{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T16:42:40Z","timestamp":1773679360625,"version":"3.50.1"},"reference-count":74,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2016,5,10]],"date-time":"2016-05-10T00:00:00Z","timestamp":1462838400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,5,10]],"date-time":"2016-05-10T00:00:00Z","timestamp":1462838400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Transl Psychiatry"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Genetic studies have linked the primate-specific gene locus <jats:italic>G72<\/jats:italic> to the development of schizophrenia and bipolar disorder. Transgenic mice carrying the entire gene locus express <jats:italic>G72<\/jats:italic> mRNA in dentate gyrus (DG) and entorhinal cortex, causing altered electrophysiological properties of their connections. These transgenic mice exhibit behavioral alterations related to psychiatric diseases, including cognitive deficits that can be reversed by treatment with <jats:italic>N<\/jats:italic>-acetylcysteine, which was also found to be effective in human patients. Here, we show that G72 transgenic mice have larger excitatory synapses with an increased amount of <jats:italic>N<\/jats:italic>-methyl-d-aspartate (NMDA) receptors in the molecular layer of DG, compared with wild-type littermates. Furthermore, transgenic animals have lower number of dentate granule cells with a parallel, but an even stronger decrease in the number of excitatory synapses in the molecular layer. Importantly, we also show that treatment with <jats:italic>N<\/jats:italic>-acetylcysteine can effectively normalize all these changes in transgenic animals, resulting in a state similar to wild-type mice. Our results show that <jats:italic>G72<\/jats:italic> transcripts induce robust alterations in the glutamatergic system at the synaptic level that can be rescued with <jats:italic>N<\/jats:italic>-acetylcysteine treatment.<\/jats:p>","DOI":"10.1038\/tp.2016.74","type":"journal-article","created":{"date-parts":[[2016,5,10]],"date-time":"2016-05-10T15:37:22Z","timestamp":1462894642000},"page":"e807-e807","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Synaptic and cellular changes induced by the schizophrenia susceptibility gene G72 are rescued by N-acetylcysteine treatment"],"prefix":"10.1038","volume":"6","author":[{"given":"B","family":"P\u00f3sfai","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C","family":"Cser\u00e9p","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P","family":"Heged\u00fcs","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"E","family":"Szabadits","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D M","family":"Otte","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A","family":"Zimmer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M","family":"Watanabe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T F","family":"Freund","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G","family":"Nyiri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2016,5,10]]},"reference":[{"key":"BFtp201674_CR1","doi-asserted-by":"publisher","first-page":"1738","DOI":"10.1056\/NEJMra035458","volume":"349","author":"R Freedman","year":"2003","unstructured":"Freedman R . Schizophrenia. N Engl J Med 2003; 349: 1738\u20131749.","journal-title":"N Engl J Med"},{"key":"BFtp201674_CR2","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/S0163-7258(02)00328-5","volume":"97","author":"C Konradi","year":"2003","unstructured":"Konradi C, Heckers S . Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment. Pharmacol Ther 2003; 97: 153\u2013179.","journal-title":"Pharmacol Ther"},{"key":"BFtp201674_CR3","doi-asserted-by":"publisher","first-page":"2410","DOI":"10.1016\/j.neubiorev.2012.10.009","volume":"37","author":"E Drews","year":"2013","unstructured":"Drews E, Otte DM, Zimmer A . Involvement of the primate specific gene G72 in schizophrenia: from genetic studies to pathomechanisms. Neurosci Biobehav Rev 2013; 37: 2410\u20132417.","journal-title":"Neurosci Biobehav Rev"},{"key":"BFtp201674_CR4","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1196\/annals.1300.020","volume":"1003","author":"JT Coyle","year":"2003","unstructured":"Coyle JT, Tsai G, Goff D . Converging evidence of NMDA receptor hypofunction in the pathophysiology of schizophrenia. Ann N Y Acad Sci 2003; 1003: 318\u2013327.","journal-title":"Ann N Y Acad Sci"},{"key":"BFtp201674_CR5","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1016\/j.brainresbull.2010.04.006","volume":"83","author":"JT Kantrowitz","year":"2010","unstructured":"Kantrowitz JT, Javitt DC . N-methyl-d-aspartate (NMDA) receptor dysfunction or dysregulation: the final common pathway on the road to schizophrenia? Brain Res Bull 2010; 83: 108\u2013121.","journal-title":"Brain Res Bull"},{"key":"BFtp201674_CR6","doi-asserted-by":"publisher","first-page":"1301","DOI":"10.1176\/ajp.148.10.1301","volume":"148","author":"DC Javitt","year":"1991","unstructured":"Javitt DC, Zukin SR . Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 1991; 148: 1301\u20131308.","journal-title":"Am J Psychiatry"},{"key":"BFtp201674_CR7","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1001\/archpsyc.1994.03950030035004","volume":"51","author":"JH Krystal","year":"1994","unstructured":"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\u2013214.","journal-title":"Arch Gen Psychiatry"},{"key":"BFtp201674_CR8","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1007\/s00213-005-0177-2","volume":"183","author":"A Parwani","year":"2005","unstructured":"Parwani A, Weiler Ma, Blaxton Ta, Warfel D, Hardin M, Frey K et al. The effects of a subanesthetic dose of ketamine on verbal memory in normal volunteers. Psychopharmacology (Berl) 2005; 183: 265\u2013274.","journal-title":"Psychopharmacology (Berl)"},{"key":"BFtp201674_CR9","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1016\/j.tins.2008.02.005","volume":"31","author":"JE Lisman","year":"2008","unstructured":"Lisman JE, Coyle JT, Green RW, Javitt DC, Benes FM, Heckers S et al. Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia. Trends Neurosci 2008; 31: 234\u2013242.","journal-title":"Trends Neurosci"},{"key":"BFtp201674_CR10","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1016\/0006-3223(94)90629-7","volume":"36","author":"a Wolkin","year":"1994","unstructured":"Wolkin a, Sanfilipo M, Angrist B, Duncan E, Wieland S, Wolf a P et al. Acute d-amphetamine challenge in schizophrenia: effects on cerebral glucose utilization and clinical symptomatology. Biol Psychiatry 1994; 36: 317\u2013325.","journal-title":"Biol Psychiatry"},{"key":"BFtp201674_CR11","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/j.schres.2006.07.002","volume":"88","author":"BP Murphy","year":"2006","unstructured":"Murphy BP, Chung Y-C, Park T-W, McGorry PD . Pharmacological treatment of primary negative symptoms in schizophrenia: a systematic review. Schizophr Res 2006; 88: 5\u201325.","journal-title":"Schizophr Res"},{"key":"BFtp201674_CR12","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1038\/sj.mp.4001558","volume":"10","author":"PJ Harrison","year":"2005","unstructured":"Harrison PJ, Weinberger DR . Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 2005; 10: 40\u201368, image 5.","journal-title":"Mol Psychiatry"},{"key":"BFtp201674_CR13","doi-asserted-by":"publisher","first-page":"1484","DOI":"10.1016\/j.neuropharm.2011.01.030","volume":"62","author":"V Labrie","year":"2012","unstructured":"Labrie V, Wong AHC, Roder JC . Contributions of the d-serine pathway to schizophrenia. Neuropharmacology 2012; 62: 1484\u20131503.","journal-title":"Neuropharmacology"},{"key":"BFtp201674_CR14","doi-asserted-by":"publisher","first-page":"13675","DOI":"10.1073\/pnas.182412499","volume":"99","author":"I Chumakov","year":"2002","unstructured":"Chumakov I, Blumenfeld M, Guerassimenko O, Cavarec L, Palicio M, Abderrahim H et al. Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia. Proc Natl Acad Sci USA 2002; 99: 13675\u201313680.","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFtp201674_CR15","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1016\/j.biopsych.2004.04.006","volume":"56","author":"M Korostishevsky","year":"2004","unstructured":"Korostishevsky M, Kaganovich M, Cholostoy A, Ashkenazi M, Ratner Y, Dahary D et al. Is the G72\/G30 locus associated with schizophrenia? Single nucleotide polymorphisms, haplotypes, and gene expression analysis. Biol Psychiatry 2004; 56: 169\u2013176.","journal-title":"Biol Psychiatry"},{"key":"BFtp201674_CR16","doi-asserted-by":"publisher","first-page":"636","DOI":"10.1038\/mp.2013.80","volume":"19","author":"C-H Lin","year":"2014","unstructured":"Lin C-H, Chang H-T, Chen Y-J, Huang C-H, Tun R, Tsai GE et al. Distinctively higher plasma G72 protein levels in patients with schizophrenia than in healthy individuals. Mol Psychiatry 2014; 19: 636\u2013637.","journal-title":"Mol Psychiatry"},{"key":"BFtp201674_CR17","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1016\/j.cell.2012.06.029","volume":"150","author":"T Papouin","year":"2012","unstructured":"Papouin T, Lad\u00e9p\u00eache L, Ruel J, Sacchi S, Labasque M, Hanini M et al. Synaptic and extrasynaptic NMDA receptors are gated by different endogenous coagonists. Cell 2012; 150: 633\u2013646.","journal-title":"Cell"},{"key":"BFtp201674_CR18","doi-asserted-by":"publisher","first-page":"22244","DOI":"10.1074\/jbc.M709153200","volume":"283","author":"S Sacchi","year":"2008","unstructured":"Sacchi S, Bernasconi M, Martineau M, Mothet JP, Ruzzene M, Pilone MS et al. pLG72 modulates intracellular D-serine levels through its interaction with D-amino acid oxidase: Effect on schizophrenia susceptibility. J Biol Chem 2008; 283: 22244\u201322256.","journal-title":"J Biol Chem"},{"key":"BFtp201674_CR19","doi-asserted-by":"publisher","first-page":"29","DOI":"10.3390\/ijms15010029","volume":"15","author":"SL Chang","year":"2013","unstructured":"Chang SL, Hsieh C, Chen Y, Wang C, Shih C, Huang P et al. The C -terminal region of G72 increases D -amino acid oxidase activity. Int J Mol Sci 2013; 15: 29\u201343.","journal-title":"Int J Mol Sci"},{"key":"BFtp201674_CR20","doi-asserted-by":"publisher","first-page":"1123","DOI":"10.1007\/s10571-014-0087-0","volume":"34","author":"D-M Otte","year":"2014","unstructured":"Otte D-M, Rask\u00f3 T, Wang M, Dreiseidler M, Drews E, Schrage H et al. Identification of the mitochondrial MSRB2 as a binding partner of LG72. Cell Mol Neurobiol 2014; 34: 1123\u20131130.","journal-title":"Cell Mol Neurobiol"},{"key":"BFtp201674_CR21","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1038\/sj.mp.4002052","volume":"13","author":"M Kvajo","year":"2008","unstructured":"Kvajo M, Dhilla A, Swor DE, Karayiorgou M, Gogos JA . Evidence implicating the candidate schizophrenia\/bipolar disorder susceptibility gene G72 in mitochondrial function. Mol Psychiatry 2008; 13: 685\u2013696.","journal-title":"Mol Psychiatry"},{"key":"BFtp201674_CR22","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1016\/j.euroneuro.2008.12.009","volume":"19","author":"DM Otte","year":"2009","unstructured":"Otte DM, Bilkei-Gorz\u00f3 A, Filiou MD, Turck CW, Yilmaz \u00d6, Holst MI et al. Behavioral changes in G72\/G30 transgenic mice. Eur Neuropsychopharmacol 2009; 19: 339\u2013348.","journal-title":"Eur Neuropsychopharmacol"},{"key":"BFtp201674_CR23","doi-asserted-by":"publisher","first-page":"2233","DOI":"10.1038\/npp.2011.109","volume":"36","author":"D-M Otte","year":"2011","unstructured":"Otte D-M, Sommersberg B, Kudin A, Guerrero C, Albayram O, Filiou MD et al. N-acetyl cysteine treatment rescues cognitive deficits induced by mitochondrial dysfunction in G72\/G30 transgenic mice. Neuropsychopharmacology 2011; 36: 2233\u20132243.","journal-title":"Neuropsychopharmacology"},{"key":"BFtp201674_CR24","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1016\/j.schres.2013.04.020","volume":"147","author":"Kirov II","year":"2013","unstructured":"Kirov II, Hardy CJ, Matsuda K, Messinger J, Cankurtaran CZ, Warren M et al. In vivo 7Tesla imaging of the dentate granule cell layer in schizophrenia. Schizophr Res 2013; 147: 362\u2013367.","journal-title":"Schizophr