Advertisement

Dynamic Changes of the Mitochondria in Psychiatric Illnesses: New Mechanistic Insights From Human Neuronal Models

      Abstract

      Mitochondria play a crucial role in neuronal function, especially in energy production, the generation of reactive oxygen species, and calcium signaling. Multiple lines of evidence have suggested the possible involvement of mitochondrial deficits in major psychiatric disorders, such as schizophrenia and bipolar disorder. This review will outline the current understanding of the physiological role of mitochondria and their dysfunction under pathological conditions, particularly in psychiatric disorders. The current knowledge about mitochondrial deficits in these disorders is somewhat limited because of the lack of effective methods to dissect dynamic changes in functional deficits that are directly associated with psychiatric conditions. Human neuronal cell model systems have been dramatically developed in recent years with the use of stem cell technology, and these systems may be key tools for overcoming this dilemma and improving our understanding of the dynamic changes in the mitochondrial deficits in patients with psychiatric disorders. We introduce recent discoveries from new experimental models and conclude the discussion by referring to future perspectives. We emphasize the significance of combining studies of human neuronal cell models with those of other experimental systems, including animal models.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Gray M.W.
        Lynn Margulis and the endosymbiont hypothesis: 50 years later.
        Mol Biol Cell. 2017; 28: 1285-1287
        • Goh S.
        • Dong Z.
        • Zhang Y.
        • DiMauro S.
        • Peterson B.S.
        Mitochondrial dysfunction as a neurobiological subtype of autism spectrum disorder: Evidence from brain imaging.
        JAMA Psychiatry. 2014; 71: 665-671
        • Bhat A.H.
        • Dar K.B.
        • Anees S.
        • Zargar M.A.
        • Masood A.
        • Sofi M.A.
        • et al.
        Oxidative stress, mitochondrial dysfunction and neurodegenerative diseases; a mechanistic insight.
        Biomed Pharmacother. 2015; 74: 101-110
        • Sorrentino V.
        • Menzies K.J.
        • Auwerx J.
        Repairing mitochondrial dysfunction in disease.
        Annu Rev Pharmacol Toxicol. 2018; 58: 9.1-9.37
        • Zhu X.H.
        • Qiao H.
        • Du F.
        • Xiong Q.
        • Liu X.
        • Zhang X.
        • et al.
        Quantitative imaging of energy expenditure in human brain.
        Neuroimage. 2012; 60: 2107-2117
        • Erecinska M.
        • Silver I.A.
        Tissue oxygen tension and brain sensitivity to hypoxia.
        Respir Physiol. 2001; 128: 263-276
        • Sena L.A.
        • Chandel N.S.
        Physiological roles of mitochondrial reactive oxygen species.
        Mol Cell. 2012; 48: 158-167
        • Sundaresan M.
        • Yu Z.X.
        • Ferrans V.J.
        • Irani K.
        • Finkel T.
        Requirement for generation of H2O2 for platelet-derived growth factor signal transduction.
        Science. 1995; 270: 296-299
        • Bae Y.S.
        • Kang S.W.
        • Seo M.S.
        • Baines I.C.
        • Tekle E.
        • Chock P.B.
        • et al.
        Epidermal growth factor (EGF)-induced generation of hydrogen peroxide. Role in EGF receptor-mediated tyrosine phosphorylation.
        J Biol Chem. 1997; 272: 217-221
        • Meng T.C.
        • Fukada T.
        • Tonks N.K.
        Reversible oxidation and inactivation of protein tyrosine phosphatases in vivo.
        Mol Cell. 2002; 9: 387-399
        • Rizzuto R.
        • De Stefani D.
        • Raffaello A.
        • Mammucari C.
        Mitochondria as sensors and regulators of calcium signalling.
        Nat Rev Mol Cell Biol. 2012; 13: 566-578
        • Chaturvedi R.K.
        • Beal M.F.
        Mitochondrial approaches for neuroprotection.
        Ann N Y Acad Sci. 2008; 1147: 395-412
        • Kornmann B.
        The molecular hug between the ER and the mitochondria.
        Curr Opin Cell Biol. 2013; 25: 443-448
        • Bagur R.
        • Hajnoczky G.
        Intracellular Ca(2+) sensing: Its role in calcium homeostasis and signaling.
        Mol Cell. 2017; 66: 780-788
        • Seidlmayer L.K.
