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. Author manuscript; available in PMC: 2014 Jun 12.
Published in final edited form as: Curr Opin Psychiatry. 2014 May;27(3):185–190. doi: 10.1097/YCO.0000000000000054

Oxidative stress and schizophrenia: recent breakthroughs from an old story

Francesco E Emiliani 1, Thomas W Sedlak 1, Akira Sawa 1
PMCID: PMC4054867  NIHMSID: NIHMS591131  PMID: 24613987

Abstract

Purpose of review

Oxidative stress has become an exciting area of schizophrenia research, and provides ample opportunities and hope for a better understanding of its pathophysiology, which may lead to novel treatment strategies. This review describes how recent methodological advances have allowed the study of oxidative stress to tackle fundamental questions and have provided several conceptual breakthroughs to the field.

Recent findings

Recent human studies support the notion that intrinsic susceptibility to oxidative stress may underlie the pathophysiology of schizophrenia. More than one animal model that may be relevant to study biology of schizophrenia also shows sign of oxidative stress in the brain.

Summary

These advances have made this topic of paramount importance to the understanding of schizophrenia, and will play a role in advancing treatment options. This review covers topics from classic biochemical studies of human biospecimens to the use of magnetic resonance spectroscopy and novel mouse models, and focuses on highlighting promising areas of research.

Keywords: oxidative stress, magnetic resonance spectroscopy, olfactory cell, glutathione, superoxide dismutase

Introduction

Recent studies, in particular studies in human genetics, have indicated that multiple combinations of genetic and environmental factors underlie the etiology of schizophrenia (SZ) [1**, 2]. Although it is very important to explore the comprehensive landscape of genetic architecture of the disease, investigators and clinicians have also acknowledged the importance of understanding pathophysiological pathways that occur more commonly under the diagnostic label. Due to current diagnostic criteria, such as the Diagnostic and Statistical Manual of Mental Disorders (DSM), stemming more from reliability of clinical phenotypes rather than etiological validity, these pathways may not be purely disease or label specific (that is, they may underlie both SZ and bipolar disorder). Nonetheless, understanding of common pathophysiological pathways will prove to be very important in identifying biomarkers and drug discovery efforts.

Oxidative stress: timely and important topic in schizophrenia research as of 2014

Although first postulated in the 1930s by Roy Hoskins [3], the significance of oxidative stress in the pathophysiology of SZ has been underestimated. Oxidative stress is biologically important, but the involvement of this cascade occurs in multiple pathological conditions, including cancer, cardiovascular disease, and neurodegenerative disorders [4-6]. This non-specific nature of oxidative stress played a role in deterring psychiatric researchers from the field. Additionally, shortage of techniques for monitoring oxidative stress inside the brain was also a concern. However, at least four conceptual and technical advances in the past decade have changed the situation:

First, important studies that reported “specific” involvement of oxidative stress on key biological mechanisms that may underlie the endophenotypes relevant to SZ, such as role for nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in interneuron deficits, have generated new opportunities for research (described below in detail) [7].

Second, recent progress in cell biology has allowed us to access patient-derived cells with the potential to reproduce traits of brain cells, such as neurons, in vitro. The generation of induced pluripotent stem cells (iPS cells) is a hot topic given their potential to differentiate into neurons and glia [8**]. Furthermore, the use of cells from olfactory epithelium is also considered as an alternative approach [9, 10]. Olfactory cells are advantageous to iPS cells in that they possess neural traits, but require no reprogramming and are higher throughput [11*].

Third, an advance in brain imaging technique, in particular the capacity to measure the levels of glutathione (GSH), a major component of antioxidant defenses, by magnetic resonance imaging (MRS) has provided us with tools for in vivo studies [12].

Finally, although many studies of SZ patients have been challenged with regards to the effect of long-term medication and other confounding factors, recent reports have provided us with evidence of oxidative stress in recent-onset cases with minimal or no medication confounding [13**]. If oxidative stress is prominent in early stage of the disease, it is very reasonable that people expect such biological change to be a target of early detection and early intervention, which always confirm better treatment outcome in any disease in medicine [14]. Taken together, oxidative stress has become an exciting area of research in SZ.

