brauninger M, et al. Human cerebral organoids recapitulate gene expression programs of fetal neocortex development. Proc Natl Acad Sci USA 2015;112:15672–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Velasco S, Kedaigle AJ, Simmons SK, Nash A, Rocha M, Quadrato G, et al. Individual brain organoids reproducibly form cell diversity of the human cerebral cortex. Nature. 2019;570:523–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Luo C, Lancaster MA, Castanon R, Nery JR, Knoblich JA, Ecker JR. Cerebral organoids recapitulate epigenomic signatures of the human fetal brain. Cell Rep. 2016;17:3369–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Amiri A, Coppola G, Scuderi S, Wu F, Roychowdhury T, Liu F, et al. Transcriptome and epigenome landscape of human cortical development modeled in organoids. Science. 2018;362:eaat6720.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Keller G. Embryonic stem cell differentiation: emergence of a new era in biology and medicine. Genes Dev. 2005;19:1129–55.

    CAS  PubMed  Google Scholar 

  44. Zhu Z, Huangfu D. Human pluripotent stem cells: an emerging model in developmental biology. Development. 2013;140:705–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Qian X, Nguyen HaN, Song Mingxi M, Hadiono C, Ogden Sarah C, Hammack C, et al. Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure. Cell. 2016;165:1238–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Paşca AM, Sloan SA, Clarke LE, Tian Y, Makinson CD, Huber N, et al. Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nat Methods. 2015;12:671–8.

    PubMed  PubMed Central  Google Scholar 

  47. Rajarajan P, Borrman T, Liao W, Schrode N, Flaherty E, Casino C et al. Neuron-specific signatures in the chromosomal connectome associated with schizophrenia risk. Science. 2018;362:eaat4311.

  48. Cunningham M, Cho J-H, Leung A, Savvidis G, Ahn S, Moon M, et al. hPSC-derived maturing GABAergic interneurons ameliorate seizures and abnormal behavior in epileptic mice. Cell Stem Cell. 2014;15:559–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Shao Z, Noh H, Bin Kim W, Ni P, Nguyen C, Cote SE, et al. Dysregulated protocadherin-pathway activity as an intrinsic defect in induced pluripotent stem cell-derived cortical interneurons from subjects with schizophrenia. Nat Neurosci. 2019;22:229–42.

    PubMed  PubMed Central  Google Scholar 

  50. Kim T-G, Yao R, Monnell T, Cho J-H, Vasudevan A, Koh A, et al. Efficient specification of interneurons from human pluripotent stem cells by dorsoventral and rostrocaudal modulation. Stem Cells. 2014;32:1789–804.

    CAS  PubMed  Google Scholar 

  51. Nicholas CR, Chen J, Tang Y, Southwell DG, Chalmers N, Vogt D, et al. Functional maturation of hPSC-derived forebrain interneurons requires an extended timeline and mimics human neural development. Cell Stem Cell. 2013;12:573–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Zecevic N, Hu F, Jakovcevski I. Interneurons in the developing human neocortex. Dev Neurobiol. 2011;71:18–33.

    PubMed  PubMed Central  Google Scholar 

  53. Aguilar-Valles A, Luheshi GN. Alterations in cognitive function and behavioral response to amphetamine induced by prenatal inflammation are dependent on the stage of pregnancy. Psychoneuroendocrinology. 2011;36:634–48.

    CAS  PubMed  Google Scholar 

  54. Li Q, Cheung C, Wei R, Hui ES, Feldon J, Meyer U, et al. Prenatal immune challenge is an environmental risk factor for brain and behavior change relevant to schizophrenia: evidence from MRI in a mouse model. PLoS One. 2009;4:e6354.

    PubMed  PubMed Central  Google Scholar 

  55. Piper M, Beneyto M, Burne TH, Eyles DW, Lewis DA, McGrath JJ. The neurodevelopmental hypothesis of schizophrenia: convergent clues from epidemiology and neuropathology. Psychiatr Clin North Am. 2012;35:571–84.

