Abstract
Schizophrenia (SZ) is a devastating psychiatric condition affecting numerous brain systems. Recent studies have identified genetic factors that confer an increased risk of SZ and participate in the disease etiopathogenesis. In parallel to such bottom-up approaches, other studies have extensively reported biological changes in patients by brain imaging, neurochemical and pharmacological approaches. This review highlights the molecular substrates identified through studies with SZ patients, namely those using top-down approaches, while also referring to the fruitful outcomes of recent genetic studies. We have subclassified the molecular substrates by system, focusing on elements of neurotransmission, targets in white matter-associated connectivity, immune/inflammatory and oxidative stress-related substrates, and molecules in endocrine and metabolic cascades. We further touch on cross-talk among these systems and comment on the utility of animal models in charting the developmental progression and interaction of these substrates. Based on this comprehensive information, we propose a framework for SZ research based on the hypothesis of an imbalance in homeostatic signaling from immune/inflammatory, oxidative stress, endocrine and metabolic cascades that, at least in part, underlies deficits in neural connectivity relevant to SZ. Thus, this review aims to provide information that is translationally useful and complementary to pathogenic hypotheses that have emerged from genetic studies. Based on such advances in SZ research, it is highly expected that we will discover biomarkers that may help in the early intervention, diagnosis or treatment of SZ.
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References
Perala J, Suvisaari J, Saarni SI, Kuoppasalmi K, Isometsa E, Pirkola S et al. Lifetime prevalence of psychotic and bipolar I disorders in a general population. Arch Gen Psychiatry 2007; 64: 19–28.
van Os J, Linscott RJ, Myin-Germeys I, Delespaul P, Krabbendam L . A systematic review and meta-analysis of the psychosis continuum: evidence for a psychosis proneness-persistence-impairment model of psychotic disorder. Psychol Med 2009; 39: 179–195.
van Os J, Kapur S . Schizophrenia. Lancet 2009; 374: 635–645.
Jaaro-Peled H, Hayashi-Takagi A, Seshadri S, Kamiya A, Brandon NJ, Sawa A . Neurodevelopmental mechanisms of schizophrenia: understanding disturbed postnatal brain maturation through neuregulin-1-ErbB4 and DISC1. Trends Neurosci 2009; 32: 485–495.
Seeman P, Lee T . Antipsychotic drugs: direct correlation between clinical potency and presynaptic action on dopamine neurons. Science (New York, NY) 1975; 188: 1217–1219.
Creese I, Burt DR, Snyder SH . Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science (New York, NY) 1976; 192: 481–483.
Snyder SH . The dopamine hypothesis of schizophrenia: focus on the dopamine receptor. Am J Psychiatry 1976; 133: 197–202.
Merritt K, McGuire P, Egerton A . Relationship between glutamate dysfunction and symptoms and cognitive function in psychosis. Front Psychiatry 2013; 4: 151.
Javitt DC, Zukin SR . Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 1991; 148: 1301–1308.
Purcell SM, Wray NR, Stone JL, Visscher PM, O'Donovan MC, Sullivan PF et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 2009; 460: 748–752.
Ripke S, O'Dushlaine C, Chambert K, Moran JL, Kahler AK, Akterin S et al. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet 2013; 45: 1150–1159.
Purcell SM, Moran JL, Fromer M, Ruderfer D, Solovieff N, Roussos P et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature 2014; 506: 185–190.
Doherty JL, O'Donovan MC, Owen MJ . Recent genomic advances in schizophrenia. Clin Genet 2012; 81: 103–109.
Fromer M, Pocklington AJ, Kavanagh DH, Williams HJ, Dwyer S, Gormley P et al. De novo mutations in schizophrenia implicate synaptic networks. Nature 2014; 506: 179–184.
Carroll LS, Owen MJ . Genetic overlap between autism, schizophrenia and bipolar disorder. Genome Med 2009; 1: 102.
Lee SH, Ripke S, Neale BM, Faraone SV, Purcell SM, Perlis RH et al. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat Genet 2013; 45: 984–994.
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.
Brandon NJ, Sawa A . Linking neurodevelopmental and synaptic theories of mental illness through DISC1. Nat Rev Neurosci 2011; 12: 707–722.
Insel T, Cuthbert B, Garvey M, Heinssen R, Pine DS, Quinn K et al. Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am J Psychiatry 2010; 167: 748–751.
Malhotra D, Sebat J . CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell 2012; 148: 1223–1241.
Sullivan PF, Daly MJ, O'Donovan M . Genetic architectures of psychiatric disorders: the emerging picture and its implications. Nat Rev Genet 2012; 13: 537–551.
Pratt J, Winchester C, Dawson N, Morris B . Advancing schizophrenia drug discovery: optimizing rodent models to bridge the translational gap. Nat Rev Drug Discov 2012; 11: 560–579.
Jaaro-Peled H, Ayhan Y, Pletnikov MV, Sawa A . Review of pathological hallmarks of schizophrenia: comparison of genetic models with patients and nongenetic models. Schizophr Bull 2010; 36: 301–313.
Kvajo M, McKellar H, Gogos JA . Avoiding mouse traps in schizophrenia genetics: lessons and promises from current and emerging mouse models. Neuroscience 2012; 211: 136–164.
Hartwell L, Mankoff D, Paulovich A, Ramsey S, Swisher E . Cancer biomarkers: a systems approach. Nat Biotechnol 2006; 24: 905–908.
Lusis AJ, Attie AD, Reue K . Metabolic syndrome: from epidemiology to systems biology. Nat Rev Genet 2008; 9: 819–830.
Orešič M . Systems Biology in Human Health and Disease. In: Orešič M, Vidal-Puig A, editors. A Systems Biology Approach to Study Metabolic Syndrome. Springer International Publishing: Dordrecht, pp 17–23, 2014.
Zhang B, Gaiteri C, Bodea LG, Wang Z, McElwee J, Podtelezhnikov AA et al. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease. Cell 2013; 153: 707–720.
McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr., Kawas CH et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimer's Dement 2011; 7: 263–269.
McGowan S, Lawrence AD, Sales T, Quested D, Grasby P . Presynaptic dopaminergic dysfunction in schizophrenia: a positron emission tomographic [18 F]fluorodopa study. Arch Gen Psychiatry 2004; 61: 134–142.
Howes OD, Montgomery AJ, Asselin MC, Murray RM, Valli I, Tabraham P et al. Elevated striatal dopamine function linked to prodromal signs of schizophrenia. Arch Gen Psychiatry 2009; 66: 13–20.
Meyer-Lindenberg A, Miletich RS, Kohn PD, Esposito G, Carson RE, Quarantelli M et al. Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nat Neurosci 2002; 5: 267–271.
Nozaki S, Kato M, Takano H, Ito H, Takahashi H, Arakawa R et al. Regional dopamine synthesis in patients with schizophrenia using L-[beta-11C]DOPA PET. Schizophr Res 2009; 108: 78–84.
Egerton A, Chaddock CA, Winton-Brown TT, Bloomfield MA, Bhattacharyya S, Allen P et al. Presynaptic striatal dopamine dysfunction in people at ultra-high risk for psychosis: findings in a second cohort. Biol Psychiatry 2013; 74: 106–112.
Breier A, Su TP, Saunders R, Carson RE, Kolachana BS, de Bartolomeis A et al. Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc Natl Acad Sci USA 1997; 94: 2569–2574.
Laruelle M, Abi-Dargham A, van Dyck CH, Gil R, D'Souza CD, Erdos J et al. Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci USA 1996; 93: 9235–9240.
Abi-Dargham A, Gil R, Krystal J, Baldwin RM, Seibyl JP, Bowers M et al. Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am J Psychiatry 1998; 155: 761–767.
Howes OD, Kapur S . The dopamine hypothesis of schizophrenia: version III—the final common pathway. Schizophr Bull 2009; 35: 549–562.
Kegeles LS, Abi-Dargham A, Frankle WG, Gil R, Cooper TB, Slifstein M et al. Increased synaptic dopamine function in associative regions of the striatum in schizophrenia. Arch Gen Psychiatry 2010; 67: 231–239.
Laruelle M . Imaging dopamine transmission in schizophrenia. A review and meta-analysis. Q J Nucl Med 1998; 42: 211–221.
Kuepper R, Skinbjerg M, Abi-Dargham A . The dopamine dysfunction in schizophrenia revisited: new insights into topography and course. Handb Exp Pharmacol 2012; 212: 1–26.
Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014; 511: 421–427.
Okubo Y, Suhara T, Suzuki K, Kobayashi K, Inoue O, Terasaki O et al. Decreased prefrontal dopamine D1 receptors in schizophrenia revealed by PET. Nature 1997; 385: 634–636.
Karlsson P, Farde L, Halldin C, Sedvall G . PET study of D(1) dopamine receptor binding in neuroleptic-naive patients with schizophrenia. Am J Psychiatry 2002; 159: 761–767.
Abi-Dargham A, Xu X, Thompson JL, Gil R, Kegeles LS, Urban N et al. Increased prefrontal cortical D(1) receptors in drug naive patients with schizophrenia: a PET study with [(1)(1)C]NNC112. J Psychopharmacol 2012; 26: 794–805.
Kestler LP, Walker E, Vega EM . Dopamine receptors in the brains of schizophrenia patients: a meta-analysis of the findings. Behav Pharmacol 2001; 12: 355–371.
Beuger M, van Kammen DP, Kelley ME, Yao J . Dopamine turnover in schizophrenia before and after haloperidol withdrawal. CSF, plasma, and urine studies. Neuropsychopharmacology 1996; 15: 75–86.
Wieselgren IM, Lindstrom LH . CSF levels of HVA and 5-HIAA in drug-free schizophrenic patients and healthy controls: a prospective study focused on their predictive value for outcome in schizophrenia. Psychiatry Res 1998; 81: 101–110.
Davis KL, Kahn RS, Ko G, Davidson M . Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry 1991; 148: 1474–1486.
Meador-Woodruff JH, Haroutunian V, Powchik P, Davidson M, Davis KL, Watson SJ . Dopamine receptor transcript expression in striatum and prefrontal and occipital cortex. Focal abnormalities in orbitofrontal cortex in schizophrenia. Arch Gen Psychiatry 1997; 54: 1089–1095.
Pantazopoulos H, Stone D, Walsh J, Benes FM . Differences in the cellular distribution of D1 receptor mRNA in the hippocampus of bipolars and schizophrenics. Synapse (New York, NY) 2004; 54: 147–155.