        • Juettner V.V.
        • Kettlewell S.
        • Pavlov E.V.
        • Blatter L.A.
        • Dedkova E.N.
        Distinct mPTP activation mechanisms in ischaemia-reperfusion: Contributions of Ca2+, ROS, pH, and inorganic polyphosphate.
        Cardiovasc Res. 2015; 106: 237-248
        • Greer P.L.
        • Greenberg M.E.
        From synapse to nucleus: Calcium-dependent gene transcription in the control of synapse development and function.
        Neuron. 2008; 59: 846-860
        • Czabotar P.E.
        • Lessene G.
        • Strasser A.
        • Adams J.M.
        Control of apoptosis by the BCL-2 protein family: Implications for physiology and therapy.
        Nat Rev Mol Cell Biol. 2014; 15: 49-63
        • Fuchs Y.
        • Steller H.
        Live to die another way: Modes of programmed cell death and the signals emanating from dying cells.
        Nat Rev Mol Cell Biol. 2015; 16: 329-344
        • Bhola P.D.
        • Letai A.
        Mitochondria-judges and executioners of cell death sentences.
        Mol Cell. 2016; 61: 695-704
        • Manji H.
        • Kato T.
        • Di Prospero N.A.
        • Ness S.
        • Beal M.F.
        • Krams M.
        • et al.
        Impaired mitochondrial function in psychiatric disorders.
        Nat Rev Neurosci. 2012; 13: 293-307
        • Sawa A.
        • Snyder S.H.
        Schizophrenia: Diverse approaches to a complex disease.
        Science. 2002; 296: 692-695
        • van Os J.
        • Kenis G.
        • Rutten B.P.
        The environment and schizophrenia.
        Nature. 2010; 468: 203-212
        • Sullivan P.F.
        • Daly M.J.
        • O’Donovan M.
        Genetic architectures of psychiatric disorders: The emerging picture and its implications.
        Nat Rev Genet. 2012; 13: 537-551
        • Gandal M.J.
        • Leppa V.
        • Won H.
        • Parikshak N.N.
        • Geschwind D.H.
        The road to precision psychiatry: Translating genetics into disease mechanisms.
        Nat Neurosci. 2016; 19: 1397-1407
        • Owen M.J.
        • Sawa A.
        • Mortensen P.B.
        Schizophrenia.
        Lancet. 2016; 388: 86-97
        • Park C.
        • Park S.K.
        Molecular links between mitochondrial dysfunctions and schizophrenia.
        Mol Cells. 2012; 33: 105-110
        • Issler O.
        • Chen A.
        Determining the role of microRNAs in psychiatric disorders.
        Nat Rev Neurosci. 2015; 16: 201-212
        • Landek-Salgado M.A.
        • Faust T.E.
        • Sawa A.
        Molecular substrates of schizophrenia: Homeostatic signaling to connectivity.
        Mol Psychiatry. 2016; 21: 10-28
        • Salminen A.
        • Haapasalo A.
        • Kauppinen A.
        • Kaarniranta K.
        • Soininen H.
        • Hiltunen M.
        Impaired mitochondrial energy metabolism in Alzheimer’ss disease: Impact on pathogenesis via disturbed epigenetic regulation of chromatin landscape.
        Prog Neurobiol. 2015; 131: 1-20
        • Swerdlow R.H.
        Bioenergetics and metabolism: A bench to bedside perspective.
        J Neurochem. 2016; 139: 126-135
        • Wallace D.C.
        Bioenergetic origins of complexity and disease.
        Cold Spring Harb Symp Quant Biol. 2011; 76: 1-16
        • Andreazza A.C.
        • Duong A.
        • Young L.T.
        Bipolar disorder as a mitochondrial disease.
        Biol Psychiatry. 2018; 83: 720-721
        • Raffa M.
        • Mechri A.
        • Othman L.B.
        • Fendri C.
        • Gaha L.
        • Kerkeni A.
        Decreased glutathione levels and antioxidant enzyme activities in untreated and treated schizophrenic patients.
        Prog Neuropsychopharmacol Biol Psychiatry. 2009; 33: 1178-1183
        • Flatow J.
        • Buckley P.
        • Miller B.J.
        Meta-analysis of oxidative stress in schizophrenia.
        Biol Psychiatry. 2013; 74: 400-409
        • Gawryluk J.W.