What is oxidative stress?

Oxidative stress results from an imbalance between an overproduction of reactive oxygen species (ROS), and a deficiency of enzymatic or non-enzymatic antioxidants (Fig. 1). When this homeostasis is lost, oxidative stress damages cell structures. Major targets of oxidative stress are proteins, lipids, and DNA [15].

graphic file with name nihms-591131-f0001.jpg

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Key mediators of oxidative stress. Oxidative stress results from an imbalance between overproduction of reactive oxygen species (ROS) and a deficiency of enzymatic or non-enzymatic antioxidants. Representative molecules of ROS include O2•− (superoxide) and H2O2 (hydrogen peroxide). Key sources of ROS are the mitochondria, as a by-product of oxidative phosphorylation, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Superoxide dismutase (SOD) is responsible for the conversion of superoxide to hydrogen peroxide, which is further converted to non-radicals by catalase (CAT) or the glutathione (GSH) pathway that includes enzymes like glutathione peroxidase.

Physiological sources of ROS include oxidative phosphorylation, crucial for cellular energy generation is the predominant source, as well as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. NADPH-oxidase oxidizes NADPH, donating the electrons to an oxygen molecule (O2) to produce superoxide (O2−).

Cellular antioxidant defenses include enzymatic components, such as superoxide dismuatase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), as well as non-enzymatic components (GSH, uric acid, vitamin C, and albumin). SOD is responsible for converting the radical form of oxygen (O2−) into hydrogen peroxide (H2O2), which can be converted to oxygen and water by CAT or GSH-Px before it converts to harmful radicals. GSH is a tripeptide that is reduced to glutathione disulfide (GSSG) by GSH-Px to convert H2O2 to water.

Biochemical evidence in human biospecimens

The goal of this short review is to provide current opinions on exciting frontline research. Therefore, we acknowledge that our coverage of the past literatures is not exhaustive and only representative articles required for the present discussion are included.

Human biospecimens that have been used for the study of oxidative stress include postmortem tissues as well as biopsied samples, such as bloods (e.g., red blood cells, plasma, serum, lymphocytes, and lymphoblasts), fibroblasts, and cerebrospinal fluid (CSF). In addition, recent reports have utilized cutting-edge resources, such as iPS cells and olfactory cells [16**, 17]. In summary, evidence from biochemical studies of protein contents and activity in human biospecimens has suggested that oxidative stress may exist in the pathophysiology of SZ. However, as discussed below, there exist substantial discrepancies amongst results.

Postmortem brain analysis has suggestively shown the trace of excess oxidative stress [18, 19]. Though the study of postmortem brain is important, this has faced difficulty due to the employment of indirect measurements of oxidative stress. Furthermore, confounding factors, such as variability in the postmortem interval are inevitable.

SZ is a condition with onset in young adulthood. Many investigators have questioned whether autopsied brain from aged patients may truly reflect the active pathophysiology. Therefore, there is great potential in the study of biopsied cells/tissues from living patients. The levels of SOD were reduced in red blood cells from subjects with first-episode psychosis as well as those from stably medicated outpatient subjects [13**, 20]. Consistent observation was also reported in CSF from recent onset SZ patients [21]. However, studies have shown an increase in the levels of SOD in plasma from SZ patients [22]. The levels of GSH-Px were decreased in red blood cells from SZ patients in acute relapse phrases and chronic inpatient subjects [23]. Discrepancies in this result, though present, where found to be insignificant[13**]. Likewise, some, but not all studies have reported a reduction of CAT in red blood cells [13**, 24].

As described above, researchers have recently welcomed technical advances that enable us to study cells with neural traits obtained from living patients [10, 17, 25]. For example, the importance of stress-associated pathways has been underscored in a study with olfactory cells: of special interest were antioxidant enzyme pathways, which include proteins, such as microsomal glutathione-S-transferase 1 (MGST1) [17]. As far as we are aware, only a few studies utilized iPS cells in schizophrenia research. Nonetheless, two exploratory studies have already suggested involvement of oxidative stress: one case report indicated an increase in reactive oxygen species in SZ [26]. Another group showed that SZ-derived iPS cells had difficulty of differentiating to neurons and exhibited substantial mitochondrial deficits [16**].

