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.

  • Article
  • Published:

iPSC-derived homogeneous populations of developing schizophrenia cortical interneurons have compromised mitochondrial function

Molecular Psychiatry volume 25, pages 2873–2888 (2020)Cite this article

Subjects

A Correction to this article was published on 31 July 2019

This article has been updated

Abstract

Schizophrenia (SCZ) is a neurodevelopmental disorder. Thus, studying pathogenetic mechanisms underlying SCZ requires studying the development of brain cells. Cortical interneurons (cINs) are consistently observed to be abnormal in SCZ postmortem brains. These abnormalities may explain altered gamma oscillation and cognitive function in patients with SCZ. Of note, currently used antipsychotic drugs ameliorate psychosis, but they are not very effective in reversing cognitive deficits. Characterizing mechanisms of SCZ pathogenesis, especially related to cognitive deficits, may lead to improved treatments. We generated homogeneous populations of developing cINs from 15 healthy control (HC) iPSC lines and 15 SCZ iPSC lines. SCZ cINs, but not SCZ glutamatergic neurons, show dysregulated Oxidative Phosphorylation (OxPhos) related gene expression, accompanied by compromised mitochondrial function. The OxPhos deficit in cINs could be reversed by Alpha Lipoic Acid/Acetyl-L-Carnitine (ALA/ALC) but not by other chemicals previously identified as increasing mitochondrial function. The restoration of mitochondrial function by ALA/ALC was accompanied by a reversal of arborization deficits in SCZ cINs. OxPhos abnormality, even in the absence of any circuit environment with other neuronal subtypes, appears to be an intrinsic deficit in SCZ cINs.

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
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Change history

References

  1. Rapoport JL, Giedd JN, Gogtay N. Neurodevelopmental model of schizophrenia: update 2012. Mol Psychiatry. 2012;17:1228–38.

    CAS  PubMed  PubMed Central  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. Harrison PJ. Postmortem studies in schizophrenia. Dialogues Clin Neurosci. 2000;2:349–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Jaffe AE. Postmortem human brain genomics in neuropsychiatric disorders–how far can we go? Curr Opin Neurobiol. 2016;36:107–11.

    CAS  PubMed  Google Scholar 

  5. Gonzalez-Burgos G, Cho RY, Lewis DA. Alterations in cortical network oscillations and parvalbumin neurons in schizophrenia. Biol Psychiatry. 2015;77:1031–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Arslan A. Imaging genetics of schizophrenia in the post-GWAS era. Prog Neuro-psychopharmacol Biol Psychiatry. 2018;80(Pt B):155–65.

    CAS  Google Scholar 

  7. Kotrla KJ, Weinberger DR. Brain imaging in schizophrenia. Ann Rev Med. 1995;46:113–22.

    CAS  PubMed  Google Scholar 

  8. Kim SY, Cohen BM, Chen X, Lukas SE, Shinn AK, Yuksel AC, et al. Redox dysregulation in schizophrenia revealed by in vivo NAD + /NADH measurement. Schizophrenia Bull. 2017;43:197–204.

    Google Scholar 

  9. Du F, Cooper AJ, Thida T, Sehovic S, Lukas SE, Cohen BM, et al. In vivo evidence for cerebral bioenergetic abnormalities in schizophrenia measured using 31P magnetization transfer spectroscopy. JAMA Psychiatry. 2014;71:19–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Matigian NA, McCurdy RD, Feron F, Perry C, Smith H, Filippich C, et al. Fibroblast and lymphoblast gene expression profiles in schizophrenia: are non-neural cells informative? PLoS ONE. 2008;3:e2412.

    PubMed  PubMed Central  Google Scholar 

  11. Hilker R, Helenius D, Fagerlund B, Skytthe A, Christensen K, Werge TM, et al. Heritability of schizophrenia and schizophrenia spectrum based on the nationwide danish twin register. Biol Psychiatry. 2018;83:492–8.

    PubMed  Google Scholar 

  12. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131:861–72.

    CAS  PubMed  Google Scholar 

  13. 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;21:305–18 e308.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Fujimori K, Ishikawa M, Otomo A, Atsuta N, Nakamura R, Akiyama T, et al. Modeling sporadic ALS in iPSC-derived motor neurons identifies a potential therapeutic agent. Nat Med. 2018;24:1579–89.