        • Wang J.F.
        • Andreazza A.C.
        • Shao L.
        • Young L.T.
        Decreased levels of glutathione, the major brain antioxidant, in post-mortem prefrontal cortex from patients with psychiatric disorders.
        Int J Neuropsychopharmacol. 2011; 14: 123-130
        • Yao J.K.
        • Leonard S.
        • Reddy R.D.
        Increased nitric oxide radicals in postmortem brain from patients with schizophrenia.
        Schizophr Bull. 2004; 30: 923-934
        • Do K.Q.
        • Trabesinger A.H.
        • Kirsten-Kruger M.
        • Lauer C.J.
        • Dydak U.
        • Hell D.
        • et al.
        Schizophrenia: Glutathione deficit in cerebrospinal fluid and prefrontal cortex in vivo.
        Eur J Neurosci. 2000; 12: 3721-3728
        • Matsuzawa D.
        • Obata T.
        • Shirayama Y.
        • Nonaka H.
        • Kanazawa Y.
        • Yoshitome E.
        • et al.
        Negative correlation between brain glutathione level and negative symptoms in schizophrenia: A 3T 1H-MRS study.
        PLoS One. 2008; 3e1944
        • Wood S.J.
        • Berger G.E.
        • Wellard R.M.
        • Proffitt T.M.
        • McConchie M.
        • Berk M.
        • et al.
        Medial temporal lobe glutathione concentration in first episode psychosis: A 1H-MRS investigation.
        Neurobiol Dis. 2009; 33: 354-357
        • Hardingham G.E.
        • Do K.Q.
        Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis.
        Nat Rev Neurosci. 2016; 17: 125-134
        • Stedehouder J.
        • Kushner S.A.
        Myelination of parvalbumin interneurons: A parsimonious locus of pathophysiological convergence in schizophrenia.
        Mol Psychiatry. 2017; 22: 4-12
        • Steullet P.
        • Cabungcal J.H.
        • Coyle J.
        • Didriksen M.
        • Gill K.
        • Grace A.A.
        • et al.
        Oxidative stress-driven parvalbumin interneuron impairment as a common mechanism in models of schizophrenia.
        Mol Psychiatry. 2017; 22: 936-943
        • Maas D.A.
        • Vallès A.
        • Martens G.J.M.
        Oxidative stress, prefrontal cortex hypomyelination and cognitive symptoms in schizophrenia.
        Transl Psychiatry. 2017; 7e1171
        • French H.M.
        • Reid M.
        • Mamontov P.
        • Simmons R.A.
        • Grinspan J.B.
        Oxidative stress disrupts oligodendrocyte maturation.
        J Neurosci Res. 2009; 87: 3076-3087
        • Massaad C.A.
        • Klann E.
        Reactive oxygen species in the regulation of synaptic plasticity and memory.
        Antioxid Redox Signal. 2011; 14: 2013-2054
        • Uttara B.
        • Singh A.V.
        • Zamboni P.
        • Mahajan R.T.
        Oxidative stress and neurodegenerative diseases: A review of upstream and downstream antioxidant therapeutic options.
        Curr Neuropharmacol. 2009; 7: 65-74
        • Koga M.
        • Serritella A.V.
        • Sawa A.
        • Sedlak T.W.
        Implications for reactive oxygen species in schizophrenia pathogenesis.
        Schizophr Res. 2016; 176: 52-71
        • Holmstrom K.M.
        • Finkel T.
        Cellular mechanisms and physiological consequences of redox-dependent signalling.
        Nat Rev Mol Cell Biol. 2014; 15: 411-421
        • Cao S.S.
        • Kaufman R.J.
        Endoplasmic reticulum stress and oxidative stress in cell fate decision and human disease.
        Antioxid Redox Signal. 2014; 21: 396-413
        • Patel S.
        • Sharma D.
        • Kalia K.
        • Tiwari V.
        Crosstalk between endoplasmic reticulum stress and oxidative stress in schizophrenia: The dawn of new therapeutic approaches.
        Neurosci Biobehav Rev. 2017; 83: 589-603
        • Psychiatric GWAS Consortium Bipolar Disorder Working Group
        Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4.
        Nat Genet. 2011; 43: 977-983
        • Schizophrenia Psychiatric Genome-Wide Association Study, C
        Genome-wide association study identifies five new schizophrenia loci.