Akil M, Pierri JN, Whitehead RE, Edgar CL, Mohila C, Sampson AR et al. Lamina-specific alterations in the dopamine innervation of the prefrontal cortex in schizophrenic subjects. Am J Psychiatry 1999; 156: 1580–1589.
Akil M, Edgar CL, Pierri JN, Casali S, Lewis DA . Decreased density of tyrosine hydroxylase-immunoreactive axons in the entorhinal cortex of schizophrenic subjects. Biol Psychiatry 2000; 47: 361–370.
Abi-Dargham A, Rodenhiser J, Printz D, Zea-Ponce Y, Gil R, Kegeles LS et al. Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci USA 2000; 97: 8104–8109.
Weinberger DR, Berman KF, Daniel DG . Mesoprefrontal cortical dopaminergic activity and prefrontal hypofunction in schizophrenia. Clin Neuropharmacol 1992; 15: 568 A–569.
Meltzer HY, Matsubara S, Lee JC . Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. J Pharmacol Exp Ther 1989; 251: 238–246.
Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Babler A, Vogel H, Hell D . Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. Neuroreport 1998; 9: 3897–3902.
Burnet PW, Eastwood SL, Harrison PJ . 5-HT1A and 5-HT2A receptor mRNAs and binding site densities are differentially altered in schizophrenia. Neuropsychopharmacology 1996; 15: 442–455.
Anticevic A, Gancsos M, Murray JD, Repovs G, Driesen NR, Ennis DJ et al. NMDA receptor function in large-scale anticorrelated neural systems with implications for cognition and schizophrenia. Proc Natl Acad Sci USA 2012; 109: 16720–16725.
Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 1994; 51: 199–214.
Glantz LA, Lewis DA . Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch Gen Psychiatry 2000; 57: 65–73.
Garey LJ, Ong WY, Patel TS, Kanani M, Davis A, Mortimer AM et al. Reduced dendritic spine density on cerebral cortical pyramidal neurons in schizophrenia. J Neurol Neurosurg Psychiatry 1998; 65: 446–453.
Ayalew M, Le-Niculescu H, Levey DF, Jain N, Changala B, Patel SD et al. Convergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk prediction. Mol Psychiatry 2012; 17: 887–905.
Poels EM, Kegeles LS, Kantrowitz JT, Slifstein M, Javitt DC, Lieberman JA et al. Imaging glutamate in schizophrenia: review of findings and implications for drug discovery. Mol Psychiatry 2014; 19: 20–29.
Marsman A, van den Heuvel MP, Klomp DW, Kahn RS, Luijten PR, Hulshoff Pol HE . Glutamate in schizophrenia: a focused review and meta-analysis of (1)H-MRS studies. Schizophr Bull 2013; 39: 120–129.
Kegeles LS, Mao X, Stanford AD, Girgis R, Ojeil N, Xu X et al. Elevated prefrontal cortex gamma-aminobutyric acid and glutamate-glutamine levels in schizophrenia measured in vivo with proton magnetic resonance spectroscopy. Arch Gen Psychiatry 2012; 69: 449–459.
Egerton A, Brugger S, Raffin M, Barker GJ, Lythgoe DJ, McGuire PK et al. Anterior cingulate glutamate levels related to clinical status following treatment in first-episode schizophrenia. Neuropsychopharmacology 2012; 37: 2515–2521.
Demjaha A, Egerton A, Murray RM, Kapur S, Howes OD, Stone JM et al. Antipsychotic treatment resistance in schizophrenia associated with elevated glutamate levels but normal dopamine function. Biol Psychiatry 2014; 75: e11–e13.
Stan AD, Ghose S, Zhao C, Hulsey K, Mihalakos P, Yanagi M et al. Magnetic resonance spectroscopy and tissue protein concentrations together suggest lower glutamate signaling in dentate gyrus in schizophrenia. Mol Psychiatry 2014; 20: 433–439.
Tsai G, van Kammen DP, Chen S, Kelley ME, Grier A, Coyle JT . Glutamatergic neurotransmission involves structural and clinical deficits of schizophrenia. Biol Psychiatry 1998; 44: 667–674.
Hashimoto K, Engberg G, Shimizu E, Nordin C, Lindstrom LH, Iyo M . Elevated glutamine/glutamate ratio in cerebrospinal fluid of first episode and drug naive schizophrenic patients. BMC Psychiatry 2005; 5: 6.
Do KQ, Lauer CJ, Schreiber W, Zollinger M, Gutteck-Amsler U, Cuenod M et al. gamma-Glutamylglutamine and taurine concentrations are decreased in the cerebrospinal fluid of drug-naive patients with schizophrenic disorders. J Neurochem 1995; 65: 2652–2662.
Schobel SA, Lewandowski NM, Corcoran CM, Moore H, Brown T, Malaspina D et al. Differential targeting of the CA1 subfield of the hippocampal formation by schizophrenia and related psychotic disorders. Arch Gen Psychiatry 2009; 66: 938–946.
Schobel SA, Chaudhury NH, Khan UA, Paniagua B, Styner MA, Asllani I et al. Imaging patients with psychosis and a mouse model establishes a spreading pattern of hippocampal dysfunction and implicates glutamate as a driver. Neuron 2013; 78: 81–93.
Wandinger KP, Saschenbrecker S, Stoecker W, Dalmau J . Anti-NMDA-receptor encephalitis: a severe, multistage, treatable disorder presenting with psychosis. J Neuroimmunol 2011; 231: 86–91.
Dalmau J, Gleichman AJ, Hughes EG, Rossi JE, Peng X, Lai M et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 2008; 7: 1091–1098.
Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R . Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol 2011; 10: 63–74.
Vincent A, Bien CG, Irani SR, Waters P . Autoantibodies associated with diseases of the CNS: new developments and future challenges. Lancet Neurol 2011; 10: 759–772.
Lesher AP, Myers TJ, Tecklenburg F, Streck CJ . Anti-N-methyl-D-aspartate receptor encephalitis associated with an ovarian teratoma in an adolescent female. J Pediatr Surg 2010; 45: 1550–1553.
Seki M, Suzuki S, Iizuka T, Shimizu T, Nihei Y, Suzuki N et al. Neurological response to early removal of ovarian teratoma in anti-NMDAR encephalitis. J Neurol Neurosurg Psychiatry 2008; 79: 324–326.
Goto N, Yoshimura R, Moriya J, Kakeda S, Ueda N, Ikenouchi-Sugita A et al. Reduction of brain gamma-aminobutyric acid (GABA) concentrations in early-stage schizophrenia patients: 3 T Proton MRS study. Schizophr Research 2009; 112: 192–193.
Tayoshi S, Nakataki M, Sumitani S, Taniguchi K, Shibuya-Tayoshi S, Numata S et al. GABA concentration in schizophrenia patients and the effects of antipsychotic medication: a proton magnetic resonance spectroscopy study. Schizophr Res 2010; 117: 83–91.
Yoon JH, Maddock RJ, Rokem A, Silver MA, Minzenberg MJ, Ragland JD et al. GABA concentration is reduced in visual cortex in schizophrenia and correlates with orientation-specific surround suppression. J Neurosci 2010; 30: 3777–3781.
Ongur D, Prescot AP, McCarthy J, Cohen BM, Renshaw PF . Elevated gamma-aminobutyric acid levels in chronic schizophrenia. Biol Psychiatry 2010; 68: 667–670.
Rowland LM, Kontson K, West J, Edden RA, Zhu H, Wijtenburg SA et al. In vivo measurements of glutamate, GABA, and NAAG in schizophrenia. Schizophr Bull 2013; 39: 1096–1104.
Cousijn H, Haegens S, Wallis G, Near J, Stokes MG, Harrison PJ et al. Resting GABA and glutamate concentrations do not predict visual gamma frequency or amplitude. Proc Natl Acad Sci USA 2014; 111: 9301–9306.
Gerner RH, Hare TA . CSF GABA in normal subjects and patients with depression, schizophrenia, mania, and anorexia nervosa. Am J Psychiatry 1981; 138: 1098–1101.
Lichtshtein D, Dobkin J, Ebstein RP, Biederman J, Rimon R, Belmaker RH . Gamma-aminobutyric acid (GABA) in the CSF of schizophrenic patients before and after neuroleptic treatment. Br J Psychiatry 1978; 132: 145–148.
Petty F, Sherman AD . Plasma GABA levels in psychiatric illness. J Affect Disord 1984; 6: 131–138.
van Kammen DP, Sternberg DE, Hare TA, Waters RN, Bunney WE Jr. . CSF levels of gamma-aminobutyric acid in schizophrenia. Low values in recently ill patients. Arch Gen Psychiatry 1982; 39: 91–97.
McCarthy BW, Gomes UR, Neethling AC, Shanley BC, Taljaard JJ, Potgieter L et al. gamma-Aminobutyric acid concentration in cerebrospinal fluid in schizophrenia. J Neurochem 1981; 36: 1406–1408.
Benes FM, Berretta S . GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology 2001; 25: 1–27.
Volk DW, Lewis DA . Early developmental disturbances of cortical inhibitory neurons: contribution to cognitive deficits in schizophrenia. Schizophr Bull 2014; 40: 952–957.
Hashimoto T, Volk DW, Eggan SM, Mirnics K, Pierri JN, Sun Z et al. Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia. J Neurosci 2003; 23: 6315–6326.
Volk DW, Matsubara T, Li S, Sengupta EJ, Georgiev D, Minabe Y et al. Deficits in transcriptional regulators of cortical parvalbumin neurons in schizophrenia. Am J Psychiatry 2012; 169: 1082–1091.
Akbarian S, Kim JJ, Potkin SG, Hagman JO, Tafazzoli A, Bunney WE Jr. et al. Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics. Arch Gen Psychiatry 1995; 52: 258–266.
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: 1061–1069.
Curley AA, Arion D, Volk DW, Asafu-Adjei JK, Sampson AR, Fish KN et al. Cortical deficits of glutamic acid decarboxylase 67 expression in schizophrenia: clinical, protein, and cell type-specific features. Am J Psychiatry 2011; 168: 921–929.
Yanagi M, Joho RH, Southcott SA, Shukla AA, Ghose S, Tamminga CA . Kv3.1-containing K(+) channels are reduced in untreated schizophrenia and normalized with antipsychotic drugs. Mol Psychiatry 2014; 19: 573–579.
Georgiev D, Arion D, Enwright JF, Kikuchi M, Minabe Y, Corradi JP et al. Lower gene expression for KCNS3 potassium channel subunit in parvalbumin-containing neurons in the prefrontal cortex in schizophrenia. Am J Psychiatry 2014; 171: 62–71.