    CAS  PubMed  Google Scholar 

  15. Srikanth P, Han K, Callahan DG, Makovkina E, Muratore CR, Lalli MA, et al. Genomic DISC1 disruption in hiPSCs alters Wnt signaling and neural cell fate. Cell Rep. 2015;12:1414–29.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Windrem MS, Osipovitch M, Liu Z, Bates J, Chandler-Militello D, Zou L, et al. Human iPSC glial mouse chimeras reveal glial contributions to schizophrenia. Cell Stem Cell. 2017;21:195–208 e196.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Barnes J, Salas F, Mokhtari R, Dolstra H, Pedrosa E, Lachman HM. Modeling the neuropsychiatric manifestations of Lowe syndrome using induced pluripotent stem cells: defective F-actin polymerization and WAVE-1 expression in neuronal cells. Mol Autism. 2018;9:44.

    PubMed  PubMed Central  Google Scholar 

  18. Kondo T, Asai M, Tsukita K, Kutoku Y, Ohsawa Y, Sunada Y, et al. Modeling Alzheimer’s disease with iPSCs reveals stress phenotypes associated with intracellular Abeta and differential drug responsiveness. Cell Stem Cell. 2013;12:487–96.

    CAS  PubMed  Google Scholar 

  19. Pak C, Danko T, Zhang Y, Aoto J, Anderson G, Maxeiner S, et al. Human neuropsychiatric disease modeling using conditional deletion reveals synaptic transmission defects caused by heterozygous mutations in NRXN1. Cell Stem Cell. 2015;17:316–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Stachowiak EK, Benson CA, Narla ST, Dimitri A, Chuye LEB, Dhiman S, et al. Cerebral organoids reveal early cortical maldevelopment in schizophrenia-computational anatomy and genomics, role of FGFR1. Transl Psychiatry. 2017;7:6.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Noh H, Shao ZC, Coyle JT, Chung SM. Modeling schizophrenia pathogenesis using patient-derived induced pluripotent stem cells (iPSCs). Bba-Mol Basis Dis. 2017;1863:2382–7.

    CAS  Google Scholar 

  22. Benes FM. The GABA system in schizophrenia: cells, molecules and microcircuitry. Schizophr Res. 2015;167:1–3.

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

    CAS  PubMed  Google Scholar 

  25. Volk DW, Lewis DA. Early developmental disturbances of cortical inhibitory neurons: contribution to cognitive deficits in schizophrenia. Schizophrenia Bull. 2014;40:952–7.

    Google Scholar 

  26. Lewis DA, Cho RY, Carter CS, Eklund K, Forster S, Kelly MA, et al. Subunit-selective modulation of GABA type A receptor neurotransmission and cognition in schizophrenia. Am J Psychiatry. 2008;165:1585–93.

    PubMed  PubMed Central  Google Scholar 

  27. Kim TG, Yao R, Monnell T, Cho JH, 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  PubMed Central  Google Scholar 

  28. Ahn S, Kim TG, Kim KS, Chung S. Differentiation of human pluripotent stem cells into Medial Ganglionic Eminence vs. Caudal Ganglionic Eminence cells. Methods. 2016;101:103–12.

    CAS  PubMed  Google Scholar 

  29. Lopez-Domenech G, Higgs NF, Vaccaro V, Ros H, Arancibia-Carcamo IL, MacAskill AF, et al. Loss of dendritic complexity precedes neurodegeneration in a mouse model with disrupted mitochondrial distribution in mature dendrites. Cell Rep. 2016;17:317–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Mendoza E, Miranda-Barrientos JA, Vazquez-Roque RA, Morales-Herrera E, Ruelas A, De la Rosa G, et al. In vivo mitochondrial inhibition alters corticostriatal synaptic function and the modulatory effects of neurotrophins. Neuroscience. 2014;280:156–70.

    CAS  PubMed  Google Scholar 

  31. Tsuyama T, Tsubouchi A, Usui T, Imamura H, Uemura T. Mitochondrial dysfunction induces dendritic loss via eIF2alpha phosphorylation. J Cell Biol. 2017;216:815–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Li Z, Okamoto K, Hayashi Y, Sheng M. The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell. 2004;119:873–87.