    PubMed  Google Scholar 

  56. Xu B, Ionita-Laza I, Roos JL, Boone B, Woodrick S, Sun Y, et al. De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia. Nat Genet. 2012;44:1365–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Lin M, Pedrosa E, Shah A, Hrabovsky A, Maqbool S, Zheng D, et al. RNA-Seq of human neurons derived from iPS cells reveals candidate long non-coding RNAs involved in neurogenesis and neuropsychiatric disorders. PLoS One. 2011;6:e23356.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Gilman SR, Chang J, Xu B, Bawa TS, Gogos JA, Karayiorgou M, et al. Diverse types of genetic variation converge on functional gene networks involved in schizophrenia. Nat Neurosci. 2012;15:1723–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Ni P, Noh H, Park G-H, Shao Z, Guan Y, Park JM et al. iPSC-derived homogeneous populations of developing schizophrenia cortical interneurons have compromised mitochondrial function. Mol Psychiatry. 2020;25:2873–88.

  60. Ni P, Noh H, Shao Z, Zhu Q, Guan Y, Park JJ, et al. Large-scale generation and characterization of homogeneous populations of migratory cortical interneurons from human pluripotent stem cells. Mol Ther Methods Clin Dev. 2019;13:414–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Maroof AM, Keros S, Tyson JA, Ying SW, Ganat YM, Merkle FT, et al. Directed differentiation and functional maturation of cortical interneurons from human embryonic stem cells. Cell Stem Cell. 2013;12:559–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Liu Y, Weick JP, Liu H, Krencik R, Zhang X, Ma L, et al. Medial ganglionic eminence-like cells derived from human embryonic stem cells correct learning and memory deficits. Nat Biotechnol. 2013;31:440–7.

    PubMed  PubMed Central  Google Scholar 

  63. Pardinas 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Goto K, Kondo H. Diacylglycerol kinase in the central nervous system-molecular heterogeneity and gene expression. Chem Phys Lipids. 1999;98:109–17.

    CAS  PubMed  Google Scholar 

  65. Nakajima K, Ishiwata M, Weitemier AZ, Shoji H, Monai H, Miyamoto H et al. Brain-specific heterozygous loss-of-function of ATP2A2, endoplasmic reticulum Ca2+ pump responsible for Darier’s disease, causes behavioral abnormalities and a hyper-dopaminergic state. Hum Mol Genet. 2021;30:1762–72.

  66. Anderson A, Masuho I, Marron Fernandez de Velasco E, Nakano A, Birnbaumer L, Martemyanov KA, et al. GPCR-dependent biasing of GIRK channel signaling dynamics by RGS6 in mouse sinoatrial nodal cells. Proc Natl Acad Sci USA 2020;117:14522–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Ahlers KE, Chakravarti B, Fisher RA. RGS6 as a novel therapeutic target in CNS diseases and cancer. AAPS J. 2016;18:560–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Verbeek DS, Goedhart J, Bruinsma L, Sinke RJ, Reits EA. PKC gamma mutations in spinocerebellar ataxia type 14 affect C1 domain accessibility and kinase activity leading to aberrant MAPK signaling. J Cell Sci. 2008;121:2339–49.

    CAS  PubMed  Google Scholar 

  69. Yamamoto K, Seki T, Adachi N, Takahashi T, Tanaka S, Hide I, et al. Mutant protein kinase C gamma that causes spinocerebellar ataxia type 14 (SCA14) is selectively degraded by autophagy. Genes Cells. 2010;15:425–38.

    CAS  PubMed  Google Scholar 

  70. Alfonso SI, Callender JA, Hooli B, Antal CE, Mullin K, Sherman MA, et al. Gain-of-function mutations in protein kinase Cα (PKCα) may promote synaptic defects in Alzheimer’s disease. Sci Signal. 2016;9:ra47.

    PubMed  PubMed Central  Google Scholar 

  71. Battaini F. Protein kinase C isoforms as therapeutic targets in nervous system disease states. Pharmacol Res. 2001;44:353–61.

    CAS  PubMed  Google Scholar 

  72. Manji HK, Moore GJ, Chen G. Bipolar disorder: leads from the molecular and cellular mechanisms of action of mood stabilizers. Br J Psychiatry Suppl. 2001;41:s107–119.