Lewis DA, Hashimoto T, Volk DW . Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 2005; 6: 312–324.
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: 147–161.
Adler LE, Hoffer LD, Wiser A, Freedman R . Normalization of auditory physiology by cigarette smoking in schizophrenic patients. Am J Psychiatry 1993; 150: 1856–1861.
Chen XS, Li CB, Smith RC, Xiao ZP, Wang JJ . Differential sensory gating functions between smokers and non-smokers among drug-naive first episode schizophrenic patients. Psychiatry Res 2011; 188: 327–333.
Kumari V, Soni W, Sharma T . Influence of cigarette smoking on prepulse inhibition of the acoustic startle response in schizophrenia. Hum Psychopharmacol 2001; 16: 321–326.
Freedman R, Coon H, Myles-Worsley M, Orr-Urtreger A, Olincy A, Davis A et al. Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proc Natl Acad Sci USA 1997; 94: 587–592.
Kaufmann CA, Suarez B, Malaspina D, Pepple J, Svrakic D, Markel PD et al. NIMH Genetics Initiative Millenium Schizophrenia Consortium: linkage analysis of African-American pedigrees. Am J Med Genet 1998; 81: 282–289.
Riley BP, Makoff A, Mogudi-Carter M, Jenkins T, Williamson R, Collier D et al. Haplotype transmission disequilibrium and evidence for linkage of the CHRNA7 gene region to schizophrenia in Southern African Bantu families. Am J Med Genet 2000; 96: 196–201.
Freedman R, Hall M, Adler LE, Leonard S . Evidence in postmortem brain tissue for decreased numbers of hippocampal nicotinic receptors in schizophrenia. Biol Psychiatry 1995; 38: 22–33.
Court J, Spurden D, Lloyd S, McKeith I, Ballard C, Cairns N et al. Neuronal nicotinic receptors in dementia with Lewy bodies and schizophrenia: alpha-bungarotoxin and nicotine binding in the thalamus. JNeurochem 1999; 73: 1590–1597.
Marutle A, Zhang X, Court J, Piggott M, Johnson M, Perry R et al. Laminar distribution of nicotinic receptor subtypes in cortical regions in schizophrenia. J Chem Neuroanat 2001; 22: 115–126.
D'Souza DC, Esterlis I, Carbuto M, Krasenics M, Seibyl J, Bois F et al. Lower ss2*-nicotinic acetylcholine receptor availability in smokers with schizophrenia. Am J Psychiatry 2012; 169: 326–334.
Brasic JR, Cascella N, Kumar A, Zhou Y, Hilton J, Raymont V et al. Positron emission tomography experience with 2-[(1)(8)F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[(1)(8)F]FA) in the living human brain of smokers with paranoid schizophrenia. Synapse (New York, NY) 2012; 66: 352–368.
Seshadri S, Zeledon M, Sawa A . Synapse-specific contributions in the cortical pathology of schizophrenia. Neurobiol Dis 2013; 53: 26–35.
Hayashi-Takagi A, Takaki M, Graziane N, Seshadri S, Murdoch H, Dunlop AJ et al. Disrupted-in-Schizophrenia 1 (DISC1) regulates spines of the glutamate synapse via Rac1. Nat Neurosci 2010; 13: 327–332.
Hayashi-Takagi A, Araki Y, Nakamura M, Vollrath B, Duron SG, Yan Z et al. PAKs inhibitors ameliorate schizophrenia-associated dendritic spine deterioration in vitro and in vivo during late adolescence. Proc Natl Acad Sci USA 2014; 111: 6461–6466.
Morris DW, Pearson RD, Cormican P, Kenny EM, O'Dushlaine CT, Perreault LP et al. An inherited duplication at the gene p21 Protein-Activated Kinase 7 (PAK7) is a risk factor for psychosis. Hum Mol Genet 2014; 23: 3316–3326.
Mirnics K, Middleton FA, Marquez A, Lewis DA, Levitt P . Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex. Neuron 2000; 28: 53–67.
Arancibia-Carcamo IL, Attwell D . The node of Ranvier in CNS pathology. Acta Neuropathol 2014; 128: 161–175.
Bjartmar C, Yin X, Trapp BD . Axonal pathology in myelin disorders. J Neurocytol 1999; 28: 383–395.
Shenton ME, Whitford TJ, Kubicki M . Structural neuroimaging in schizophrenia: from methods to insights to treatments. Dial Clin Neurosci 2010; 12: 317–332.
Kanaan R, Barker G, Brammer M, Giampietro V, Shergill S, Woolley J et al. White matter microstructure in schizophrenia: effects of disorder, duration and medication. Br J Psychiatry 2009; 194: 236–242.
White T, Nelson M, Lim KO . Diffusion tensor imaging in psychiatric disorders. Top Magn Reson Imaging 2008; 19: 97–109.
Ellison-Wright I, Bullmore E . Meta-analysis of diffusion tensor imaging studies in schizophrenia. Schizophr Res 2009; 108: 3–10.
Witthaus H, Brune M, Kaufmann C, Bohner G, Ozgurdal S, Gudlowski Y et al. White matter abnormalities in subjects at ultra high-risk for schizophrenia and first-episode schizophrenic patients. Schizophr Res 2008; 102: 141–149.
Epstein KA, Cullen KR, Mueller BA, Robinson P, Lee S, Kumra S . White matter abnormalities and cognitive impairment in early-onset schizophrenia-spectrum disorders. J Am Acad Child Adolesc Psychiatry 2014; 53: 362–72 e1-2.
Andreasen NC, Nopoulos P, Magnotta V, Pierson R, Ziebell S, Ho BC . Progressive brain change in schizophrenia: a prospective longitudinal study of first-episode schizophrenia. Biol Psychiatry 2011; 70: 672–679.
Yang GJ, Murray JD, Repovs G, Cole MW, Savic A, Glasser MF et al. Altered global brain signal in schizophrenia. Proc Natl Acad Sci USA 2014; 111: 7438–7443.
Lynall ME, Bassett DS, Kerwin R, McKenna PJ, Kitzbichler M, Muller U et al. Functional connectivity and brain networks in schizophrenia. J Neurosci 2010; 30: 9477–9487.
Cole MW, Anticevic A, Repovs G, Barch D . Variable global dysconnectivity and individual differences in schizophrenia. Biol Psychiatry 2011; 70: 43–50.
Baker JT, Holmes AJ, Masters GA, Yeo BT, Krienen F, Buckner RL et al. Disruption of cortical association networks in schizophrenia and psychotic bipolar disorder. JAMA Psychiatry 2014; 71: 109–118.
Woodward ND, Karbasforoushan H, Heckers S . Thalamocortical dysconnectivity in schizophrenia. Am J Psychiatry 2012; 169: 1092–1099.
Anticevic A, Cole MW, Repovs G, Murray JD, Brumbaugh MS, Winkler AM et al. Characterizing Thalamo-Cortical Disturbances in Schizophrenia and Bipolar Illness. Cereb Cortex (New York, NY: 1991) 2013; 24: 3116–3130.
Jeong B, Kubicki M . Reduced task-related suppression during semantic repetition priming in schizophrenia. Psychiatry Res 2010; 181: 114–120.
Chai XJ, Whitfield-Gabrieli S, Shinn AK, Gabrieli JD, Nieto Castanon A, McCarthy JM et al. Abnormal medial prefrontal cortex resting-state connectivity in bipolar disorder and schizophrenia. Neuropsychopharmacology 2011; 36: 2009–2017.
Anticevic A, Cole MW, Murray JD, Corlett PR, Wang XJ, Krystal JH . The role of default network deactivation in cognition and disease. Trends Cogn Sci 2012; 16: 584–592.
Fitzsimmons J, Kubicki M, Shenton ME . Review of functional and anatomical brain connectivity findings in schizophrenia. Curr Opin Psychiatry 2013; 26: 172–187.
Fornito A, Zalesky A, Pantelis C, Bullmore ET . Schizophrenia, neuroimaging and connectomics. NeuroImage. 2012; 62: 2296–2314.
Anticevic A, Cole MW, Repovs G, Savic A, Driesen NR, Yang G et al. Connectivity, pharmacology, and computation: toward a mechanistic understanding of neural system dysfunction in schizophrenia. Front Psychiatry 2013; 4: 169.
Sequeira PA, Martin MV, Vawter MP . The first decade and beyond of transcriptional profiling in schizophrenia. Neurobiol Dis 2012; 45: 23–36.
Hof PR, Haroutunian V, Friedrich VL Jr., Byne W, Buitron C, Perl DP et al. Loss and altered spatial distribution of oligodendrocytes in the superior frontal gyrus in schizophrenia. Biol Psychiatry 2003; 53: 1075–1085.
Hakak Y, Walker JR, Li C, Wong WH, Davis KL, Buxbaum JD et al. Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia. Proc Natl Acad Sci USA 2001; 98: 4746–4751.
Tkachev D, Mimmack ML, Ryan MM, Wayland M, Freeman T, Jones PB et al. Oligodendrocyte dysfunction in schizophrenia and bipolar disorder. Lancet 2003; 362: 798–805.
Aston C, Jiang L, Sokolov BP . Microarray analysis of postmortem temporal cortex from patients with schizophrenia. J Neurosci Res 2004; 77: 858–866.
Katsel P, Davis KL, Haroutunian V . Variations in myelin and oligodendrocyte-related gene expression across multiple brain regions in schizophrenia: a gene ontology study. Schizophr Res 2005; 79: 157–173.
Haroutunian V, Katsel P, Dracheva S, Stewart DG, Davis KL . Variations in oligodendrocyte-related gene expression across multiple cortical regions: implications for the pathophysiology of schizophrenia. Int J Neuropsychopharmacol 2007; 10: 565–573.
Takahashi N, Sakurai T, Davis KL, Buxbaum JD . Linking oligodendrocyte and myelin dysfunction to neurocircuitry abnormalities in schizophrenia. Prog Neurobiol 2011; 93: 13–24.
Stefansson H, Sigurdsson E, Steinthorsdottir V, Bjornsdottir S, Sigmundsson T, Ghosh S et al. Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 2002; 71: 877–892.
Williams NM, Preece A, Spurlock G, Norton N, Williams HJ, Zammit S et al. Support for genetic variation in neuregulin 1 and susceptibility to schizophrenia. Mol Psychiatry 2003; 8: 485–487.
Corfas G, Roy K, Buxbaum JD . Neuregulin 1-erbB signaling and the molecular/cellular basis of schizophrenia. Nat Neurosci 2004; 7: 575–580.