Res"},{"key":"BFtp201674_CR25","doi-asserted-by":"publisher","first-page":"318596","DOI":"10.1155\/2013\/318596","volume":"2013","author":"H Hagihara","year":"2013","unstructured":"Hagihara H, Takao K, Walton NM, Matsumoto M, Miyakawa T . Immature dentate gyrus: an endophenotype of neuropsychiatric disorders. Neural Plast 2013; 2013: 318596.","journal-title":"Neural Plast"},{"key":"BFtp201674_CR26","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1038\/mp.2014.54","volume":"20","author":"AD Stan","year":"2015","unstructured":"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 2015; 20: 433\u2013439.","journal-title":"Mol Psychiatry"},{"key":"BFtp201674_CR27","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1016\/j.schres.2014.05.006","volume":"159","author":"T Das","year":"2014","unstructured":"Das T, Ivleva EI, Wagner AD, Stark CEL, Tamminga Ca . Loss of pattern separation performance in schizophrenia suggests dentate gyrus dysfunction. Schizophr Res 2014; 159: 193\u2013197.","journal-title":"Schizophr Res"},{"key":"BFtp201674_CR28","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1111\/bdi.12046","volume":"15","author":"T Elvs\u00e5shagen","year":"2013","unstructured":"Elvs\u00e5shagen T, Westlye LT, B\u00f8en E, Hol PK, Andersson S, Andreassen Oa et al. Evidence for reduced dentate gyrus and fimbria volume in bipolar II disorder. Bipolar Disord 2013; 15: 167\u2013176.","journal-title":"Bipolar Disord"},{"key":"BFtp201674_CR29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jpsychires.2014.09.014","volume":"60","author":"JM Gatt","year":"2015","unstructured":"Gatt JM, Burton KLO, Williams LM, Schofield PR . Specific and common genes implicated across major mental disorders: a review of meta-analysis studies. J Psychiatr Res 2015; 60: 1\u201313.","journal-title":"J Psychiatr Res"},{"key":"BFtp201674_CR30","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.biopsych.2006.01.019","volume":"60","author":"SD Detera-Wadleigh","year":"2006","unstructured":"Detera-Wadleigh SD, McMahon FJ . G72\/G30 in schizophrenia and bipolar disorder: review and meta-analysis. Biol Psychiatry 2006; 60: 106\u2013114.","journal-title":"Biol Psychiatry"},{"key":"BFtp201674_CR31","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1016\/j.biopsych.2013.03.018","volume":"74","author":"J Flatow","year":"2013","unstructured":"Flatow J, Buckley P, Miller BJ . Meta-analysis of oxidative stress in schizophrenia. Biol Psychiatry 2013; 74: 400\u2013409.","journal-title":"Biol Psychiatry"},{"key":"BFtp201674_CR32","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1016\/j.ijdevneu.2010.08.007","volume":"29","author":"HB Clay","year":"2011","unstructured":"Clay HB, Sillivan S, Konradi C . Mitochondrial dysfunction and pathology in bipolar disorder and schizophrenia. Int J Dev Neurosci 2011; 29: 311\u2013324.","journal-title":"Int J Dev Neurosci"},{"key":"BFtp201674_CR33","doi-asserted-by":"publisher","first-page":"2011","DOI":"10.1089\/ars.2010.3603","volume":"15","author":"JK Yao","year":"2011","unstructured":"Yao JK, Keshavan MS . Antioxidants, redox signaling, and pathophysiology in schizophrenia: an integrative view. Antioxid Redox Signal 2011; 15: 2011\u20132035.","journal-title":"Antioxid Redox Signal"},{"key":"BFtp201674_CR34","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1016\/j.pnpbp.2012.07.013","volume":"39","author":"M Raffa","year":"2012","unstructured":"Raffa M, Barhoumi S, Atig F, Fendri C, Kerkeni A, Mechri A . Reduced antioxidant defense systems in schizophrenia and bipolar I disorder. Prog Neuro-Psychopharmacol Biol Psychiatry 2012; 39: 371\u2013375.","journal-title":"Prog Neuro-Psychopharmacol Biol Psychiatry"},{"key":"BFtp201674_CR35","doi-asserted-by":"publisher","first-page":"2187","DOI":"10.1038\/sj.npp.1301624","volume":"33","author":"S Lavoie","year":"2008","unstructured":"Lavoie S, Murray MM, Deppen P, Knyazeva MG, Berk M, Boulat O et al. Glutathione precursor, N-acetyl-cysteine, improves mismatch negativity in schizophrenia patients. Neuropsychopharmacology 2008; 33: 