    CAS  PubMed  Google Scholar 

  73. Amrollahi Z, Rezaei F, Salehi B, Modabbernia AH, Maroufi A, Esfandiari GR, et al. Double-blind, randomized, placebo-controlled 6-week study on the efficacy and safety of the tamoxifen adjunctive to lithium in acute bipolar mania. J Affect Disord. 2011;129:327–31.

    CAS  PubMed  Google Scholar 

  74. Bebchuk JM, Arfken CL, Dolan-Manji S, Murphy J, Hasanat K, Manji HK. A preliminary investigation of a protein kinase C inhibitor in the treatment of acute mania. Arch Gen Psychiatry. 2000;57:95–97.

    CAS  PubMed  Google Scholar 

  75. Yildiz A, Guleryuz S, Ankerst DP, Ongur D, Renshaw PF. Protein kinase C inhibition in the treatment of mania: a double-blind, placebo-controlled trial of tamoxifen. Arch Gen Psychiatry. 2008;65:255–63.

    CAS  PubMed  Google Scholar 

  76. Birnbaum SG, Yuan PX, Wang M, Vijayraghavan S, Bloom AK, Davis DJ, et al. Protein kinase C overactivity impairs prefrontal cortical regulation of working memory. Science. 2004;306:882–4.

    CAS  PubMed  Google Scholar 

  77. Brennan AR, Yuan P, Dickstein DL, Rocher AB, Hof PR, Manji H, et al. Protein kinase C activity is associated with prefrontal cortical decline in aging. Neurobiol Aging. 2009;30:782–92.

    CAS  PubMed  Google Scholar 

  78. Runyan JD, Moore AN, Dash PK. A role for prefrontal calcium-sensitive protein phosphatase and kinase activities in working memory. Learn Mem. 2005;12:103–10.

    PubMed  PubMed Central  Google Scholar 

  79. Calabrese B, Halpain S. Essential role for the PKC target MARCKS in maintaining dendritic spine morphology. Neuron. 2005;48:77–90.

    CAS  PubMed  Google Scholar 

  80. Callender JA, Newton AC. Conventional protein kinase C in the brain: 40 years later. Neuronal Signal. 2017;1:Ns20160005.

    PubMed  PubMed Central  Google Scholar 

  81. Tagawa K, Homma H, Saito A, Fujita K, Chen X, Imoto S, et al. Comprehensive phosphoproteome analysis unravels the core signaling network that initiates the earliest synapse pathology in preclinical Alzheimer’s disease brain. Hum Mol Genet. 2015;24:540–58.

    CAS  PubMed  Google Scholar 

  82. Garrett AM, Schreiner D, Lobas MA, Weiner JA. γ-protocadherins control cortical dendrite arborization by regulating the activity of a FAK/PKC/MARCKS signaling pathway. Neuron. 2012;74:269–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Huang L, Wang C, Zhao S, Ge R, Guan S, Wang JH. PKC and CaMK-II inhibitions coordinately rescue ischemia-induced GABAergic neuron dysfunction. Oncotarget. 2017;8:39309–22.

    PubMed  PubMed Central  Google Scholar 

  84. Chen Y, Cantrell AR, Messing RO, Scheuer T, Catterall WA. Specific modulation of Na+ channels in hippocampal neurons by protein kinase C epsilon. J Neurosci. 2005;25:507–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Carr DB, Cooper DC, Ulrich SL, Spruston N, Surmeier DJ. Serotonin receptor activation inhibits sodium current and dendritic excitability in prefrontal cortex via a protein kinase C-dependent mechanism. J Neurosci. 2002;22:6846–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Castro-Alamancos MA, Arevalo MA, Torres-Aleman I. Involvement of protein kinase C and nitric oxide in the modulation by insulin-like growth factor-I of glutamate-induced GABA release in the cerebellum. Neuroscience. 1996;70:843–7.

    CAS  PubMed  Google Scholar 

  87. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 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:eaat8127.

  89. Wang D, Liu S, Warrell J, Won H, Shi X, Navarro FCP, et al. Comprehensive functional genomic resource and integrative model for the human brain. Science. 2018;362:eaat8464.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 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:eaat7615.