Novak G, Kim D, Seeman P, Tallerico T . Schizophrenia and Nogo: elevated mRNA in cortex, and high prevalence of a homozygous CAA insert. Brain Res Mol Brain Res 2002; 107: 183–189.
Tan EC, Chong SA, Wang H, Chew-Ping Lim E, Teo YY . Gender-specific association of insertion/deletion polymorphisms in the nogo gene and chronic schizophrenia. Brain Res Mol Brain Res 2005; 139: 212–216.
Sinibaldi L, De Luca A, Bellacchio E, Conti E, Pasini A, Paloscia C et al. Mutations of the Nogo-66 receptor (RTN4R) gene in schizophrenia. Hum Mutat 2004; 24: 534–535.
Prata DP, Kanaan RA, Barker GJ, Shergill S, Woolley J, Georgieva L et al. Risk variant of oligodendrocyte lineage transcription factor 2 is associated with reduced white matter integrity. Hum Brain Mapping 2013; 34: 2025–2031.
Felsky D, Voineskos AN, Lerch JP, Nazeri A, Shaikh SA, Rajji TK et al. Myelin-associated glycoprotein gene and brain morphometry in schizophrenia. Front Psychiatry 2012; 3: 40.
Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium. Genome-wide association study identifies five new schizophrenia loci. Nat Genet 2011; 43: 969–976.
Yu H, Bi W, Liu C, Zhao Y, Zhang JF, Zhang D et al. A hypothesis-driven pathway analysis reveals myelin-related pathways that contribute to the risk of schizophrenia and bipolar disorder. Prog Neuro-psychopharmacol 2014; 51: 140–145.
Goudriaan A, de Leeuw C, Ripke S, Hultman CM, Sklar P, Sullivan PF et al. Specific glial functions contribute to schizophrenia susceptibility. Schizophr Bull 2013.
McIntosh AM, Moorhead TW, Job D, Lymer GK, Munoz Maniega S, McKirdy J et al. The effects of a neuregulin 1 variant on white matter density and integrity. Mol Psychiatry 2008; 13: 1054–1059.
Roussos P, Katsel P, Davis KL, Bitsios P, Giakoumaki SG, Jogia J et al. Molecular and genetic evidence for abnormalities in the nodes of Ranvier in schizophrenia. Arch Gen Psychiatry 2012; 69: 7–15.
Roussos P, Haroutunian V . Schizophrenia: susceptibility genes and oligodendroglial and myelin related abnormalities. Front Cell Neurosci 2014; 8: 5.
Voineskos AN . Genetic underpinnings of white matter 'connectivity': Heritability, risk, and heterogeneity in schizophrenia. Schizophr Res 2014; 161: 50–60.
Bartzokis G . Neuroglialpharmacology: myelination as a shared mechanism of action of psychotropic treatments. Neuropharmacology 2012; 62: 2137–2153.
Reis Marques T, Taylor H, Chaddock C, Dell'acqua F, Handley R, Reinders AA et al. White matter integrity as a predictor of response to treatment in first episode psychosis. Brain 2014; 137: 172–182.
Brown AS . The environment and susceptibility to schizophrenia. Progr Neurobiol 2011; 93: 23–58.
Insel TR . Rethinking schizophrenia. Nature 2010; 468: 187–193.
Drexhage RC, Weigelt K, van Beveren N, Cohen D, Versnel MA, Nolen WA et al. Immune and neuroimmune alterations in mood disorders and schizophrenia. Int Rev Neurobiol 2011; 101: 169–201.
Zhang XY, Zhou DF, Cao LY, Wu GY, Shen YC . Cortisol and cytokines in chronic and treatment-resistant patients with schizophrenia: association with psychopathology and response to antipsychotics. Neuropsychopharmacology 2005; 30: 1532–1538.
Ebrinc S, Top C, Oncul O, Basoglu C, Cavuslu S, Cetin M . Serum interleukin 1 alpha and interleukin 2 levels in patients with schizophrenia. J Int Med Res 2002; 30: 314–317.
Monteleone P, Fabrazzo M, Tortorella A, Maj M . Plasma levels of interleukin-6 and tumor necrosis factor alpha in chronic schizophrenia: effects of clozapine treatment. Psychiatry Res 1997; 71: 11–17.
Song XQ, Lv LX, Li WQ, Hao YH, Zhao JP . The interaction of nuclear factor-kappa B and cytokines is associated with schizophrenia. Biol Psychiatry 2009; 65: 481–488.
Erbagci AB, Herken H, Koyluoglu O, Yilmaz N, Tarakcioglu M . Serum IL-1beta sIL-2 R, IL-6, IL-8 and TNF-alpha in schizophrenic patients, relation with symptomatology and responsiveness to risperidone treatment. Mediat Inflamm 2001; 10: 109–115.
Theodoropoulou S, Spanakos G, Baxevanis CN, Economou M, Gritzapis AD, Papamichail MP et al. Cytokine serum levels, autologous mixed lymphocyte reaction and surface marker analysis in never medicated and chronically medicated schizophrenic patients. Schizophr Res 2001; 47: 13–25.
Upthegrove R, Manzanares-Teson N, Barnes NM . Cytokine function in medication-naive first episode psychosis: a systematic review and meta-analysis. Schizophr Res 2014; 155: 101–108.
Tourjman V, Kouassi E, Koue ME, Rocchetti M, Fortin-Fournier S, Fusar-Poli P et al. Antipsychotics' effects on blood levels of cytokines in schizophrenia: a meta-analysis. Schizophr Res 2013; 151: 43–47.
Brown AS, Hooton J, Schaefer CA, Zhang H, Petkova E, Babulas V et al. Elevated maternal interleukin-8 levels and risk of schizophrenia in adult offspring. Am J Psychiatry 2004; 161: 889–895.
Buka SL, Tsuang MT, Torrey EF, Klebanoff MA, Wagner RL, Yolken RH . Maternal cytokine levels during pregnancy and adult psychosis. Brain Behav Immun 2001; 15: 411–420.
Hayes LN, Severance EG, Leek JT, Gressitt KL, Rohleder C, Coughlin JM et al. Inflammatory molecular signature associated with infectious agents in psychosis. Schizophr Bull 2014; 40: 963–972.
Beumer W, Gibney SM, Drexhage RC, Pont-Lezica L, Doorduin J, Klein HC et al. The immune theory of psychiatric diseases: a key role for activated microglia and circulating monocytes. J Leukoc Biol 2012; 92: 959–975.
Nikkila HV, Muller K, Ahokas A, Miettinen K, Rimon R, Andersson LC . Accumulation of macrophages in the CSF of schizophrenic patients during acute psychotic episodes. Am J Psychiatry 1999; 156: 1725–1729.
Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 2012; 74: 691–705.
Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P et al. Synaptic pruning by microglia is necessary for normal brain development. Science (New York, NY) 2011; 333: 1456–1458.
Ji K, Miyauchi J, Tsirka SE . Microglia: an active player in the regulation of synaptic activity. Neural Plast 2013; 2013: 627325.
Feinberg I . Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence? J Psychiatr Res 1982; 17: 319–334.
Wierzba-Bobrowicz T, Lewandowska E, Lechowicz W, Stepien T, Pasennik E . Quantitative analysis of activated microglia, ramified and damage of processes in the frontal and temporal lobes of chronic schizophrenics. Folia Neuropathol 2005; 43: 81–89.
Radewicz K, Garey LJ, Gentleman SM, Reynolds R . Increase in HLA-DR immunoreactive microglia in frontal and temporal cortex of chronic schizophrenics. J Neuropathol Exp Neurol 2000; 59: 137–150.
Arnold SE, Trojanowski JQ, Gur RE, Blackwell P, Han LY, Choi C . Absence of neurodegeneration and neural injury in the cerebral cortex in a sample of elderly patients with schizophrenia. Arch Gen Psychiatry 1998; 55: 225–232.
Falke E, Han LY, Arnold SE . Absence of neurodegeneration in the thalamus and caudate of elderly patients with schizophrenia. Psychiatry Res 2000; 93: 103–110.
Kahn RS, Sommer IE . The neurobiology and treatment of first-episode schizophrenia. Mol Psychiatry 2014; 20: 84–97.
Fillman SG, Cloonan N, Catts VS, Miller LC, Wong J, McCrossin T et al. Increased inflammatory markers identified in the dorsolateral prefrontal cortex of individuals with schizophrenia. Mol Psychiatry 2013; 18: 206–214.
Fillman SG, Cloonan N, Miller LC, Weickert CS . Markers of inflammation in the prefrontal cortex of individuals with schizophrenia. Mol Psychiatry 2013; 18: 133.
Rupprecht R, Papadopoulos V, Rammes G, Baghai TC, Fan J, Akula N et al. Translocator protein (18 kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders. Nat Rev Drug Discov 2010; 9: 971–988.
Banati RB, Newcombe J, Gunn RN, Cagnin A, Turkheimer F, Heppner F et al. The peripheral benzodiazepine binding site in the brain in multiple sclerosis: quantitative in vivo imaging of microglia as a measure of disease activity. Brain 2000; 123: 2321–2337.
Banati RB, Egensperger R, Maassen A, Hager G, Kreutzberg GW, Graeber MB . Mitochondria in activated microglia in vitro. J Neurocytol 2004; 33: 535–541.
Doorduin J, de Vries EF, Willemsen AT, de Groot JC, Dierckx RA, Klein HC . Neuroinflammation in schizophrenia-related psychosis: a PET study. J Nucl Med 2009; 50: 1801–1807.
van Berckel BN, Bossong MG, Boellaard R, Kloet R, Schuitemaker A, Caspers E et al. Microglia activation in recent-onset schizophrenia: a quantitative (R)-[11C]PK11195 positron emission tomography study. Biol Psychiatry 2008; 64: 820–822.
Doorduin J, de Vries EF, Dierckx RA, Klein HC . PET imaging of the peripheral benzodiazepine receptor: monitoring disease progression and therapy response in neurodegenerative disorders. Curr Pharm Des 2008; 14: 3297–3315.
Owen DR, Yeo AJ, Gunn RN, Song K, Wadsworth G, Lewis A et al. An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. J Cereb Blood Flow Metab 2012; 32: 1–5.
Manji H, Kato T, Di Prospero NA, Ness S, Beal MF, Krams M et al. Impaired mitochondrial function in psychiatric disorders. Nat Rev Neurosci 2012; 13: 293–307.
McGrath JJ, Mortensen PB, Visscher PM, Wray NR . Where GWAS and epidemiology meet: opportunities for the simultaneous study of genetic and environmental risk factors in schizophrenia. Schizophr Bull 2013; 39: 955–959.