    CAS  PubMed  Google Scholar 

  33. Haak LL, Grimaldi M, Smaili SS, Russell JT. Mitochondria regulate Ca2+ wave initiation and inositol trisphosphate signal transduction in oligodendrocyte progenitors. J Neurochem. 2002;80:405–15.

    CAS  PubMed  Google Scholar 

  34. Montalvo GB, Artalejo AR, Gilabert JA. ATP from subplasmalemmal mitochondria controls Ca2+ -dependent inactivation of CRAC channels. J Biol Chem. 2006;281:35616–23.

    CAS  PubMed  Google Scholar 

  35. Vanden Berghe P, Kenyon JL, Smith TK. Mitochondrial Ca2 + uptake regulates the excitability of myenteric neurons. J Neurosci. 2002;22:6962–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Demaurex N, Poburko D, Frieden M. Regulation of plasma membrane calcium fluxes by mitochondria. Biochim et Biophys Acta. 2009;1787:1383–94.

    CAS  Google Scholar 

  37. Katsura K, Kristian T, Siesjo BK. Energy metabolism, ion homeostasis, and cell damage in the brain. Biochem Soc Trans. 1994;22:991–6.

    CAS  PubMed  Google Scholar 

  38. Hiraoka M. Metabolic pathways for ion homeostasis and persistent Na(+) current. J Cardiovasc Electrophysiol. 2006;17:S124–S126.

    PubMed  Google Scholar 

  39. Bergman O, Ben-Shachar D. Mitochondrial oxidative phosphorylation system (OXPHOS) deficits in schizophrenia: possible interactions with cellular processes. Can J Psychiatry. 2016;61:457–69.

    PubMed  PubMed Central  Google Scholar 

  40. Wallace DC. A Mitochondrial etiology of neuropsychiatric disorders. JAMA Psychiatry. 2017;74:863–4.

    PubMed  Google Scholar 

  41. Cuperfain AB, Zhang ZL, Kennedy JL, Goncalves VF. The complex interaction of mitochondrial genetics and mitochondrial pathways in psychiatric disease. Mol Neuropsychiatry. 2018;4:52–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Devaraju P, Yu J, Eddins D, Mellado-Lagarde MM, Earls LR, Westmoreland JJ, et al. Haploinsufficiency of the 22q11.2 microdeletion gene Mrpl40 disrupts short-term synaptic plasticity and working memory through dysregulation of mitochondrial calcium. Mol Psychiatry. 2016;22:1313.

    PubMed  PubMed Central  Google Scholar 

  43. Inan M, Zhao M, Manuszak M, Karakaya C, Rajadhyaksha AM, Pickel VM, et al. Energy deficit in parvalbumin neurons leads to circuit dysfunction, impaired sensory gating and social disability. Neurobiol Dis. 2016;93:35–46.

    CAS  PubMed  Google Scholar 

  44. Kim H, Kim HJ, Lee K, Kim JM, Kim HS, Kim JR, et al. alpha-Lipoic acid attenuates vascular calcification via reversal of mitochondrial function and restoration of Gas6/Axl/Akt survival pathway. J Cell Mol Med. 2012;16:273–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Hiller S, DeKroon R, Xu LQ, Robinette J, Winnik W, Alzate O, et al. alpha-Lipoic acid protects mitochondrial enzymes and attenuates lipopolysaccharide-induced hypothermia in mice. Free Radical Bio Med. 2014;71:362–7.

    CAS  Google Scholar 

  46. Patel SP, Sullivan PG, Lyttle TS, Rabchevsky AG. Acetyl-L-carnitine ameliorates mitochondrial dysfunction following contusion spinal cord injury. J Neurochem. 2010;114:291–301.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Li X, Zhang C, Zhang X, Wang S, Meng Q, Wu S, et al. An acetyl-L-carnitine switch on mitochondrial dysfunction and rescue in the metabolomics study on aluminum oxide nanoparticles. Part Fibre Toxicol. 2016;13:4.

    PubMed  PubMed Central  Google Scholar 

  48. 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 

  49. liss LA, Sams MR, Deep-Soboslay A, Ren-Patterson R, Jaffe AE, Chenoweth JG, et al. Use of postmortem human dura mater and scalp for deriving human fibroblast cultures. PloS ONE. 2012;7:e45282.