  91. 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.e722.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Wang Q, Chen R, Cheng F, Wei Q, Ji Y, Yang H, et al. A Bayesian framework that integrates multi-omics data and gene networks predicts risk genes from schizophrenia GWAS data. Nat Neurosci. 2019;22:691–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Gusev A, Mancuso N, Won H, Kousi M, Finucane HK, Reshef Y, et al. Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights. Nat Genet. 2018;50:538–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 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.

    PubMed  PubMed Central  Google Scholar 

  95. Hisatsune C, Nakamura K, Kuroda Y, Nakamura T, Mikoshiba K. Amplification of Ca2+ signaling by diacylglycerol-mediated inositol 1,4,5-trisphosphate production. J Biol Chem. 2005;280:11723–30.

    CAS  PubMed  Google Scholar 

  96. Liu L, Yudin Y, Rohacs T. Diacylglycerol kinases regulate TRPV1 channel activity. J Biol Chem. 2020;295:8174–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Kunkel MT, Newton AC. Calcium transduces plasma membrane receptor signals to produce diacylglycerol at Golgi membranes. J Biol Chem. 2010;285:22748–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Young KW, Nash MS, Challiss RA, Nahorski SR. Role of Ca2+ feedback on single cell inositol 1,4,5-trisphosphate oscillations mediated by G-protein-coupled receptors. J Biol Chem. 2003;278:20753–60.

    CAS  PubMed  Google Scholar 

  99. Trubetskoy V, Pardinas AF, Qi T, Panagiotaropoulou G, Awasthi S, Bigdeli TB et al. Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature 2022;604:502–8.

  100. Ward LD, Kellis M. HaploReg v4: systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease. Nucleic Acids Res. 2016;44:D877–881.

    CAS  PubMed  Google Scholar 

  101. Schrode N, Ho SM, Yamamuro K, Dobbyn A, Huckins L, Matos MR, et al. Synergistic effects of common schizophrenia risk variants. Nat Genet. 2019;51:1475–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Tian R, Abarientos A, Hong J, Hashemi SH, Yan R, Drager N, et al. Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis. Nat Neurosci. 2021;24:1020–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Lai RK, Xu IM, Chiu DK, Tse AP, Wei LL, Law CT, et al. NDUFA4L2 fine-tunes oxidative stress in hepatocellular carcinoma. Clin Cancer Res. 2016;22:3105–17.

    CAS  PubMed  Google Scholar 

  104. Liu Z, Chaillou T, Santos Alves E, Mader T, Jude B, Ferreira DMS, et al. Mitochondrial NDUFA4L2 is a novel regulator of skeletal muscle mass and force. FASEB J. 2021;35:e22010.

    CAS  PubMed  Google Scholar 

  105. Moore SJ, Murphy GG. The role of L-type calcium channels in neuronal excitability and aging. Neurobiol Learn Mem. 2020;173:107230.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Schierberl K, Hao J, Tropea TF, Ra S, Giordano TP, Xu Q, et al. Cav1.2 L-type Ca2+ channels mediate cocaine-induced GluA1 trafficking in the nucleus accumbens, a long-term adaptation dependent on ventral tegmental area Ca(v)1.3 channels. J Neurosci Off J Soc Neurosci. 2011;31:13562–75.

    CAS  Google Scholar 

  107. Shibasaki M, Kurokawa K, Ohkuma S. Upregulation of L-type Ca(v)1 channels in the development of psychological dependence. Synapse. 2010;64:440–4.

    CAS  PubMed  Google Scholar 

  108. 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;19:194–194.

    PubMed  PubMed Central  Google Scholar 

  109. Ding J, Adiconis X, Simmons SK, Kowalczyk MS, Hession CC, Marjanovic ND, et al. Systematic comparison of single-cell and single-nucleus RNA-sequencing methods. Nat Biotechnol. 2020;38:737–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Mereu E, Lafzi A, Moutinho C, Ziegenhain C, McCarthy DJ, Alvarez-Varela A, et al. Benchmarking single-cell RNA-sequencing protocols for cell atlas projects. Nat Biotechnol. 2020;38:747–55.

    CAS  PubMed  Google Scholar 

  111. Marsh SE, Walker AJ, Kamath T, Dissing-Olesen L, Hammond TR, de Soysa TY, et al. Dissection of artifactual and confounding glial signatures by single-cell sequencing of mouse and human brain. Nat Neurosci. 2022;25:306–16.