2187\u20132199.","journal-title":"Neuropsychopharmacology"},{"key":"BFtp201674_CR36","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1016\/j.biopsych.2008.03.004","volume":"64","author":"M Berk","year":"2008","unstructured":"Berk M, Copolov D, Dean O, Lu K, Jeavons S, Schapkaitz I et al. N-Acetyl cysteine as a glutathione precursor for schizophrenia-A double-blind, randomized, placebo-controlled trial. Biol Psychiatry 2008; 64: 361\u2013368.","journal-title":"Biol Psychiatry"},{"key":"BFtp201674_CR37","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1016\/j.jad.2011.06.005","volume":"135","author":"M Berk","year":"2011","unstructured":"Berk M, Dean O, Cotton SM, Gama CS, Kapczinski F, Fernandes BS et al. The efficacy of N-acetylcysteine as an adjunctive treatment in bipolar depression: an open label trial. J Affect Disord 2011; 135: 389\u2013394.","journal-title":"J Affect Disord"},{"key":"BFtp201674_CR38","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1590\/S1516-44462011000400011","volume":"33","author":"PV Magalh\u00e3es","year":"2011","unstructured":"Magalh\u00e3es PV, Dean OM, Bush AI, Copolov DL, Malhi GS, Kohlmann K et al. N-acetylcysteine for major depressive episodes in bipolar disorder. Rev Bras Psiquiatr 2011; 33: 374\u2013378.","journal-title":"Rev Bras Psiquiatr"},{"key":"BFtp201674_CR39","doi-asserted-by":"publisher","first-page":"4855","DOI":"10.1073\/pnas.0830996100","volume":"100","author":"M Fukaya","year":"2003","unstructured":"Fukaya M, Kato A, Lovett C, Tonegawa S, Watanabe M . Retention of NMDA receptor NR2 subunits in the lumen of endoplasmic reticulum in targeted NR1 knockout mice. Proc Natl Acad Sci USA 2003; 100: 4855\u20134860.","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFtp201674_CR40","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1002\/ar.1092310411","volume":"231","author":"MJ West","year":"1991","unstructured":"West MJ, Slomianka L, Gundersen HJ . Unbiased stereological estimation of the total number of neurons in the subdivisions of the rat hippocampus using the optical fractionator. Anat Rec 1991; 231: 482\u2013497.","journal-title":"Anat Rec"},{"key":"BFtp201674_CR41","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/S0079-6123(07)63001-5","volume":"163","author":"DG Amaral","year":"2007","unstructured":"Amaral DG, Scharfman HE, Lavenex P . The dentate gyrus: fundamental neuroanatomical organization (dentate gyrus for dummies). Prog Brain Res 2007; 163: 3\u201322.","journal-title":"Prog Brain Res"},{"key":"BFtp201674_CR42","doi-asserted-by":"publisher","first-page":"1217","DOI":"10.1126\/science.256.5060.1217","volume":"256","author":"H Monyer","year":"1992","unstructured":"Monyer H, Sprengel R, Schoepfer R, Herb A, Higuchi M, Lomeli H et al. Heteromeric NMDA receptors: molecular and functional distinction of subtypes. Science 1992; 256: 1217\u20131221.","journal-title":"Science"},{"key":"BFtp201674_CR43","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1046\/j.1460-9568.1999.00535.x","volume":"11","author":"Z Nusser","year":"1999","unstructured":"Nusser Z . A new approach to estimate the number, density and variability of receptors at central synapses. Eur J Neurosci 1999; 11: 745\u2013752.","journal-title":"Eur J Neurosci"},{"key":"BFtp201674_CR44","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1016\/S0306-4522(03)00157-X","volume":"119","author":"G Ny\u00edri","year":"2003","unstructured":"Ny\u00edri G, Stephenson FA, Freund TF, Somogyi P . Large variability in synaptic N-methyl-D-aspartate receptor density on interneurons and a comparison with pyramidal-cell spines in the rat hippocampus. Neuroscience 2003; 119: 347\u2013363.","journal-title":"Neuroscience"},{"key":"BFtp201674_CR45","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1186\/1744-9081-5-28","volume":"5","author":"NJ Bass","year":"2009","unstructured":"Bass NJ, Datta SR, McQuillin A, Puri V, Choudhury K, Thirumalai S et al. Evidence for the association of the DAOA (G72) gene with schizophrenia and bipolar disorder but not for the association of the DAO gene with schizophrenia. Behav Brain Funct 