Ayhan Y, Sawa A, Ross CA, Pletnikov MV . Animal models of gene-environment interactions in schizophrenia. Behav Brain Res 2009; 204: 274–281.
Kannan G, Sawa A, Pletnikov MV . Mouse models of gene-environment interactions in schizophrenia. Neurobiol Dis 2013; 57: 5–11.
Benros ME, Eaton WW, Mortensen PB . The epidemiologic evidence linking autoimmune diseases and psychosis. Biol Psychiatry 2013; 75: 300–306.
Eaton WW, Byrne M, Ewald H, Mors O, Chen CY, Agerbo E et al. Association of schizophrenia and autoimmune diseases: linkage of Danish national registers. Am J Psychiatry 2006; 163: 521–528.
Stefansson H, Ophoff RA, Steinberg S, Andreassen OA, Cichon S, Rujescu D et al. Common variants conferring risk of schizophrenia. Nature 2009; 460: 744–747.
Jia P, Wang L, Fanous AH, Chen X, Kendler KS, Zhao Z . A bias-reducing pathway enrichment analysis of genome-wide association data confirmed association of the MHC region with schizophrenia. J Med Genet 2012; 49: 96–103.
Bitanihirwe BK, Woo TU . Oxidative stress in schizophrenia: an integrated approach. Neurosci Biobehav Rev 2011; 35: 878–893.
Emiliani FE, Sedlak TW, Sawa A . Oxidative stress and schizophrenia: recent breakthroughs from an old story. Curr Opin Psychiatry 2014; 27: 185–190.
Flatow J, Buckley P, Miller BJ . Meta-analysis of oxidative stress in schizophrenia. Biol Psychiatry 2013; 74: 400–409.
Gawryluk JW, Wang JF, Andreazza AC, Shao L, Young LT . 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.
Evans DR, Parikh VV, Khan MM, Coussons C, Buckley PF, Mahadik SP . Red blood cell membrane essential fatty acid metabolism in early psychotic patients following antipsychotic drug treatment. Prostaglandins Leukot Essent Fatty Acids 2003; 69: 393–399.
Coughlin JM, Ishizuka K, Kano SI, Edwards JA, Seifuddin FT, Shimano MA et al. Marked reduction of soluble superoxide dismutase-1 (SOD1) in cerebrospinal fluid of patients with recent-onset schizophrenia. Mol Psychiatry 2013; 18: 10–11.
Raffa M, Atig F, Mhalla A, Kerkeni A, Mechri A . Decreased glutathione levels and impaired antioxidant enzyme activities in drug-naive first-episode schizophrenic patients. BMC Psychiatry 2011; 11: 124.
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.
Do KQ, Trabesinger AH, Kirsten-Kruger M, Lauer CJ, Dydak U, Hell D et al. Schizophrenia: glutathione deficit in cerebrospinal fluid and prefrontal cortex in vivo. Eur J Neurosci 2000; 12: 3721–3728.
Terpstra M, Vaughan TJ, Ugurbil K, Lim KO, Schulz SC, Gruetter R . Validation of glutathione quantitation from STEAM spectra against edited 1H NMR spectroscopy at 4 T: application to schizophrenia. Magma (New York, NY) 2005; 18: 276–282.
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 3 T 1H-MRS study. PLoS One 2008; 3: e1944.
Wood SJ, Berger GE, Wellard RM, Proffitt TM, 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.
Borges S, Gayer-Anderson C, Mondelli V . A systematic review of the activity of the hypothalamic-pituitary-adrenal axis in first episode psychosis. Psychoneuroendocrinology 2013; 38: 603–611.
Pariante CM, Vassilopoulou K, Velakoulis D, Phillips L, Soulsby B, Wood SJ et al. Pituitary volume in psychosis. Br J Psychiatry 2004; 185: 5–10.
Takahashi T, Nakamura K, Nishiyama S, Furuichi A, Ikeda E, Kido M et al. Increased pituitary volume in subjects at risk for psychosis and patients with first-episode schizophrenia. Psychiatry Clin Neurosci 2013; 67: 540–548.
Buschlen J, Berger GE, Borgwardt SJ, Aston J, Gschwandtner U, Pflueger MO et al. Pituitary volume increase during emerging psychosis. Schizophr Res 2011; 125: 41–48.
Romo-Nava F, Hoogenboom WS, Pelavin PE, Alvarado JL, Bobrow LH, Macmaster FP et al. Pituitary volume in schizophrenia spectrum disorders. Schizophr Res 2013; 146: 301–307.
Gruner P, Christian C, Robinson DG, Sevy S, Gunduz-Bruce H, Napolitano B et al. Pituitary volume in first-episode schizophrenia. Psychiatry Res 2012; 203: 100–102.
Tournikioti K, Tansella M, Perlini C, Rambaldelli G, Cerini R, Versace A et al. Normal pituitary volumes in chronic schizophrenia. Psychiatry Res 2007; 154: 41–48.
Upadhyaya AR, El-Sheikh R, MacMaster FP, Diwadkar VA, Keshavan MS . Pituitary volume in neuroleptic-naive schizophrenia: a structural MRI study. Schizophr Res 2007; 90: 266–273.
Tognin S, Rambaldelli G, Perlini C, Bellani M, Marinelli V, Zoccatelli G et al. Enlarged hypothalamic volumes in schizophrenia. Psychiatry Res 2012; 204: 75–81.
Goldstein JM, Seidman LJ, Makris N, Ahern T, O'Brien LM, Caviness VS Jr. et al. Hypothalamic abnormalities in schizophrenia: sex effects and genetic vulnerability. Biol Psychiatry 2007; 61: 935–945.
Koolschijn PC, van Haren NE, Hulshoff Pol HE, Kahn RS . Hypothalamus volume in twin pairs discordant for schizophrenia. Eur Neuropsychopharmacol 2008; 18: 312–315.
Klomp A, Koolschijn PC, Hulshoff Pol HE, Kahn RS, Haren NE . Hypothalamus and pituitary volume in schizophrenia: a structural MRI study. Int J Neuropsychopharmacol 2012; 15: 281–288.
Walsh P, Spelman L, Sharifi N, Thakore JH . Male patients with paranoid schizophrenia have greater ACTH and cortisol secretion in response to metoclopramide-induced AVP release. Psychoneuroendocrinology 2005; 30: 431–437.
Ritsner M, Gibel A, Maayan R, Ratner Y, Ram E, Modai I et al. State and trait related predictors of serum cortisol to DHEA(S) molar ratios and hormone concentrations in schizophrenia patients. Eur Neuropsychopharmacol 2007; 17: 257–264.
Gallagher P, Watson S, Smith MS, Young AH, Ferrier IN . Plasma cortisol-dehydroepiandrosterone (DHEA) ratios in schizophrenia and bipolar disorder. Schizophr Res 2007; 90: 258–265.
Yilmaz N, Herken H, Cicek HK, Celik A, Yurekli M, Akyol O . Increased levels of nitric oxide, cortisol and adrenomedullin in patients with chronic schizophrenia. Med Princ Pract 2007; 16: 137–141.
Ryan MC, Sharifi N, Condren R, Thakore JH . Evidence of basal pituitary-adrenal overactivity in first episode, drug naive patients with schizophrenia. Psychoneuroendocrinology 2004; 29: 1065–1070.
Walker EF, Trotman HD, Pearce BD, Addington J, Cadenhead KS, Cornblatt BA et al. Cortisol levels and risk for psychosis: initial findings from the North American prodrome longitudinal study. Biol Psychiatry 2013; 74: 410–417.
Strous RD, Maayan R, Lapidus R, Goredetsky L, Zeldich E, Kotler M et al. Increased circulatory dehydroepiandrosterone and dehydroepiandrosterone-sulphate in first-episode schizophrenia: relationship to gender, aggression and symptomatology. Schizophr Res 2004; 71: 427–434.
Venkatasubramanian G, Chittiprol S, Neelakantachar N, Shetty T, Gangadhar BN . Effect of antipsychotic treatment on Insulin-like Growth Factor-1 and cortisol in schizophrenia: a longitudinal study. Schizophr Res 2010; 119: 131–137.
Krishnamurthy D, Harris LW, Levin Y, Koutroukides TA, Rahmoune H, Pietsch S et al. Metabolic, hormonal and stress-related molecular changes in post-mortem pituitary glands from schizophrenia subjects. World J Biol Psychiatry 2013; 14: 478–489.
Perlman WR, Webster MJ, Kleinman JE, Weickert CS . Reduced glucocorticoid and estrogen receptor alpha messenger ribonucleic acid levels in the amygdala of patients with major mental illness. Biol Psychiatry 2004; 56: 844–852.
Webster MJ, Knable MB, O'Grady J, Orthmann J, Weickert CS . Regional specificity of brain glucocorticoid receptor mRNA alterations in subjects with schizophrenia and mood disorders. Mol Psychiatry 2002; 7: 985–994, 24.
Hirsch D, Orr G, Kantarovich V, Hermesh H, Stern E, Blum I . Cushing's syndrome presenting as a schizophrenia-like psychotic state. Isr J Psychiatry Relat Sci 2000; 37: 46–50.
Hall RC, Popkin MK, Stickney SK, Gardner ER . Presentation of the steroid psychoses. J Nerv Ment Dis 1979; 167: 229–236.
Flores BH, Kenna H, Keller J, Solvason HB, Schatzberg AF . Clinical and biological effects of mifepristone treatment for psychotic depression. Neuropsychopharmacology 2006; 31: 628–636.
Schatzberg AF, Lindley S . Glucocorticoid antagonists in neuropsychiatric [corrected] disorders. Eur J Pharmacol 2008; 583: 358–364.
Myers B, McKlveen JM, Herman JP . Glucocorticoid actions on synapses, circuits, and behavior: implications for the energetics of stress. Front Neuroendocrinol 2014; 35: 180–196.
Niwa M, Jaaro-Peled H, Tankou S, Seshadri S, Hikida T, Matsumoto Y et al. Adolescent stress-induced epigenetic control of dopaminergic neurons via glucocorticoids. Science (New York, NY) 2013; 339: 335–339.
Huber TJ, Tettenborn C, Leifke E, Emrich HM . Sex hormones in psychotic men. Psychoneuroendocrinology 2005; 30: 111–114.
Bergemann N, Mundt C, Parzer P, Jannakos I, Nagl I, Salbach B et al. Plasma concentrations of estradiol in women suffering from schizophrenia treated with conventional versus atypical antipsychotics. Schizophr Res 2005; 73: 357–366.