    CAS  PubMed  Google Scholar 

  112. Li YE, Preissl S, Hou X, Zhang Z, Zhang K, Qiu Y, et al. An atlas of gene regulatory elements in adult mouse cerebrum. Nature. 2021;598:129–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Preissl S, Fang R, Huang H, Zhao Y, Raviram R, Gorkin DU, et al. Single-nucleus analysis of accessible chromatin in developing mouse forebrain reveals cell-type-specific transcriptional regulation. Nat Neurosci. 2018;21:432–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Li Z, Kuppe C, Ziegler S, Cheng M, Kabgani N, Menzel S, et al. Chromatin-accessibility estimation from single-cell ATAC-seq data with scOpen. Nat Commun. 2021;12:6386.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Lal A, Chiang ZD, Yakovenko N, Duarte FM, Israeli J, Buenrostro JD. Deep learning-based enhancement of epigenomics data with AtacWorks. Nat Commun. 2021;12:1507.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Battaini F, Pascale A. Protein kinase C signal transduction regulation in physiological and pathological aging. Ann N Y Acad Sci. 2005;1057:177–92.

    CAS  PubMed  Google Scholar 

  117. Huang KP. The mechanism of protein kinase C activation. Trends Neurosci. 1989;12:425–32.

    CAS  PubMed  Google Scholar 

  118. Larsson C. Protein kinase C and the regulation of the actin cytoskeleton. Cell Signal. 2006;18:276–84.

    CAS  PubMed  Google Scholar 

  119. Bemben MA, Nguyen TA, Li Y, Wang T, Nicoll RA, Roche KW. Isoform-specific cleavage of neuroligin-3 reduces synapse strength. Mol Psychiatry. 2019;24:145–60.

    CAS  PubMed  Google Scholar 

  120. Kabir ZD, Lee AS, Rajadhyaksha AM. L-type Ca(2+) channels in mood, cognition and addiction: integrating human and rodent studies with a focus on behavioural endophenotypes. J Physiol. 2016;594:5823–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Pinggera A, Lieb A, Benedetti B, Lampert M, Monteleone S, Liedl KR, et al. CACNA1D de novo mutations in autism spectrum disorders activate Cav1.3 L-type calcium channels. Biol Psychiatry. 2015;77:816–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Kim SH, Park YR, Lee B, Choi B, Kim H, Kim CH. Reduction of Cav1.3 channels in dorsal hippocampus impairs the development of dentate gyrus newborn neurons and hippocampal-dependent memory tasks. PLoS One. 2017;12:e0181138.

    PubMed  PubMed Central  Google Scholar 

  123. Marschallinger J, Sah A, Schmuckermair C, Unger M, Rotheneichner P, Kharitonova M, et al. The L-type calcium channel Cav1.3 is required for proper hippocampal neurogenesis and cognitive functions. Cell Calcium. 2015;58:606–16.

    CAS  PubMed  Google Scholar 

  124. Liu Y, Harding M, Pittman A, Dore J, Striessnig J, Rajadhyaksha A, et al. Cav1.2 and Cav1.3 L-type calcium channels regulate dopaminergic firing activity in the mouse ventral tegmental area. J Neurophysiol. 2014;112:1119–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Deuchars SA, Atkinson L, Brooke RE, Musa H, Milligan CJ, Batten TF, et al. Neuronal P2X7 receptors are targeted to presynaptic terminals in the central and peripheral nervous systems. J Neurosci Off J Soc Neurosci. 2001;21:7143–52.

    CAS  Google Scholar 

  126. Díaz-Hernandez M, del Puerto A, Díaz-Hernandez JI, Diez-Zaera M, Lucas JJ, Garrido JJ, et al. Inhibition of the ATP-gated P2X7 receptor promotes axonal growth and branching in cultured hippocampal neurons. J Cell Sci. 2008;121:3717–28.

    PubMed  Google Scholar 

  127. Lalisse S, Hua J, Lenoir M, Linck N, Rassendren F, Ulmann L. Sensory neuronal P2RX4 receptors controls BDNF signaling in inflammatory pain. Sci Rep. 2018;8:964.