Provided that these results are supportive to the notion that oxidative stress may underlie the pathophysiology of SZ, it is important to account for contradictory results in these studies. We regard that there are at least three possible reasons: first, SZ is highly heterogeneous under the same clinical diagnosis. Second, redox dysfunction may be, at least in part, state dependent. Third, tissue-specific change may underlie the pathophysiology. Meta-analyses that consider these points will be useful to the field.

Magnetic resonance spectroscopy (MRS)

As described above, most current biochemical studies utilize peripheral tissues, such as blood materials. A major breakthrough in the past decade is the use of MRS in measuring brain levels of GSH in living subjects directly [27, 28]. A pioneering study in schizophrenia research was made with H1-MRS at 1.5-Tesla and reported a 52% reduction of GSH in medial prefrontal cortex of drug free patients with SZ [29]. Subsequent studies, however, found difficulties in replication. The second report on brain GSH in medicated patients with SZ at 4-Tesla did not report a difference in the level of GSH in the anterior cingulate [30]. The third study also failed to observe the change in prefrontal cortex using a 3-Tesla machine, but noted a negative correlation of GSH with negative symptoms [31]. The forth group studying subjects with first episode psychosis reported an increase in GSH in the medial temporal lobe also at 3-Tesla [32].

Although the direct measurement of GSH in the brain of living subjects is tempting, the results are thus far inconsistent in studies of SZ. This discrepancy might be explained in part because different sequences are used for measurement and analyses in each study. The first study had been reported even before the introduction of the editing sequence [33]. In addition, although acceptable as brain imaging study each study had rather small sample size, and observed slightly different brain regions. More fundamentally, MRS cannot distinguish intracellular from extracellular GSH: this distinction is biologically crucial given the large difference in GSH concentrations. Thus, careful discussion on how to analyze the data of brain GSH measured by MRS is required for valid interpretation. A meta-analysis will be valuable once more studies with MRS are published.

What does oxidative stress elicit in the context of SZ pathophysiology?

Multiple groups have identified neuropathological defects associated with interneurons, in particular parvalbumin (PV)-positive interneurons, in the brains of SZ patients [34*-36]. Proper function of interneurons is required for the maintenance of gamma oscillations, which are responsible for cognition and are altered in SZ patients [37, 38]. Recent studies in preclinical models have shown that oxidative stress preferentially affects interneurons [7, 39*-41**]. The effectiveness of antioxidants in rescuing parvalbumin interneurons, give credence to antioxidant therapies [41**].

Furthermore, the lipid-rich white matter is sensitive to oxidative stress [42]. Thus, oxidative stress may underlie myelin-associated deficits in SZ [43, 44]. Oxidative stress can affect cellular signaling cascades, which may underlie the disease pathophysiology [45, 46].

Insight from animal models

In the present chapter, we have introduced a brief summary of human studies on SZ and oxidative stress. When attempting to elucidate the pathophysiology of a human disease or condition, study of human subjects is essential. Nonetheless, animal models are useful in linking the pathophysiology to the pathological trajectory during neurodevelopment, and in clarifying the molecular changes in the context of neural circuitry disturbance and behavioral changes.

In a strict sense, there is no animal model for SZ. However, for the present discussion we will consider animals that show behavioral changes relevant to some endophenotypes of SZ with some level of genetic evidence. Under this less stringent criterion, there exist at least three animal models that show signs of excess oxidative stress.

The first model focuses on Glutamate-cysteine ligase (GCL): this is the rate-limiting enzyme in GSH production, which is composed of modifier (GCLM) and catalytic (GCLC) subunits. A trinucleotide-repeat polymorphism in the GCLC gene is reportedly associated with SZ [47]. Gclm knockout mice showed a robust reduction in the level of GSH [48]. Of interest, this mouse model displayed reduced PV immunoreactivity in the CA3 and dentate gyrus, as well as predicted deficits in gamma oscillations [49]. The animals also showed deficits in prepulse inhibition and hyperlocomotion selective to environmental novelty and stress, and in response to acute amphetamine injection [50, 51]. Oxidative stress is prominent in adolescence, but the behavioral phenotypes relevant to SZ become more prominent after puberty, suggesting an idea that oxidative stress may be involved in early stage of the pathological trajectory [49, 52]. Finally some of these abnormalities were normalized by administration of the GSH precursor N-acetylcysteine (NAC) [52].