        Nat Genet. 2011; 43: 969-976
        • Cross-Disorder Group of the Psychiatric Genomics Consortium
        Identification of risk loci with shared effects on five major psychiatric disorders: A genome-wide analysis.
        Lancet. 2013; 381: 1371-1379
        • Schizophrenia Working Group of the Psychiatric Genomics Consortium
        Biological insights from 108 schizophrenia-associated genetic loci.
        Nature. 2014; 511: 421-427
        • Dubovsky S.L.
        • Daurignac E.
        • Leonard K.E.
        Increased platelet intracellular calcium ion concentration is specific to bipolar disorder.
        J Affect Disord. 2014; 164: 38-42
        • Dubovsky S.L.
        • Murphy J.
        • Thomas M.
        • Rademacher J.
        Abnormal intracellular calcium ion concentration in platelets and lymphocytes of bipolar patients.
        Am J Psychiatry. 1992; 149: 118-120
        • Linnoila M.
        • MacDonald E.
        • Reinila M.
        • Leroy A.
        • Rubinow D.R.
        • Goodwin F.K.
        RBC membrane adenosine triphosphatase activities in patients with major affective disorders.
        Arch Gen Psychiatry. 1983; 40: 1021-1026
        • Ripova D.
        • Strunecka A.
        • Nemcova V.
        • Farska I.
        Phospholipids and calcium alterations in platelets of schizophrenic patients.
        Physiol Res. 1997; 46: 59-68
        • Harrison P.J.
        Molecular neurobiological clues to the pathogenesis of bipolar disorder.
        Curr Opin Neurobiol. 2016; 36: 1-6
        • Warsh J.J.
        • Andreopoulos S.
        • Li P.P.
        Role of intracellular calcium signaling in the pathophysiology and pharmacotherapy of bipolar disorder: Current status.
        Clin Neurosci Res. 2004; 4: 201-213
        • Peng T.I.
        • Jou M.J.
        Oxidative stress caused by mitochondrial calcium overload.
        Ann N Y Acad Sci. 2010; 1201: 183-188
        • Feissner R.F.
        • Skalska J.
        • Gaum W.E.
        • Sheu S.S.
        Crosstalk signaling between mitochondrial Ca2+ and ROS.
        Front Biosci (Landmark Ed). 2009; 14: 1197-1218
        • Kriks S.
        • Shim J.W.
        • Piao J.
        • Ganat Y.M.
        • Wakeman D.R.
        • Xie Z.
        • et al.
        Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease.
        Nature. 2011; 480: 547-551
        • Oki K.
        • Tatarishvili J.
        • Wood J.
        • Koch P.
        • Wattananit S.
        • Mine Y.
        • et al.
        Human-induced pluripotent stem cells form functional neurons and improve recovery after grafting in stroke-damaged brain.
        Stem Cells. 2012; 30: 1120-1133
        • Shi Y.
        • Kirwan P.
        • Smith J.
        • Robinson H.P.
        • Livesey F.J.
        Human cerebral cortex development from pluripotent stem cells to functional excitatory synapses.
        Nat Neurosci. 2012; 15 (S471): 477-486
        • Haggarty S.J.
        • Silva M.C.
        • Cross A.
        • Brandon N.J.
        • Perlis R.H.
        Advancing drug discovery for neuropsychiatric disorders using patient-specific stem cell models.
        Mol Cell Neurosci. 2016; 73: 104-115
        • Ladewig J.
        • Mertens J.
        • Kesavan J.
        • Doerr J.
        • Poppe D.
        • Glaue F.
        • et al.
        Small molecules enable highly efficient neuronal conversion of human fibroblasts.
        Nat Methods. 2012; 9: 575-578
        • Passeri E.
        • Wilson A.M.
        • Primerano A.
        • Kondo M.A.
        • Sengupta S.
        • Srivastava R.
        • et al.
        Enhanced conversion of induced neuronal cells (iN cells) from human fibroblasts: Utility in uncovering cellular deficits in mental illness-associated chromosomal abnormalities.
        Neurosci Res. 2015; 101: 57-61
        • Pang Z.P.
        • Yang N.
        • Vierbuchen T.
        • Ostermeier A.
        • Fuentes D.R.
        • Yang T.Q.
        • et al.
        Induction of human neuronal cells by defined transcription factors.