    Google Scholar 

  50. Warren L, Ni Y, Wang J, Guo X. Feeder-free derivation of human induced pluripotent stem cells with messenger RNA. Sci Rep. 2012;2:657.

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  52. Luo W, Brouwer C. Pathview: an R/Bioconductor package for pathway-based data integration and visualization. Bioinformatics. 2013;29:1830–1.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550.

    PubMed  PubMed Central  Google Scholar 

  54. Kanehisa M, Furumichi M, Tanabe M, Sato Y, Morishima K. KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res. 2017;45(D1):D353–D361.

    CAS  PubMed  Google Scholar 

  55. Horton R, Wilming L, Rand V, Lovering RC, Bruford EA, Khodiyar VK, et al. Gene map of the extended human MHC. Nat Rev Genet. 2004;5:889–99.

    CAS  PubMed  Google Scholar 

  56. Quiros PM, Mottis A, Auwerx J. Mitonuclear communication in homeostasis and stress. Nat Rev Mol Cell Biol. 2016;17:213–26.

    CAS  PubMed  Google Scholar 

  57. Biswas G, Guha M, Avadhani NG. Mitochondria-to-nucleus stress signaling in mammalian cells: nature of nuclear gene targets, transcription regulation, and induced resistance to apoptosis. Gene. 2005;354:132–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Pellegrino MW, Nargund AM, Haynes CM. Signaling the mitochondrial unfolded protein response. Biochimica et Biophysica Acta. 2013;1833:410–6.

    CAS  PubMed  Google Scholar 

  59. Cagin U, Enriquez JA. The complex crosstalk between mitochondria and the nucleus: What goes in between? Int J Biochem Cell Biol. 2015;63:10–15.

    CAS  PubMed  Google Scholar 

  60. Herring AH. Applied longitudinal analysis, Vol. 23. 2nd edn. In: Garrett M. Fitzmaurice, Nan M. Laird, James H. Ware, (editors) John Wiley & Sons 2011; 2013. p. 940–1.

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

    CAS  PubMed  Google Scholar 

  62. Zhang Y, Pak C, Han Y, Ahlenius H, Zhang Z, Chanda S, et al. Rapid single-step induction of functional neurons from human pluripotent stem cells. Neuron. 2013;78:785–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Nehme R, Zuccaro E, Ghosh SD, Li C, Sherwood JL, Pietilainen O, et al. Combining NGN2 programming with developmental patterning generates human excitatory neurons with NMDAR-mediated synaptic transmission. Cell Rep. 2018;23:2509–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Van Haute L, Powell CA, Minczuk M. Dealing with an unconventional genetic code in mitochondria: the biogenesis and pathogenic defects of the 5-formylcytosine modification in mitochondrial tRNA(Met). Biomolecules. 2017;7:E24. pii

    PubMed  Google Scholar 

  65. Trixl L, Amort T, Wille A, Zinni M, Ebner S, Hechenberger C, et al. RNA cytosine methyltransferase Nsun3 regulates embryonic stem cell differentiation by promoting mitochondrial activity. Cell Mol Life Sci. 2018;75:1483–97.

    CAS  PubMed  Google Scholar 

  66. Korman SH, Kanazawa N, Abu-Libdeh B, Gutman A, Tsujino S. Hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome with evidence of mitochondrial dysfunction due to a novel SLC25A15 (ORNT1) gene mutation in a Palestinian family. J Neurol Sci. 2004;218:53–58.

    CAS  PubMed  Google Scholar 

  67. Geiger J, Dalgaard LT. Interplay of mitochondrial metabolism and microRNAs. Cell Mol Life Sci. 2017;74:631–46.

    CAS  PubMed  Google Scholar 

  68. Meister G. Argonaute proteins: functional insights and emerging roles. Nat Rev Genet. 2013;14:447–59.

    CAS  PubMed  Google Scholar 

  69. Ogita K, Okuda H, Kitano M, Fujinami Y, Ozaki K, Yoneda Y. Localization of activator protein-1 complex with DNA binding activity in mitochondria of murine brain after in vivo treatment with kainate. J Neurosci. 2002;22:2561–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Ogita K, Fujinami Y, Kitano M, Yoneda Y. Transcription factor activator protein-1 expressed by kainate treatment can bind to the non-coding region of mitochondrial genome in murine hippocampus. J Neurosci Res. 2003;73:794–802.