2009; 5: 28.","journal-title":"Behav Brain Funct"},{"key":"BFtp201674_CR46","doi-asserted-by":"publisher","first-page":"1604","DOI":"10.1523\/JNEUROSCI.17-05-01604.1997","volume":"17","author":"MJ Schell","year":"1997","unstructured":"Schell MJ, Brady RO, Molliver ME, Snyder SH . D-serine as a neuromodulator: regional and developmental localizations in rat brain glia resemble NMDA receptors. J Neurosci 1997; 17: 1604\u20131615.","journal-title":"J Neurosci"},{"key":"BFtp201674_CR47","first-page":"39","volume":"7","author":"MR Van Horn","year":"2013","unstructured":"Van Horn MR, Sild M, Ruthazer ES . D-serine as a gliotransmitter and its roles in brain development and disease. Front Cell Neurosci 2013; 7: 39.","journal-title":"Front Cell Neurosci"},{"key":"BFtp201674_CR48","doi-asserted-by":"publisher","first-page":"E2400","DOI":"10.1073\/pnas.1304308110","volume":"110","author":"DT Balu","year":"2013","unstructured":"Balu DT, Li Y, Puhl MD, Benneyworth Ma, Basu AC, Takagi S et al. Multiple risk pathways for schizophrenia converge in serine racemase knockout mice, a mouse model of NMDA receptor hypofunction. Proc Natl Acad Sci USA 2013; 110: E2400\u2013E2409.","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFtp201674_CR49","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1001\/archpsyc.60.6.572","volume":"60","author":"K Hashimoto","year":"2003","unstructured":"Hashimoto K, Fukushima T, Shimizu E, Komatsu N, Watanabe H, Shinoda N et al. Decreased serum levels of D-serine in patients with schizophrenia: evidence in support of the N-methyl-D-aspartate receptor hypofunction hypothesis of schizophrenia. Arch Gen Psychiatry 2003; 60: 572\u2013576.","journal-title":"Arch Gen Psychiatry"},{"key":"BFtp201674_CR50","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/j.schres.2006.10.010","volume":"90","author":"I Bendikov","year":"2007","unstructured":"Bendikov I, Nadri C, Amar S, Panizzutti R, De Miranda J, Wolosker H et al. A CSF and postmortem brain study of d-serine metabolic parameters in schizophrenia. Schizophr Res 2007; 90: 41\u201351.","journal-title":"Schizophr Res"},{"key":"BFtp201674_CR51","doi-asserted-by":"publisher","first-page":"1081","DOI":"10.1016\/S0006-3223(98)00279-0","volume":"44","author":"G Tsai","year":"1998","unstructured":"Tsai G, Yang P, Chung LC, Lange N, Coyle JT . D-serine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 1998; 44: 1081\u20131089.","journal-title":"Biol Psychiatry"},{"key":"BFtp201674_CR52","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1016\/j.biopsych.2004.12.037","volume":"57","author":"U Heresco-Levy","year":"2005","unstructured":"Heresco-Levy U, Javitt DC, Ebstein R, Vass A, Lichtenberg P, Bar G et al. D-serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment-refractory schizophrenia. Biol Psychiatry 2005; 57: 577\u2013585.","journal-title":"Biol Psychiatry"},{"key":"BFtp201674_CR53","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fnsyn.2014.00014","volume":"6","author":"J Sasabe","year":"2014","unstructured":"Sasabe J, Suzuki M, Imanishi N, Aiso S . Activity of D-amino acid oxidase is widespread in the human central nervous system. Front Synaptic Neurosci 2014; 6: 1\u201310.","journal-title":"Front Synaptic Neurosci"},{"key":"BFtp201674_CR54","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.jpba.2015.02.013","volume":"116","author":"J Billard","year":"2015","unstructured":"Billard J . d-Serine in the aging hippocampus. J Pharm Biomed Anal 2015; 116: 18\u201324.","journal-title":"J Pharm Biomed Anal"},{"key":"BFtp201674_CR55","doi-asserted-by":"publisher","first-page":"980","DOI":"10.1016\/j.biopsych.2011.01.010","volume":"69","author":"M Rosenfeld","year":"2011","unstructured":"Rosenfeld M, Brenner-Lavie H, Ari SGB, Kavushansky A, Ben-Shachar D . Perturbation in mitochondrial network dynamics and in complex I dependent cellular respiration in schizophrenia. Biol Psychiatry 2011; 69: 980\u2013988.","journal-title":"Biol Psychiatry"},{"key":"BFtp201674_CR56","doi-asserted-by":"publisher","first-page":"e4","DOI":"10.1016\/j.biopsych.2012.06.028","volume":"73","author":"G