        Nature. 2011; 476: 220-223
        • Kano S.
        • Yuan M.
        • Cardarelli R.A.
        • Maegawa G.
        • Higurashi N.
        • Gaval-Cruz M.
        • et al.
        Clinical utility of neuronal cells directly converted from fibroblasts of patients for neuropsychiatric disorders: Studies of lysosomal storage diseases and channelopathy.
        Curr Mol Med. 2015; 15: 138-145
        • 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: 785-798
        • Kano S.
        • Colantuoni C.
        • Han F.
        • Zhou Z.
        • Yuan Q.
        • Wilson A.
        • et al.
        Genome-wide profiling of multiple histone methylations in olfactory cells: Further implications for cellular susceptibility to oxidative stress in schizophrenia.
        Mol Psychiatry. 2013; 18: 740-742
        • Horiuchi Y.
        • Kano S.
        • Ishizuka K.
        • Cascella N.G.
        • Ishii S.
        • Talbot Jr., C.C.
        • et al.
        Olfactory cells via nasal biopsy reflect the developing brain in gene expression profiles: utility and limitation of the surrogate tissues in research for brain disorders.
        Neurosci Res. 2013; 77: 247-250
        • Mackay-Sim A.
        Concise review: Patient-derived olfactory stem cells: new models for brain diseases.
        Stem Cells. 2012; 30: 2361-2365
        • Gamo N.J.
        • Sawa A.
        Human stem cells and surrogate tissues for basic and translational study of mental disorders.
        Biol Psychiatry. 2014; 75: 918-919
        • O’Brien L.C.
        • Keeney P.M.
        • Bennett Jr., J.P.
        Differentiation of human neural stem cells into motor neurons stimulates mitochondrial biogenesis and decreases glycolytic flux.
        Stem Cells Dev. 2015; 24: 1984-1994
        • Saporta M.A.
        • Dang V.
        • Volfson D.
        • Zou B.
        • Xie X.S.
        • Adebola A.
        • et al.
        Axonal Charcot-Marie-Tooth disease patient-derived motor neurons demonstrate disease-specific phenotypes including abnormal electrophysiological properties.
        Exp Neurol. 2015; 263: 190-199
        • Robicsek O.
        • Karry R.
        • Petit I.
        • Salman-Kesner N.
        • Muller F.J.
        • 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: 1067-1076
        • Mertens J.
        • Wang Q.W.
        • Kim Y.
        • Yu D.X.
        • Pham S.
        • Yang B.
        • et al.
        Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder.
        Nature. 2015; 527: 95-99
        • van Os J.
        • Rutten B.P.
        • Poulton R.
        Gene-environment interactions in schizophrenia: Review of epidemiological findings and future directions.
        Schizophr Bull. 2008; 34: 1066-1082
        • Yang N.
        • Ng Y.H.
        • Pang Z.P.
        • Sudhof T.C.
        • Wernig M.
        Induced neuronal cells: How to make and define a neuron.
        Cell Stem Cell. 2011; 9: 517-525
        • Lavoie J.
        • Gasso Astorga P.
        • Segal-Gavish H.
        • Wu Y.C.
        • Chung Y.
        • Cascella N.G.
        • et al.
        The olfactory neural epithelium as a tool in neuroscience.
        Trends Mol Med. 2017; 23: 100-103
        • Brennand K.
        • Savas J.N.
        • 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: 361-368
        • 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: 1547-1559
        • Hahn C.G.
        • Gomez G.
        • Restrepo D.
        • Friedman E.
        • Josiassen R.
        • Pribitkin E.A.
        • et al.
        Aberrant intracellular calcium signaling in olfactory neurons from patients with bipolar disorder.
        Am J Psychiatry. 2005; 162: 616-618
        • Stern S.
        • Santos R.
        • Marchetto M.C.
        • Mendes A.P.
        • Rouleau G.A.
        • Biesmans S.
        • et al.
        Neurons derived from patients with bipolar disorder divide into intrinsically different sub-populations of neurons, predicting the patients’ responsiveness to lithium.
        Mol Psychiatry. 2017; ([published online ahead of print Feb 28])
        • Shtrichman R.
        • Germanguz I.
        • Itskovitz-Eldor J.
        Induced pluripotent stem cells (iPSCs) derived from different cell sources and their potential for regenerative and personalized medicine.