Weickert CS, Miranda-Angulo AL, Wong J, Perlman WR, Ward SE, Radhakrishna V et al. Variants in the estrogen receptor alpha gene and its mRNA contribute to risk for schizophrenia. Hum Mol Genet 2008; 17: 2293–2309.
Kulkarni J, Hayes E, Gavrilidis E . Hormones and schizophrenia. Curr Opin Psychiatry 2012; 25: 89–95.
Lokuge S, Frey BN, Foster JA, Soares CN, Steiner M . The rapid effects of estrogen: a mini-review. Behav Pharmacol 2010; 21: 465–472.
Cyr M, Ghribi O, Di Paolo T . Regional and selective effects of oestradiol and progesterone on NMDA and AMPA receptors in the rat brain. J Neuroendocrinol 2000; 12: 445–452.
Allison DB, Fontaine KR, Heo M, Mentore JL, Cappelleri JC, Chandler LP et al. The distribution of body mass index among individuals with and without schizophrenia. J Clin Psychiatry 1999; 60: 215–220.
American Diabetes Association American Psychiatric Association American Association of Clinical Endocrinologists North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. J Clin Psychiatry 2004; 65: 267–272.
Boke O, Aker S, Sarisoy G, Saricicek EB, Sahin AR . Prevalence of metabolic syndrome among inpatients with schizophrenia. Int J Psychiatry Med 2008; 38: 103–112.
Takayanagi Y, Cascella NG, Sawa A, Eaton WW . Diabetes is associated with lower global cognitive function in schizophrenia. Schizophr Res 2012; 142: 183–187.
Popovic V, Doknic M, Maric N, Pekic S, Damjanovic A, Miljic D et al. Changes in neuroendocrine and metabolic hormones induced by atypical antipsychotics in normal-weight patients with schizophrenia. Neuroendocrinology 2007; 85: 249–256.
Doknic M, Maric NP, Britvic D, Pekic S, Damjanovic A, Miljic D et al. Bone remodeling, bone mass and weight gain in patients with stabilized schizophrenia in real-life conditions treated with long-acting injectable risperidone. Neuroendocrinology 2011; 94: 246–254.
De Hert M, Peuskens J, van Winkel R . Mortality in patients with schizophrenia. Lancet 2009; 374: 1591, author reply 2-3.
Spelman LM, Walsh PI, Sharifi N, Collins P, Thakore JH . Impaired glucose tolerance in first-episode drug-naive patients with schizophrenia. Diabet Med 2007; 24: 481–485.
Ryan MC, Collins P, Thakore JH . Impaired fasting glucose tolerance in first-episode, drug-naive patients with schizophrenia. Am J Psychiatry 2003; 160: 284–289.
Kirkpatrick B . Schizophrenia as a systemic disease. Schizophr Bull 2009; 35: 381–382.
Guest PC, Martins-de-Souza D, Vanattou-Saifoudine N, Harris LW, Bahn S . Abnormalities in metabolism and hypothalamic-pituitary-adrenal axis function in schizophrenia. Int Rev Neurobiol 2011; 101: 145–168.
Holmes E, Tsang TM, Huang JT, Leweke FM, Koethe D, Gerth CW et al. Metabolic profiling of CSF: evidence that early intervention may impact on disease progression and outcome in schizophrenia. PLoS Med 2006; 3: e327.
Tamminga CA, Thaker GK, Buchanan R, Kirkpatrick B, Alphs LD, Chase TN et al. Limbic system abnormalities identified in schizophrenia using positron emission tomography with fluorodeoxyglucose and neocortical alterations with deficit syndrome. Arch Gen Psychiatry 1992; 49: 522–530.
Buchsbaum MS, Buchsbaum BR, Hazlett EA, Haznedar MM, Newmark R, Tang CY et al. Relative glucose metabolic rate higher in white matter in patients with schizophrenia. Am J Psychiatry 2007; 164: 1072–1081.
Lin CY, Sawa A, Jaaro-Peled H . Better understanding of mechanisms of schizophrenia and bipolar disorder: from human gene expression profiles to mouse models. Neurobiol Disease 2012; 45: 48–56.
Zhao Z, Ksiezak-Reding H, Riggio S, Haroutunian V, Pasinetti GM . Insulin receptor deficits in schizophrenia and in cellular and animal models of insulin receptor dysfunction. Schizophr Res 2006; 84: 1–14.
Bernstein HG, Ernst T, Lendeckel U, Bukowska A, Ansorge S, Stauch R et al. Reduced neuronal expression of insulin-degrading enzyme in the dorsolateral prefrontal cortex of patients with haloperidol-treated, chronic schizophrenia. J Psychiatr Res 2009; 43: 1095–1105.
O'Neill C, Kiely AP, Coakley MF, Manning S, Long-Smith CM . Insulin and IGF-1 signalling: longevity, protein homoeostasis and Alzheimer's disease. Biochem Soc Trans 2012; 40: 721–727.
O' Neill C . PI3-kinase/Akt/mTOR signaling: impaired on/off switches in aging, cognitive decline and Alzheimer's disease. Exp Gerontol 2013; 48: 647–653.
McEvoy JP, Meyer JM, Goff DC, Nasrallah HA, Davis SM, Sullivan L et al. Prevalence of the metabolic syndrome in patients with schizophrenia: baseline results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial and comparison with national estimates from NHANES III. Schizophr Res 2005; 80: 19–32.
Stone WS, Faraone SV, Su J, Tarbox SI, Van Eerdewegh P, Tsuang MT . Evidence for linkage between regulatory enzymes in glycolysis and schizophrenia in a multiplex sample. Am J Med Genet B Neuropsychiatr Genet 2004; 127B: 5–10.
Olsen L, Hansen T, Jakobsen KD, Djurovic S, Melle I, Agartz I et al. The estrogen hypothesis of schizophrenia implicates glucose metabolism: association study in three independent samples. BMC Med Genet 2008; 9: 39.
Freyberg Z, Ferrando SJ, Javitch JA . Roles of the Akt/GSK-3 and Wnt signaling pathways in schizophrenia and antipsychotic drug action. Am J Psychiatry 2010; 167: 388–396.
Sinha MK, Opentanova I, Ohannesian JP, Kolaczynski JW, Heiman ML, Hale J et al. Evidence of free and bound leptin in human circulation. Studies in lean and obese subjects and during short-term fasting. J Clin Invest 1996; 98: 1277–1282.
Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. New Engl J Med 1996; 334: 292–295.
Pasco JA, Jacka FN, Williams LJ, Henry MJ, Nicholson GC, Kotowicz MA et al. Leptin in depressed women: cross-sectional and longitudinal data from an epidemiologic study. J Affect Disord 2008; 107: 221–225.
Malcher-Lopes R, Di S, Marcheselli VS, Weng FJ, Stuart CT, Bazan NG et al. Opposing crosstalk between leptin and glucocorticoids rapidly modulates synaptic excitation via endocannabinoid release. J Neurosci 2006; 26: 6643–6650.
Kern A, Albarran-Zeckler R, Walsh HE, Smith RG . Apo-ghrelin receptor forms heteromers with DRD2 in hypothalamic neurons and is essential for anorexigenic effects of DRD2 agonism. Neuron 2012; 73: 317–332.
Sentissi O, Epelbaum J, Olie JP, Poirier MF . Leptin and ghrelin levels in patients with schizophrenia during different antipsychotics treatment: a review. Schizophr Bull 2008; 34: 1189–1199.
Huang JT, Wang L, Prabakaran S, Wengenroth M, Lockstone HE, Koethe D et al. Independent protein-profiling studies show a decrease in apolipoprotein A1 levels in schizophrenia CSF, brain and peripheral tissues. Mol Psychiatry 2008; 13: 1118–1128.
Wu X, Huang Z, Wu R, Zhong Z, Wei Q, Wang H et al. The comparison of glycometabolism parameters and lipid profiles between drug-naive, first-episode schizophrenia patients and healthy controls. Schizophr Res 2013; 150: 157–162.
Martins-De-Souza D, Wobrock T, Zerr I, Schmitt A, Gawinecka J, Schneider-Axmann T et al. Different apolipoprotein E, apolipoprotein A1 and prostaglandin-H2 D-isomerase levels in cerebrospinal fluid of schizophrenia patients and healthy controls. World J Biol Psychiatry 2010; 11: 719–728.
Cieslak K, Feingold J, Antonius D, Walsh-Messinger J, Dracxler R, Rosedale M et al. Low Vitamin D levels predict clinical features of schizophrenia. Schizophr Res 2014; 159: 543–545.
Crews M, Lally J, Gardner-Sood P, Howes O, Bonaccorso S, Smith S et al. Vitamin D deficiency in first episode psychosis: a case-control study. Schizophr Res 2013; 150: 533–537.
McGrath JJ, Burne TH, Feron F, Mackay-Sim A, Eyles DW . Developmental vitamin D deficiency and risk of schizophrenia: a 10-year update. Schizophr Bull 2010; 36: 1073–1078.
Kao AC, Muller DJ . Genetics of antipsychotic-induced weight gain: update and current perspectives. Pharmacogenomics 2013; 14: 2067–2083.
Wallace TJ, Zai CC, Brandl EJ, Muller DJ . Role of 5-HT(2C) receptor gene variants in antipsychotic-induced weight gain. Pharmacogenomics Pers Med 2011; 4: 83–93.
Sicard MN, Zai CC, Tiwari AK, Souza RP, Meltzer HY, Lieberman JA et al. Polymorphisms of the HTR2C gene and antipsychotic-induced weight gain: an update and meta-analysis. Pharmacogenomics 2010; 11: 1561–1571.
Malhotra AK, Correll CU, Chowdhury NI, Muller DJ, Gregersen PK, Lee AT et al. Association between common variants near the melanocortin 4 receptor gene and severe antipsychotic drug-induced weight gain. Arch Gen Psychiatry 2012; 69: 904–912.
Brandl EJ, Frydrychowicz C, Tiwari AK, Lett TA, Kitzrow W, Buttner S et al. Association study of polymorphisms in leptin and leptin receptor genes with antipsychotic-induced body weight gain. Prog Neuro-psychopharmacol Biol Psychiatry 2012; 38: 134–141.
Bellavance MA, Rivest S . The HPA - immune axis and the immunomodulatory actions of glucocorticoids in the brain. Front Immunol 2014; 5: 136.
Valleau JC, Sullivan EL . The impact of leptin on perinatal development and psychopathology. J Chem Neuroanat 2014; 61-62: 221–232.