    CAS  PubMed  Google Scholar 

  71. Marrocco I, Altieri F, Peluso I. Measurement and clinical significance of biomarkers of oxidative stress in humans. Oxid Med Cell Longev. 2017;2017:6501046.

    PubMed  PubMed Central  Google Scholar 

  72. Hagen TM, Liu J, Lykkesfeldt J, Wehr CM, Ingersoll RT, Vinarsky V, et al. Feeding acetyl-L-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. Proc Natl Acad Sci USA. 2002;99:1870–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Liu J. The effects and mechanisms of mitochondrial nutrient alpha-lipoic acid on improving age-associated mitochondrial and cognitive dysfunction: an overview. Neurochem Res. 2008;33:194–203.

    CAS  PubMed  Google Scholar 

  74. Shay KP, Moreau RF, Smith EJ, Smith AR, Hagen TM. Alpha-lipoic acid as a dietary supplement: molecular mechanisms and therapeutic potential. Biochimica et Biophysica Acta. 2009;1790:1149–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Afshordel S, Hagl S, Werner D, Rohner N, Kogel D, Bazan NG, et al. Omega-3 polyunsaturated fatty acids improve mitochondrial dysfunction in brain aging–impact of Bcl-2 and NPD-1 like metabolites. Prostaglandins Leukot Essent Fatty Acids. 2015;92:23–31.

    CAS  PubMed  Google Scholar 

  76. Kitajka K, Puskas LG, Zvara A, Hackler L Jr., Barcelo-Coblijn G, et al. The role of n-3 polyunsaturated fatty acids in brain: modulation of rat brain gene expression by dietary n-3 fatty acids. Proc Natl Acad Sci USA. 2002;99:2619–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Kitajka K, Sinclair AJ, Weisinger RS, Weisinger HS, Mathai M, Jayasooriya AP, et al. Effects of dietary omega-3 polyunsaturated fatty acids on brain gene expression. Proc Natl Acad Sci USA. 2004;101:10931–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Harbeby E, Jouin M, Alessandri JM, Lallemand MS, Linard A, Lavialle M, et al. n-3 PUFA status affects expression of genes involved in neuroenergetics differently in the fronto-parietal cortex compared to the CA1 area of the hippocampus: effect of rest and neuronal activation in the rat. Prostaglandins Leukot Essent Fatty Acids. 2012;86:211–20.

    CAS  PubMed  Google Scholar 

  79. Schniertshauer D, Gebhard D, Bergemann J. Age-dependent loss of mitochondrial function in epithelial tissue can be reversed by coenzyme Q10. J Aging Res. 2018;2018:6354680.

    PubMed  PubMed Central  Google Scholar 

  80. Chokchaiwong S, Kuo YT, Lin SH, Hsu YC, Hsu SP, Liu YT, et al. Coenzyme Q10 serves to couple mitochondrial oxidative phosphorylation and fatty acid beta-oxidation, and attenuates NLRP3 inflammasome activation. Free Radic Res. 2018;52:1–11.

  81. Martinez M, Ferrandiz ML, De Juan E, Miquel J. Age-related changes in glutathione and lipid peroxide content in mouse synaptic mitochondria: relationship to cytochrome c oxidase decline. Neurosci Lett. 1994;170:121–4.

    CAS  PubMed  Google Scholar 

  82. Martinez Banaclocha M. N-acetylcysteine elicited increase in complex I activity in synaptic mitochondria from aged mice: implications for treatment of Parkinson’s disease. Brain Res. 2000;859:173–5.

    CAS  PubMed  Google Scholar 

  83. Navarro A, Bandez MJ, Lopez-Cepero JM, Gomez C, Boveris A. High doses of vitamin E improve mitochondrial dysfunction in rat hippocampus and frontal cortex upon aging. Am J Physiol Regul Integr Comp Physiol. 2011;300:R827–834.

    CAS  PubMed  Google Scholar 

  84. Maurer I, Zierz S, Moller H. Evidence for a mitochondrial oxidative phosphorylation defect in brains from patients with schizophrenia. Schizophr Res. 2001;48:125–36.