    PubMed  PubMed Central  Google Scholar 

  128. Khaira SK, Pouton CW, Haynes JM. P2X2, P2X4 and P2Y1 receptors elevate intracellular Ca2+ in mouse embryonic stem cell-derived GABAergic neurons. Br J Pharm. 2009;158:1922–31.

    CAS  Google Scholar 

  129. Sim JA, Chaumont S, Jo J, Ulmann L, Young MT, Cho K, et al. Altered hippocampal synaptic potentiation in P2X4 knock-out mice. J Neurosci Off J Soc Neurosci. 2006;26:9006–9.

    CAS  Google Scholar 

  130. Konur S, Ghosh A. Calcium signaling and the control of dendritic development. Neuron. 2005;46:401–5.

    CAS  PubMed  Google Scholar 

  131. Lovisolo D, Ariano P, Distasi C. Calcium signaling in neuronal motility: pharmacological tools for investigating specific pathways. Curr Med Chem. 2012;19:5793–801.

    CAS  PubMed  Google Scholar 

  132. Horigane SI, Ozawa Y, Yamada H, Takemoto-Kimura S. Calcium signalling: a key regulator of neuronal migration. J Biochem. 2019;165:401–9.

    CAS  PubMed  Google Scholar 

  133. West AE, Chen WG, Dalva MB, Dolmetsch RE, Kornhauser JM, Shaywitz AJ, et al. Calcium regulation of neuronal gene expression. Proc Natl Acad Sci USA 2001;98:11024–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Mateos-Aparicio P, Rodríguez-Moreno A. Calcium dynamics and synaptic plasticity. Adv Exp Med Biol. 2020;1131:965–84.

    CAS  PubMed  Google Scholar 

  135. Fairless R, Williams SK, Diem R. Dysfunction of neuronal calcium signalling in neuroinflammation and neurodegeneration. Cell Tissue Res. 2014;357:455–62.

    CAS  PubMed  Google Scholar 

  136. Jaskova K, Pavlovicova M, Jurkovicova D. Calcium transporters and their role in the development of neuronal disease and neuronal damage. Gen Physiol Biophys. 2012;31:375–82.

    CAS  PubMed  Google Scholar 

  137. Raudvere U, Kolberg L, Kuzmin I, Arak T, Adler P, Peterson H, et al. g:Profiler: a web server for functional enrichment analysis and conversions of gene lists (2019 update). Nucleic Acids Res. 2019;47:W191–w198.

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Ho SM, Hartley BJ, Flaherty E, Rajarajan P, Abdelaal R, Obiorah I, et al. Evaluating synthetic activation and repression of neuropsychiatric-related genes in hiPSC-derived NPCs, neurons, and astrocytes. Stem Cell Rep. 2017;9:615–28.

    CAS  Google Scholar 

  139. Bray NL, Pimentel H, Melsted P, Pachter L. Near-optimal probabilistic RNA-seq quantification. Nat Biotechnol. 2016;34:525–7.

    CAS  PubMed  Google Scholar 

  140. Hong S, Hwang DY, Yoon S, Isacson O, Ramezani A, Hawley RG, et al. Functional analysis of various promoters in lentiviral vectors at different stages of in vitro differentiation of mouse embryonic stem cells. Mol Ther. 2007;15:1630–9.

    CAS  PubMed  Google Scholar 

  141. Buenrostro JD, Wu B, Chang HY, Greenleaf WJ. ATAC-seq: a method for assaying chromatin accessibility genome-wide. Curr Protoc Mol Biol. 2015;109:21.29.21–21.29.29.

    Google Scholar 

  142. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The sequence alignment/map format and SAMtools. Bioinformatics. 2009;25:2078–9.

    PubMed  PubMed Central  Google Scholar 

  143. Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS, Bernstein BE, et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 2008;9:R137.

    PubMed  PubMed Central  Google Scholar 

  144. Langmead B, Salzberg SL. Fast gapped-read alignment with Bowtie 2. Nat Methods. 2012;9:357–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Feng J, Liu T, Qin B, Zhang Y, Liu XS. Identifying ChIP-seq enrichment using MACS. Nat Protoc. 2012;7:1728–40.