Cai D, Liu T . Inflammatory cause of metabolic syndrome via brain stress and NF-kappaB. Aging 2012; 4: 98–115.
Bernstein HG, Steiner J, Guest PC, Dobrowolny H, Bogerts B . Glial cells as key players in schizophrenia pathology: recent insights and concepts of therapy. Schizophr Res 2014; 161: 4–18.
Inui M, Miyado M, Igarashi M, Tamano M, Kubo A, Yamashita S et al. Rapid generation of mouse models with defined point mutations by the CRISPR/Cas9 system. Sci Rep 2014; 4: 5396.
Shen B, Zhang W, Zhang J, Zhou J, Wang J, Chen L et al. Efficient genome modification by CRISPR-Cas9 nickase with minimal off-target effects. Nat Methods 2014; 11: 399–402.
Wijshake T, Baker DJ, van de Sluis B . Endonucleases: new tools to edit the mouse genome. Biochim Biophys Acta 2014; 1842: 1942–1950.
Hiroi N, Takahashi T, Hishimoto A, Izumi T, Boku S, Hiramoto T . Copy number variation at 22q11.2: from rare variants to common mechanisms of developmental neuropsychiatric disorders. Mol Psychiatry 2013; 18: 1153–1165.
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 2014; 20: 361–368.
Abazyan B, Nomura J, Kannan G, Ishizuka K, Tamashiro KL, Nucifora F et al. Prenatal interaction of mutant DISC1 and immune activation produces adult psychopathology. Biol Psychiatry 2010; 68: 1172–1181.
Desbonnet L, O'Tuathaigh C, Clarke G, O'Leary C, Petit E, Clarke N et al. Phenotypic effects of repeated psychosocial stress during adolescence in mice mutant for the schizophrenia risk gene neuregulin-1: a putative model of gene x environment interaction. Brain Behav Immun 2012; 26: 660–671.
Vuillermot S, Joodmardi E, Perlmann T, Ogren SO, Feldon J, Meyer U . Prenatal immune activation interacts with genetic Nurr1 deficiency in the development of attentional impairments. J Neurosci 2012; 32: 436–451.
Niwa M, Kamiya A, Murai R, Kubo K, Gruber AJ, Tomita K et al. Knockdown of DISC1 by in utero gene transfer disturbs postnatal dopaminergic maturation in the frontal cortex and leads to adult behavioral deficits. Neuron 2010; 65: 480–489.
Goto Y, O'Donnell P . Delayed mesolimbic system alteration in a developmental animal model of schizophrenia. J Neurosci 2002; 22: 9070–9077.
Feleder C, Tseng KY, Calhoon GG, O'Donnell P . Neonatal intrahippocampal immune challenge alters dopamine modulation of prefrontal cortical interneurons in adult rats. Biol Psychiatry 2010; 67: 386–392.
Kluge W, Alsaif M, Guest PC, Schwarz E, Bahn S . Translating potential biomarker candidates for schizophrenia and depression to animal models of psychiatric disorders. Exp Rev Mol Diagn 2011; 11: 721–733.
Pechnick RN, George R, Poland RE, Hiramatsu M, Cho AK . Characterization of the effects of the acute and chronic administration of phencyclidine on the release of adrenocorticotropin, corticosterone and prolactin in the rat: evidence for the differential development of tolerance. J Pharmacol Exp Ther 1989; 250: 534–540.
Fattorini G, Melone M, Bragina L, Candiracci C, Cozzi A, Pellegrini Giampietro DE et al. GLT-1 expression and Glu uptake in rat cerebral cortex are increased by phencyclidine. Glia 2008; 56: 1320–1327.
Murai R, Noda Y, Matsui K, Kamei H, Mouri A, Matsuba K et al. Hypofunctional glutamatergic neurotransmission in the prefrontal cortex is involved in the emotional deficit induced by repeated treatment with phencyclidine in mice: implications for abnormalities of glutamate release and NMDA-CaMKII signaling. Behav Brain Res 2007; 180: 152–160.
Jenkins TA, Harte MK, McKibben CE, Elliott JJ, Reynolds GP . Disturbances in social interaction occur along with pathophysiological deficits following sub-chronic phencyclidine administration in the rat. Behav Brain Res 2008; 194: 230–235.
McKibben CE, Jenkins TA, Adams HN, Harte MK, Reynolds GP . Effect of pretreatment with risperidone on phencyclidine-induced disruptions in object recognition memory and prefrontal cortex parvalbumin immunoreactivity in the rat. Behav Brain Res 2010; 208: 132–136.
Braun I, Genius J, Grunze H, Bender A, Moller HJ, Rujescu D . Alterations of hippocampal and prefrontal GABAergic interneurons in an animal model of psychosis induced by NMDA receptor antagonism. Schizophr Res 2007; 97: 254–263.
Bullock WM, Bolognani F, Botta P, Valenzuela CF, Perrone-Bizzozero NI . Schizophrenia-like GABAergic gene expression deficits in cerebellar Golgi cells from rats chronically exposed to low-dose phencyclidine. Neurochem Int 2009; 55: 775–782.
Choi YK, Snigdha S, Shahid M, Neill JC, Tarazi FI . Subchronic effects of phencyclidine on dopamine and serotonin receptors: implications for schizophrenia. J Mol Neurosci 2009; 38: 227–235.
Beninger RJ, Beuk J, Banasikowski TJ, van Adel M, Boivin GA, Reynolds JN . Subchronic phencyclidine in rats: alterations in locomotor activity, maze performance, and GABA(A) receptor binding. Behav Pharmacol 2010; 21: 1–10.
Hyde JF . Effects of phencyclidine on 5-hydroxytryptophan- and suckling-induced prolactin release. Brain Res 1992; 573: 204–208.
Takahashi M, Kakita A, Futamura T, Watanabe Y, Mizuno M, Sakimura K et al. Sustained brain-derived neurotrophic factor up-regulation and sensorimotor gating abnormality induced by postnatal exposure to phencyclidine: comparison with adult treatment. J Neurochem 2006; 99: 770–780.
Oskvig DB, Elkahloun AG, Johnson KR, Phillips TM, Herkenham M . Maternal immune activation by LPS selectively alters specific gene expression profiles of interneuron migration and oxidative stress in the fetus without triggering a fetal immune response. Brain Behav Immun 2012; 26: 623–634.
Meyer U . Prenatal poly(i:C) exposure and other developmental immune activation models in rodent systems. Biol Psychiatry 2014; 75: 307–315.
Xiu Y, Kong XR, Zhang L, Qiu X, Chao FL, Peng C et al. White matter injuries induced by MK-801 in a mouse model of schizophrenia based on NMDA antagonism. Anat Rec 2014; 297: 1498–1507.
Zhu S, Wang H, Shi R, Zhang R, Wang J, Kong L et al. Chronic phencyclidine induces inflammatory responses and activates GSK3beta in mice. Neurochem Res 2014; 39: 2385–2393.
Venancio C, Felix L, Almeida V, Coutinho J, Antunes L, Peixoto F et al. Acute ketamine impairs mitochondrial function and promotes superoxide dismutase activity in the rat brain. Anesth Analga 2014; 120: 320–328.
Dean B, Karl T, Pavey G, Boer S, Duffy L, Scarr E . Increased levels of serotonin 2 A receptors and serotonin transporter in the CNS of neuregulin 1 hypomorphic/mutant mice. Schizophr Res 2008; 99: 341–349.
Iltis I, Koski DM, Eberly LE, Nelson CD, Deelchand DK, Valette J et al. Neurochemical changes in the rat prefrontal cortex following acute phencyclidine treatment: an in vivo localized (1)H MRS study. NMR Biomed 2009; 22: 737–744.
Ernst A, Ma D, Garcia-Perez I, Tsang TM, Kluge W, Schwarz E et al. Molecular validation of the acute phencyclidine rat model for schizophrenia: identification of translational changes in energy metabolism and neurotransmission. J Proteome Res 2012; 11: 3704–3714.
Hou XJ, Ni KM, Yang JM, Li XM . Neuregulin 1/ErbB4 enhances synchronized oscillations of prefrontal cortex neurons via inhibitory synapses. Neuroscience 2014; 261: 107–117.
Ginsberg Y, Lotan P, Khatib N, Awad N, Errison S, Weiner Z et al. Maternal lipopolysaccharide alters the newborn oxidative stress and C-reactive protein levels in response to an inflammatory stress. J Dev Orig Health Dis 2012; 3: 358–363.
Kirsten TB, Lippi LL, Bevilacqua E, Bernardi MM . LPS exposure increases maternal corticosterone levels, causes placental injury and increases IL-1Beta levels in adult rat offspring: relevance to autism. PLoS One 2013; 8: e82244.
Burt MA, Tse YC, Boksa P, Wong TP . Prenatal immune activation interacts with stress and corticosterone exposure later in life to modulate N-methyl-D-aspartate receptor synaptic function and plasticity. Int J Neuropsychopharmacol 2013; 16: 1835–1848.
Pacheco-Lopez G, Giovanoli S, Langhans W, Meyer U . Priming of metabolic dysfunctions by prenatal immune activation in mice: relevance to schizophrenia. Schizophr Bull 2013; 39: 319–329.
Cole TB, Giordano G, Co AL, Mohar I, Kavanagh TJ, Costa LG . Behavioral characterization of GCLM-knockout mice, a model for enhanced susceptibility to oxidative stress. J Toxicol 2011; 2011: 157687.
Flores C, Wen X, Labelle-Dumais C, Kolb B . Chronic phencyclidine treatment increases dendritic spine density in prefrontal cortex and nucleus accumbens neurons. Synapse (New York, NY) 2007; 61: 978–984.
Mohn AR, Gainetdinov RR, Caron MG, Koller BH . Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell 1999; 98: 427–436.
Fradley RL, O'Meara GF, Newman RJ, Andrieux A, Job D, Reynolds DS . STOP knockout and NMDA NR1 hypomorphic mice exhibit deficits in sensorimotor gating. Behav Brain Res 2005; 163: 257–264.
Holloway T, Moreno JL, Umali A, Rayannavar V, Hodes GE, Russo SJ et al. Prenatal stress induces schizophrenia-like alterations of serotonin 2 A and metabotropic glutamate 2 receptors in the adult offspring: role of maternal immune system. J Neurosci 2013; 33: 1088–1098.
Tezuka T, Tamura M, Kondo MA, Sakaue M, Okada K, Takemoto K et al. Cuprizone short-term exposure: astrocytic IL-6 activation and behavioral changes relevant to psychosis. Neurobiol Dis 2013; 59: 63–68.