    CAS  PubMed  Google Scholar 

  85. Karry R, Klein E, Ben Shachar D. Mitochondrial complex I subunits expression is altered in schizophrenia: a postmortem study. Biol Psychiatry. 2004;55:676–84.

    CAS  PubMed  Google Scholar 

  86. Iwamoto K, Bundo M, Kato T. Altered expression of mitochondria-related genes in postmortem brains of patients with bipolar disorder or schizophrenia, as revealed by large-scale DNA microarray analysis. Hum Mol Genet. 2005;14:241–53.

    CAS  PubMed  Google Scholar 

  87. Roberts RC. Postmortem studies on mitochondria in schizophrenia. Schizophr Res. 2017;187:17–25.

    PubMed  PubMed Central  Google Scholar 

  88. 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.

    PubMed  PubMed Central  Google Scholar 

  89. Scaini G, Quevedo J, Velligan D, Roberts DL, Raventos H, Walss-Bass C. Second generation antipsychotic-induced mitochondrial alterations: Implications for increased risk of metabolic syndrome in patients with schizophrenia. Eur Neuropsychopharmacol. 2018;28:369–80.

    CAS  PubMed  Google Scholar 

  90. Toker L, Mancarci BO, Tripathy S, Pavlidis P. Transcriptomic evidence for alterations in astrocytes and parvalbumin interneurons in subjects with bipolar disorder and schizophrenia. Biol Psychiatry. 2018;84:787–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Bitanihirwe BK, Woo TU. Oxidative stress in schizophrenia: an integrated approach. Neurosci Biobehav Rev. 2011;35:878–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Do KQ, Cuenod M, Hensch TK. Targeting oxidative stress and aberrant critical period plasticity in the developmental trajectory to schizophrenia. Schizophr Bull. 2015;41:835–46.

    PubMed  PubMed Central  Google Scholar 

  93. Handy DE, Loscalzo J. Redox regulation of mitochondrial function. Antioxid Redox Signal. 2012;16:1323–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Robicsek O, Ene HM, Karry R, Ytzhaki O, Asor E, McPhie D, et al. Isolated mitochondria transfer improves neuronal differentiation of schizophrenia-derived induced pluripotent stem cells and rescues deficits in a rat model of the disorder. Schizophr Bull. 2018;44:432–42.

    PubMed  Google Scholar 

  95. Moraes CT. Mitochondrial disorders. Curr Opin Neurol. 1996;9:369–74.

    CAS  PubMed  Google Scholar 

  96. Suomalainen A. Mitochondrial roles in disease: a box full of surprises. EMBO Mol Med. 2015;7:1245–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Tarnopolsky MA. The mitochondrial cocktail: rationale for combined nutraceutical therapy in mitochondrial cytopathies. Adv Drug Delivery Rev. 2008;60:1561–7.

    CAS  Google Scholar 

  98. Liu J, Head E, Gharib AM, Yuan W, Ingersoll RT, Hagen TM, et al. Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: partial reversal by feeding acetyl-L-carnitine and/or R-alpha -lipoic acid. Proc Natl Acad Sci USA. 2002;99:2356–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Arnold LE, Amato A, Bozzolo H, Hollway J, Cook A, Ramadan Y, et al. Acetyl-L-carnitine (ALC) in attention-deficit/hyperactivity disorder: a multi-site, placebo-controlled pilot trial. J Child Adolesc Psychopharmacol. 2007;17:791–802.

    PubMed  Google Scholar 

  100. Applegate MA, Humphries KM, Szweda LI. Reversible inhibition of alpha-ketoglutarate dehydrogenase by hydrogen peroxide: glutathionylation and protection of lipoic acid. Biochemistry. 2008;47:473–8.

    CAS  PubMed  Google Scholar 

  101. Packer L, Witt EH, Tritschler HJ. alpha-Lipoic acid as a biological antioxidant. Free Rad Biol Med. 1995;19:227–50.

    CAS  PubMed  Google Scholar 

  102. Ou P, Tritschler HJ, Wolff SP. Thioctic (lipoic) acid: a therapeutic metal-chelating antioxidant? Biochemical Pharmacol. 1995;50:123–6.