Scola","year":"2013","unstructured":"Scola G, Kim HK, Young LT, Andreazza AC . A fresh look at complex i in microarray data: Clues to understanding disease-specific mitochondrial alterations in bipolar disorder. Biol Psychiatry 2013; 73: e4\u2013e5.","journal-title":"Biol Psychiatry"},{"key":"BFtp201674_CR57","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1146\/annurev.genet.39.110304.095751","volume":"39","author":"DC Wallace","year":"2005","unstructured":"Wallace DC . A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet 2005; 39: 359\u2013407.","journal-title":"Annu Rev Genet"},{"key":"BFtp201674_CR58","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/j.psychres.2014.04.005","volume":"218","author":"NC Brown","year":"2014","unstructured":"Brown NC, Andreazza AC, Young LT . An updated meta-analysis of oxidative stress markers in bipolar disorder. Psychiatry Res 2014; 218: 61\u201368.","journal-title":"Psychiatry Res"},{"key":"BFtp201674_CR59","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1097\/YCO.0000000000000054","volume":"27","author":"FE Emiliani","year":"2014","unstructured":"Emiliani FE, Sedlak TW, Sawa A . Oxidative stress and schizophrenia: recent breakthroughs from an old story. Curr Opin Psychiatry 2014; 27: 185\u2013190.","journal-title":"Curr Opin Psychiatry"},{"key":"BFtp201674_CR60","doi-asserted-by":"publisher","first-page":"140","DOI":"10.2174\/1570159X11666131120230309","volume":"12","author":"S Salim","year":"2014","unstructured":"Salim S . Oxidative stress and psychological disorders. Curr Neuropharmacol 2014; 12: 140\u2013147.","journal-title":"Curr Neuropharmacol"},{"key":"BFtp201674_CR61","doi-asserted-by":"publisher","first-page":"1359","DOI":"10.1016\/j.jpsychires.2012.07.004","volume":"46","author":"MD Filiou","year":"2012","unstructured":"Filiou MD, Teplytska L, Otte DM, Zimmer A, Turck CW . Myelination and oxidative stress alterations in the cerebellum of the G72\/G30 transgenic schizophrenia mouse model. J Psychiatr Res 2012; 46: 1359\u20131365.","journal-title":"J Psychiatr Res"},{"key":"BFtp201674_CR62","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1016\/S0165-6147(00)89077-X","volume":"16","author":"H Gozlan","year":"1995","unstructured":"Gozlan H, Ben-Ari Y . NMDA receptor redox sites: are they targets for selective neuronal protection? Trends Pharmacol Sci 1995; 16: 368\u2013374.","journal-title":"Trends Pharmacol Sci"},{"key":"BFtp201674_CR63","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1016\/j.neuroscience.2005.10.014","volume":"137","author":"P Steullet","year":"2006","unstructured":"Steullet P, Neijt HC, Cu\u00e9nod M, Do KQ . Synaptic plasticity impairment and hypofunction of NMDA receptors induced by glutathione deficit: Relevance to schizophrenia. Neuroscience 2006; 137: 807\u2013819.","journal-title":"Neuroscience"},{"key":"BFtp201674_CR64","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1038\/nrn.2015.19","volume":"17","author":"G Hardingham","year":"2016","unstructured":"Hardingham G, Do KQ . Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis. Nat Rev Neurosci 2016; 17: 125\u2013134.","journal-title":"Nat Rev Neurosci"},{"key":"BFtp201674_CR65","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1002\/(SICI)1098-2396(20000615)36:4<286::AID-SYN5>3.0.CO;2-T","volume":"36","author":"ACW Weeks","year":"2000","unstructured":"Weeks ACW, Ivanco TL, Leboutillier JC, Racine RJ, Petit TL . Sequential changes in the synaptic structural profile following long- term potentiation in the rat dentate gyrus. II. Induction\/early maintenance phase. Synapse 2000; 36: 286\u2013296.","journal-title":"Synapse"},{"key":"BFtp201674_CR66","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1016\/S0962-8924(00)01838-9","volume":"10","author":"DL Benson","year":"2000","unstructured":"Benson DL, Schnapp LM, Shapiro L, Huntley GW . Making memories stick: cell-adhesion molecules in synaptic plasticity. Trends Cell Biol 2000; 10: 473\u2013482.","journal-title":"Trends Cell Biol"},{"key":"BFtp201674_CR67","doi-asserted-by":"publisher","first-page":"10428","DOI":"10.1073\/pnas.181336998","volume":"98","author":"a Dosemeci","year":"2001","unstructured":"Dosemeci a, Tao-Cheng JH, Vinade L, Winters Ca, Pozzo-Miller L, Reese TS . Glutamate-induced transient modification of the postsynaptic density. Proc Natl Acad Sci U S A 2001; 98: 10428\u201310432.