Cabungcal JH, Steullet P, Morishita H, Kraftsik R, Cuenod M, Hensch TK et al. Perineuronal nets protect fast-spiking interneurons against oxidative stress. Proc Natl Acad Sci USA 2013; 110: 9130–9135.
Monin A, Baumann PS, Griffa A, Xin L, Mekle R, Fournier M et al. Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients. Mol Psychiatry 2014; 20: 827–838.
Kendig EL, Chen Y, Krishan M, Johansson E, Schneider SN, Genter MB et al. Lipid metabolism and body composition in Gclm(-/-) mice. Toxicol Appl Pharmacol 2011; 257: 338–348.
Kulak A, Cuenod M, Do KQ . Behavioral phenotyping of glutathione-deficient mice: relevance to schizophrenia and bipolar disorder. Behav Brain Res 2012; 226: 563–570.
Chen Y, Curran CP, Nebert DW, Patel KV, Williams MT, Vorhees CV . Effect of chronic glutathione deficiency on the behavioral phenotype of Gclm-/- knockout mice. Neurotoxicol Teratol 2012; 34: 450–457.
Eyles D, Almeras L, Benech P, Patatian A, Mackay-Sim A, McGrath J et al. Developmental vitamin D deficiency alters the expression of genes encoding mitochondrial, cytoskeletal and synaptic proteins in the adult rat brain. J Steroid Biochem Mol Biol 2007; 103: 538–545.
Kesby JP, Burne TH, McGrath JJ, Eyles DW . Developmental vitamin D deficiency alters MK 801-induced hyperlocomotion in the adult rat: An animal model of schizophrenia. Biol Psychiatry 2006; 60: 591–596.
Eyles DW, Burne TH, McGrath JJ . Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front Neuroendocrinol 2013; 34: 47–64.
Lai WS, Xu B, Westphal KG, Paterlini M, Olivier B, Pavlidis P et al. Akt1 deficiency affects neuronal morphology and predisposes to abnormalities in prefrontal cortex functioning. Proc Natl Acad Sci USA 2006; 103: 16906–16911.
Balu DT, Carlson GC, Talbot K, Kazi H, Hill-Smith TE, Easton RM et al. Akt1 deficiency in schizophrenia and impairment of hippocampal plasticity and function. Hippocampus 2012; 22: 230–240.
Cho H, Thorvaldsen JL, Chu Q, Feng F, Birnbaum MJ . Akt1/PKBalpha is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. J Biol Chem 2001; 276: 38349–38352.
Dummler B, Hemmings BA . Physiological roles of PKB/Akt isoforms in development and disease. Biochem Soc Trans 2007; 35: 231–235.
Makinodan M, Rosen KM, Ito S, Corfas G . A critical period for social experience-dependent oligodendrocyte maturation and myelination. Science (New York, NY) 2012; 337: 1357–1360.
Toua C, Brand L, Moller M, Emsley RA, Harvey BH . The effects of sub-chronic clozapine and haloperidol administration on isolation rearing induced changes in frontal cortical N-methyl-D-aspartate and D1 receptor binding in rats. Neuroscience 2010; 165: 492–499.
Malone DT, Kearn CS, Chongue L, Mackie K, Taylor DA . Effect of social isolation on CB1 and D2 receptor and fatty acid amide hydrolase expression in rats. Neuroscience 2008; 152: 265–272.
Cassidy AW, Mulvany SK, Pangalos MN, Murphy KJ, Regan CM . Developmental emergence of reelin deficits in the prefrontal cortex of Wistar rats reared in social isolation. Neuroscience 2010; 166: 377–385.
Lipska BK, Lerman DN, Khaing ZZ, Weinberger DR . The neonatal ventral hippocampal lesion model of schizophrenia: effects on dopamine and GABA mRNA markers in the rat midbrain. Eur J Neurosci 2003; 18: 3097–3104.
Wan RQ, Giovanni A, Kafka SH, Corbett R . Neonatal hippocampal lesions induced hyperresponsiveness to amphetamine: behavioral and in vivo microdialysis studies. Behav Brain Res 1996; 78: 211–223.
Mitchell CP, Goldman MB . Neonatal lesions of the ventral hippocampal formation disrupt neuroendocrine responses to auditory stress in the adult rat. Psychoneuroendocrinology 2004; 29: 1317–1325.
Francois J, Koning E, Ferrandon A, Sandner G, Nehlig A . Metabolic activity in the brain of juvenile and adult rats with a neonatal ventral hippocampal lesion. Hippocampus 2010; 20: 841–851.
Meng Y, Payne C, Li L, Hu X, Zhang X, Bachevalier J . Alterations of hippocampal projections in adult macaques with neonatal hippocampal lesions: a Diffusion Tensor Imaging study. NeuroImage. 2014; 102: 828–837.
Roy K, Murtie JC, El-Khodor BF, Edgar N, Sardi SP, Hooks BM et al. Loss of erbB signaling in oligodendrocytes alters myelin and dopaminergic function, a potential mechanism for neuropsychiatric disorders. Proc Natl Acad Sci USA 2007; 104: 8131–8136.
Brinkmann BG, Agarwal A, Sereda MW, Garratt AN, Muller T, Wende H et al. Neuregulin-1/ErbB signaling serves distinct functions in myelination of the peripheral and central nervous system. Neuron 2008; 59: 581–595.
Flagstad P, Mork A, Glenthoj BY, van Beek J, Michael-Titus AT, Didriksen M . Disruption of neurogenesis on gestational day 17 in the rat causes behavioral changes relevant to positive and negative schizophrenia symptoms and alters amphetamine-induced dopamine release in nucleus accumbens. Neuropsychopharmacology 2004; 29: 2052–2064.
Penschuck S, Flagstad P, Didriksen M, Leist M, Michael-Titus AT . Decrease in parvalbumin-expressing neurons in the hippocampus and increased phencyclidine-induced locomotor activity in the rat methylazoxymethanol (MAM) model of schizophrenia. Eur J Neurosci 2006; 23: 279–284.
Matsutani T . A neurochemical study of experimental microencephalic rat. J Toxicol Sci 1984; 9: 205–218.
Chin CL, Curzon P, Schwartz AJ, O'Connor EM, Rueter LE, Fox GB et al. Structural abnormalities revealed by magnetic resonance imaging in rats prenatally exposed to methylazoxymethanol acetate parallel cerebral pathology in schizophrenia. Synapse (New York, NY) 2011; 65: 393–403.
Fonnum F, Lock EA . The contributions of excitotoxicity, glutathione depletion and DNA repair in chemically induced injury to neurones: exemplified with toxic effects on cerebellar granule cells. J Neurochem 2004; 88: 513–531.
Zimmerman EC, Bellaire M, Ewing SG, Grace AA . Abnormal stress responsivity in a rodent developmental disruption model of schizophrenia. Neuropsychopharmacology 2013; 38: 2131–2139.
Fiore M, Grace AA, Korf J, Stampachiacchiere B, Aloe L . Impaired brain development in the rat following prenatal exposure to methylazoxymethanol acetate at gestational day 17 and neurotrophin distribution. Neuroreport 2004; 15: 1791–1795.
Makinodan M, Tatsumi K, Manabe T, Yamauchi T, Makinodan E, Matsuyoshi H et al. Maternal immune activation in mice delays myelination and axonal development in the hippocampus of the offspring. Journal of neuroscience research 2008; 86: 2190–2200.
Marcotte ER, Pearson DM, Srivastava LK . Animal models of schizophrenia: a critical review. J Psychiatry Neurosci 2001; 26: 395–410.
Lipska BK, Weinberger DR . To model a psychiatric disorder in animals: schizophrenia as a reality test. Neuropsychopharmacology 2000; 23: 223–239.
Johnson AW, Jaaro-Peled H, Shahani N, Sedlak TW, Zoubovsky S, Burruss D et al. Cognitive and motivational deficits together with prefrontal oxidative stress in a mouse model for neuropsychiatric illness. Proc Natl Acad Sci USA 2013; 110: 12462–12467.
Yang Y, Dieter MZ, Chen Y, Shertzer HG, Nebert DW, Dalton TP . Initial characterization of the glutamate-cysteine ligase modifier subunit Gclm(-/-) knockout mouse. Novel model system for a severely compromised oxidative stress response. J Biol Chem 2002; 277: 49446–49452.
Steullet P, Cabungcal JH, Kulak A, Kraftsik R, Chen Y, Dalton TP et al. Redox dysregulation affects the ventral but not dorsal hippocampus: impairment of parvalbumin neurons, gamma oscillations, and related behaviors. J Neurosci 2010; 30: 2547–2558.
Matrisciano F, Tueting P, Dalal I, Kadriu B, Grayson DR, Davis JM et al. Epigenetic modifications of GABAergic interneurons are associated with the schizophrenia-like phenotype induced by prenatal stress in mice. Neuropharmacology 2013; 68: 184–194.
Ferdman N, Murmu RP, Bock J, Braun K, Leshem M . Weaning age, social isolation, and gender, interact to determine adult explorative and social behavior, and dendritic and spine morphology in prefrontal cortex of rats. Behav Brain Res 2007; 180: 174–182.
Acknowledgements
We thank Alan Anticevic, Anissa Abi-Dargham, Jennifer Coughlin and Anouk Marsman for scientific discussion. We thank Yukiko Lema for organizing the figures, in particular for contributing to the formatting process. MRI images were kindly provided by Susumu Mori and Michael Jacobs. This work was supported by USPHS grants MH-084018 (AS), MH-094268 Silvo O. Conte center (AS), MH-069853 (AS), MH-085226 (AS), MH-088753 (AS), MH-092443 (AS), Stanley (AS), RUSK (AS), S-R foundations (AS), NARSAD (AS) and the Maryland Stem Cell Research Fund (AS).
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AS currently receives research funding from Johnson and Johnson, Astellas, Takeda, Tanabe-Mitsubishi, Dainippon-Sumitomo and Sucampo; has served as an advisory board and consultant for Amgen, Asubio, Eli Lilly, Pfizer, Sucampo, Taisho and Takeda, and collaborated with Afraxis, Astrazeneca and Sanofi-Aventis. However, none of these relationships affected the contents and statements of this review article.
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Landek-Salgado, M., Faust, T. & Sawa, A. Molecular substrates of schizophrenia: homeostatic signaling to connectivity. Mol Psychiatry 21, 10–28 (2016). https://doi.org/10.1038/mp.2015.141
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DOI: https://doi.org/10.1038/mp.2015.141
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