        Curr Mol Med. 2013; 13: 792-805
        • Sanchez-Freire V.
        • Lee A.S.
        • Hu S.
        • Abilez O.J.
        • Liang P.
        • Lan F.
        • et al.
        Effect of human donor cell source on differentiation and function of cardiac induced pluripotent stem cells.
        J Am Coll Cardiol. 2014; 64: 436-448
        • Kyttälä A.
        • Moraghebi R.
        • Valensisi C.
        • Kettunen J.
        • Andrus C.
        • Pasumarthy K.K.
        • et al.
        Genetic variability overrides the impact of parental cell type and determines iPSC differentiation potential.
        Stem Cell Reports. 2016; 6: 200-212
        • Fagiolini A.
        • Chengappa K.N.
        • Soreca I.
        • Chang J.
        Bipolar disorder and the metabolic syndrome: Causal factors, psychiatric outcomes and economic burden.
        CNS Drugs. 2008; 22: 655-669
        • Vancampfort D.
        • Stubbs B.
        • Mitchell A.J.
        • De Hert M.
        • Wampers M.
        • Ward P.B.
        • et al.
        Risk of metabolic syndrome and its components in people with schizophrenia and related psychotic disorders, bipolar disorder and major depressive disorder: a systematic review and meta-analysis.
        World Psychiatry. 2015; 14: 339-347
        • Correll C.U.
        • Joffe B.I.
        • Rosen L.M.
        • Sullivan T.B.
        • Joffe R.T.
        Cardiovascular and cerebrovascular risk factors and events associated with second-generation antipsychotic compared to antidepressant use in a non-elderly adult sample: Results from a claims-based inception cohort study.
        World Psychiatry. 2015; 14: 56-63
        • Lancaster M.A.
        • Knoblich J.A.
        Organogenesis in a dish: Modeling development and disease using organoid technologies.
        Science. 2014; 345: 1247125
        • Lancaster M.A.
        • Renner M.
        • Martin C.A.
        • Wenzel D.
        • Bicknell L.S.
        • Hurles M.E.
        • et al.
        Cerebral organoids model human brain development and microcephaly.
        Nature. 2013; 501: 373-379
        • Qian X.
        • Nguyen H.N.
        • Song M.M.
        • Hadiono C.
        • Ogden S.C.
        • Hammack C.
        • et al.
        Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure.
        Cell. 2016; 165: 1238-1254
        • Di Lullo E.
        • Kriegstein A.R.
        The use of brain organoids to investigate neural development and disease.
        Nat Rev Neurosci. 2017; 18: 573-584
        • Nestler E.J.
        • Hyman S.E.
        Animal models of neuropsychiatric disorders.
        Nat Neurosci. 2010; 13: 1161-1169
        • Kaiser T.
        • Feng G.
        Modeling psychiatric disorders for developing effective treatments.
        Nat Med. 2015; 21: 979-988
        • Ugurbil K.
        What is feasible with imaging human brain function and connectivity using functional magnetic resonance imaging.
        Philos Trans R Soc Lond B Biol Sci. 2016; 371 (20150361)
        • Nguyen H.N.
        • Byers B.
        • Cord B.
        • Shcheglovitov A.
        • Byrne J.
        • Gujar P.
        • et al.
        LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress.
        Cell Stem Cell. 2011; 8: 267-280
        • Suzuki S.
        • Akamatsu W.
        • Kisa F.
        • Sone T.
        • Ishikawa K.I.
        • Kuzumaki N.
        • et al.
        Efficient induction of dopaminergic neuron differentiation from induced pluripotent stem cells reveals impaired mitophagy in PARK2 neurons.
        Biochem Biophys Res Commun. 2017; 483: 88-93
        • Chen H.M.
        • DeLong C.J.
        • Bame M.
        • Rajapakse I.
        • Herron T.J.
        • McInnis M.G.
        • et al.
        Transcripts involved in calcium signaling and telencephalic neuronal fate are altered in induced pluripotent stem cells from bipolar disorder patients.
        Transl Psychiatry. 2014; 4: e375
        • Yoshimizu T.
        • Pan J.Q.
        • Mungenast A.E.
        • Madison J.M.
        • Su S.
        • Ketterman J.
        • et al.
        Functional implications of a psychiatric risk variant within CACNA1C in induced human neurons.
        Mol Psychiatry. 2015; 20: 162-169