    CAS  Google Scholar 

  103. Rebouche CJ. Carnitine function and requirements during the life cycle. FASEB J. 1992;6:3379–86.

    CAS  PubMed  Google Scholar 

  104. Costell M, Grisolia S. Effect of carnitine feeding on the levels of heart and skeletal muscle carnitine of elderly mice. FEBS Lett. 1993;315:43–46.

    CAS  PubMed  Google Scholar 

  105. Gulcin I. Antioxidant and antiradical activities of L-carnitine. Life Sci. 2006;78:803–11.

    PubMed  Google Scholar 

  106. Robicsek O, Karry R, Petit I, Salman-Kesner N, Muller 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 

  107. Paulsen Bda S, de Moraes Maciel R, Galina A, Souza da Silveira M, dos Santos Souza C, Drummond H, et al. Altered oxygen metabolism associated to neurogenesis of induced pluripotent stem cells derived from a schizophrenic patient. Cell Transplant. 2012;21:1547–59.

    PubMed  Google Scholar 

  108. Brennand K, Savas JN, Kim Y, Tran N, Simone A, Hashimoto-Torii K, et al. Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia. Mol Psychiatry. 2015;20:361–8.

    CAS  PubMed  Google Scholar 

  109. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421–7.

    PubMed Central  Google Scholar 

  110. Hjelm BE, Rollins B, Mamdani F, Lauterborn JC, Kirov G, Lynch G, et al. Evidence of mitochondrial dysfunction within the complex genetic etiology of schizophrenia. Mol Neuropsychiatry. 2015;1:201–19.

    PubMed  PubMed Central  Google Scholar 

  111. Corvin A, Sullivan PF. What next in schizophrenia genetics for the psychiatric genomics Consortium? Schizophr Bull. 2016;42:538–41.

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported by MH107884 (S.C.) and NYSTEM C32607GG (S.C.). We thank Karen F. Berman, MD and Jose Apud, MD PhD at the National Institute of Mental Health for their contribution in providing patient samples.

Authors contributions

P.N., H.N., G.-H.P., Z.S. and S.C. designed the experiments. P.N., H.N., G.-H.P., Z.S., Y.G., J.M.P., S.Y., J.S.P., J.T.C., C.Y., W.H. and S.C. conducted experiments, collected data, and analyzed the data. P.N., W.H., and S.C. wrote the manuscript. D.R.W., R.E.S., B.M.C. and D.L.M. provided patient cell lines and reviewed data interpretation and manuscript contents. H.-Y.K. performed statistical analysis. S.C. supported this study financially.

Author information

Author notes

  1. These authors contributed equally: Peiyan Ni, Haneul Noh

Authors and Affiliations

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

    Peiyan Ni, Haneul Noh, Gun-Hoo Park, Youxin Guan, James M. Park, Sophy Yu, Joy S. Park & Sangmi Chung

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

    Peiyan Ni, Haneul Noh, Zhicheng Shao, Joseph T. Coyle, Bruce M. Cohen, Donna L. McPhie & Sangmi Chung

  3. Psychiatric Laboratory and Mental Health Center, The State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, 610041, Chengdu, China

    Peiyan Ni

  4. Lieber Institute for Brain Development, Johns Hopkins University, Baltimore, MD, 21218, USA

    Daniel R. Weinberger & Richard E. Straub

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

    Changhong Yin & Weihua Huang

  6. Department of Public Health, New York Medical College, Valhalla, NY, 10595, USA

    Hae-Young Kim

Authors
  1. Peiyan Ni
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Haneul Noh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gun-Hoo Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhicheng Shao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Youxin Guan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. James M. Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sophy Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Joy S. Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Joseph T. Coyle
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Daniel R. Weinberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Richard E. Straub
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Bruce M. Cohen
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Donna L. McPhie
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Changhong Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Weihua Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Hae-Young Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Sangmi Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sangmi Chung.

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.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ni, P., Noh, H., Park, GH. et al. iPSC-derived homogeneous populations of developing schizophrenia cortical interneurons have compromised mitochondrial function. Mol Psychiatry 25, 2873–2888 (2020). https://doi.org/10.1038/s41380-019-0423-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-019-0423-3

This article is cited by

Search

Advanced search

Quick links