    CAS  PubMed  Google Scholar 

  146. Herring AH. Applied Longitudinal Analysis, 2nd Edition, by Garrett M. Fitzmaurice, Nan M. Laird, and James H. Ware, John Wiley & Sons, 2011. J Biopharmaceutical Stat. 2013;23:940–1.

    Google Scholar 

  147. Laird NM, Ware JH. Random-effects models for longitudinal data. Biometrics. 1982;38:963–74.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Karen F. Berman, MD and Jose Apud, MD Ph.D. at the National Institute of Mental Health for their contribution in providing patient fibroblast samples. We thank Daniel R. Weinberger, M.D. at the Lieber Institute for Brain Development for supplying patient fibroblast samples and for critical review of the manuscript.

Funding

This study was supported by MH125246 (PR), MH116442 (PR), MH118339 (J-HC). DP2MH122403 (HW), MH107884 (SC), NS121541 (SC) and NYSTEM C32607GG (SC).

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Authors and Affiliations

  1. Department of Cell biology and Anatomy, New York Medical College, Valhalla, NY, 10595, USA

    Dongxin Liu, Amy Zinski, Akanksha Mishra, Haneul Noh, Gun-Hoo Park, Yiren Qin, Oshoname Olorife, James M. Park, Chiderah P. Abani, Joy S. Park, Janice Fung, Farah Sawaqed, Xiaolei Zhang, Patric K. Stanton & Sangmi Chung

  2. Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China

    Dongxin Liu

  3. Department of Psychiatry, McLean Hospital/Harvard Medical School, Belmont, MA, 02478, USA

    Haneul Noh, Joseph T. Coyle & Sangmi Chung

  4. Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY, 10029, USA

    Eli Stahl, Jaroslav Bendl, John F. Fullard & Panos Roussos

  5. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY, 10029, USA

    Eli Stahl, Jaroslav Bendl, John F. Fullard & Panos Roussos

  6. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY, 10029, USA

    Eli Stahl, Jaroslav Bendl, John F. Fullard & Panos Roussos

  7. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY, 10029, USA

    Jaroslav Bendl, John F. Fullard & Panos Roussos

  8. Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY, 10029, USA

    Jaroslav Bendl, John F. Fullard & Panos Roussos

  9. Mental Illness Research Education and Clinical Center (VISN 2 South), James J. Peters VA Medical Center, Bronx, NY, 10468, USA

    Panos Roussos

  10. Department of Pathology, New York Medical College, Valhalla, NY, 10595, USA

    Changhong Yin & Weihua Huang

  11. Department of Public Health, New York Medical College, Valhalla, NY, USA

    Hae-Young Kim

  12. Department of Genetics, University of North Carolina, Chapel Hill, NC, 27599, USA

    Hyejung Won

  13. Department of Molecular, Cell and Systems Biology, University of California, Riverside, CA, 92521, USA

    Jun-Hyeong Cho

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  1. Dongxin Liu
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Contributions

DL, AZ, AM, HN, G-HP, YQ, JB, JFF, PR, XZ, PS, J-HC and SC designed the experiments. DL, AZ, AM, HN, G-HP, YQ and JMP differentiated cortical interneurons and analyzed them by qPCR and immunocytochemistry. DL, JSP and FS performed arborization analysis. DL, AZ and JF performed synapse analysis. DL, AZ, OO and CA did Western blot analysis. JTC reviewed data interpretation and manuscript contents. ES provided SCZ GWAS fine mapping data. JB, JFF, PR and HW did ATAC-seq analysis. J-HC did patch clamp analysis in brain slices. XZ and PS did patch clamp analysis in culture. CY and WH did RNA-seq and ChiP-seq analysis. H-YK performed statistical analysis. DL, JB, JFF, PR, XZ, PKS, HW, J-HC and SC wrote the manuscript. PR, J-HC, HW and SC supported this study financially.

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Correspondence to Dongxin Liu or Sangmi Chung.

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Liu, D., Zinski, A., Mishra, A. et al. Impact of schizophrenia GWAS loci converge onto distinct pathways in cortical interneurons vs glutamatergic neurons during development. Mol Psychiatry 27, 4218–4233 (2022). https://doi.org/10.1038/s41380-022-01654-z

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  • DOI: https://doi.org/10.1038/s41380-022-01654-z

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