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"BFtp201674_CR68","doi-asserted-by":"publisher","first-page":"1032","DOI":"10.1002\/dneu.22014","volume":"72","author":"JM Song","year":"2012","unstructured":"Song JM, Christian K, Ming GL, Song H . Modification of hippocampal circuitry by adult neurogenesis. Dev Neurobiol 2012; 72: 1032\u20131043.","journal-title":"Dev Neurobiol"},{"key":"BFtp201674_CR69","doi-asserted-by":"publisher","first-page":"929","DOI":"10.1038\/nature05028","volume":"442","author":"A Tashiro","year":"2006","unstructured":"Tashiro A, Sandler VM, Toni N, Zhao C, Gage FH . NMDA-receptor-mediated, cell-specific integration of new neurons in adult dentate gyrus. Nature 2006; 442: 929\u2013933.","journal-title":"Nature"},{"key":"BFtp201674_CR70","doi-asserted-by":"publisher","first-page":"738","DOI":"10.1016\/j.semcdb.2012.04.003","volume":"23","author":"TT Huang","year":"2012","unstructured":"Huang TT, Zou Y, Corniola R . Oxidative stress and adult neurogenesis-effects of radiation and superoxide dismutase deficiency. Semin Cell Dev Biol 2012; 23: 738\u2013744.","journal-title":"Semin Cell Dev Biol"},{"key":"BFtp201674_CR71","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1016\/j.bbrc.2014.08.123","volume":"452","author":"M Sasaki","year":"2014","unstructured":"Sasaki M, Kajiya H, Ozeki S, Okabe K, Ikebe T . Reactive oxygen species promotes cellular senescence in normal human epidermal keratinocytes through epigenetic regulation of p16INK4a. Biochem Biophys Res Commun 2014; 452: 622\u2013628.","journal-title":"Biochem Biophys Res Commun"},{"key":"BFtp201674_CR72","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1038\/sj.mp.4001791","volume":"11","author":"a Reif","year":"2006","unstructured":"Reif a, Fritzen S, Finger M, Strobel a, Lauer M, Schmitt a et al. Neural stem cell proliferation is decreased in schizophrenia, but not in depression. Mol Psychiatry 2006; 11: 514\u2013522.","journal-title":"Mol Psychiatry"},{"key":"BFtp201674_CR73","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1016\/j.mehy.2012.04.042","volume":"79","author":"RB Lu","year":"2012","unstructured":"Lu RB, Chen SL, Lee SY, Chang YH, Chen SH, Chu CH et al. Neuroprotective and neurogenesis agent for treating bipolar II disorder: add-on memantine to mood stabilizer works. Med Hypotheses 2012; 79: 280\u2013283.","journal-title":"Med Hypotheses"},{"key":"BFtp201674_CR74","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1503\/jpn.100057","volume":"36","author":"O Dean","year":"2011","unstructured":"Dean O, Giorlando F, Berk M . N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action. J Psychiatry Neurosci 2011; 36: 78\u201386.","journal-title":"J Psychiatry Neurosci"}],"container-title":["Translational Psychiatry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/tp201674.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/tp201674","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/tp201674.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T08:49:23Z","timestamp":1672822163000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/tp201674"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,5,10]]},"references-count":74,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2016,5]]}},"alternative-id":["BFtp201674"],"URL":"https:\/\/doi.org\/10.1038\/tp.2016.74","relation":{},"ISSN":["2158-3188"],"issn-type":[{"value":"2158-3188","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,5,10]]},"assertion":[{"value":"7 December 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 February 2016","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 March 2016","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 May 2016","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}