DISC1 is a representative gene in which a rare variant provides strong biological influence on mental disease, such as depression and schizophrenia [53]. Transgenic mice expressing a putative dominant-negative mutant displayed a reduction in the levels of parvalbumin immunoreactivity, indicating interneuron deficits [54]. Consequently, several behavioral deficits have also reported [39*, 54]. Given that interneuron deficits occur as downstream of oxidative stress, our group studied whether excess of oxidative stress may exist, and observed the sign in the frontal cortex, in particular orbitofrontal cortex [39*]. Of special interest, these mice showed an augmentation of the nuclear glyceraldehyde-3-phosphate-dehydrogenase (GAPDH) cascade, which is reportedly elicited by oxidative stress [39*, 55]. The nuclear GAPDH pathway is important in gene transcriptional and epigenetic controls upon stressors [56], thus the augmentation of this cascade triggered by oxidative stress may underlie stress-mediated epigenetic contribution to the disease pathophyisology.

The third model mice are deficient in excitatory amino acid transporter 3 (EAAT3/EAAC1) encoded by the gene Eaac1/Slc1a1, which reduces GSH production by limiting neuronal glutamate uptake [57]. Recent genetic studies have provided some evidence of Eaac1 association with SZ [58, 59].

Treatment perspectives

In an animal model (Gclm knockout mice) that is relevant to study biology of SZ, oxidative stress occurs in early phase of the pathological trajectory and administration of NAC ameliorated the abnormal behaviors [41**]. Although NAC is not a compound purely specific to oxidative stress, the preclinical study provided us with a hope to use NAC and related compounds in the treatment of SZ, in particular earlier phase of SZ [49]. In another model (Disc1 dominant-negative model), the nuclear GAPDH stress cascade was augmented [39*]. Because a set of selective compounds that block this cascade is available in humans [60], they may be tried for possible treatment of SZ.

Conclusion

In this short review, we have described how the story of oxidative stress in SZ has been rediscovered in the past decade, according to recent methodological advances in science. This biological process can be intervened in many ways, providing us with hope of developing novel treatment strategies to this devastating mental condition.

Key points.

Recent meta-analyses and replication studies with human biospecimens have further suggested the presence and role of oxidative stress in schizophrenia.

New techniques, such as magnetic resonance spectroscopy and stem cells obtained from living patients, have allowed more thorough studies.

Genetic mouse models relevant to schizophrenia show the signs of excess oxidative stress

We may develop novel strategies for treatment of schizophrenia by targeting oxidative stress in its pathophysiology.

Acknowledgements

We would like to thank Yukiko Lema for preparing the figure and formatting, and Dr. Mari Kondo for critical reading of the manuscript. This work was supported by USPHS grants of MH-084018 (A.S.), MH-094268 Silvo O. Conte center (A.S.), MH-069853 (A.S.), MH-085226 (A.S.), MH-088753 (A.S.), and MH-092443 (A.S.); grants from Stanley (A.S.), RUSK (A.S.), S-R foundations (A.S.), BBRF (A.S.), and Maryland Stem Cell Research Fund (A.S.).

Footnotes

Conflicts of Interest The authors declare no conflict of interest within the scope of the present manuscript.

References

  • 1.McGrath JJ, Mortensen PB, Visscher PM, et al. Where GWAS and epidemiology meet: opportunities for the simultaneous study of genetic and environmental risk factors in schizophrenia. Schizophr Bull. 2013;39(5):955–9. doi: 10.1093/schbul/sbt108. **This work provides an overview of the role of genetic and environmental factors in the development of schizophrenia.
  • 2.Owen MJ, Craddock N, O’Donovan MC. Suggestion of roles for both common and rare risk variants in genome-wide studies of schizophrenia. Arch Gen Psychiatry. 2010;67(7):667–73. doi: 10.1001/archgenpsychiatry.2010.69. [DOI] [PubMed] [Google Scholar]
  • 3.Hoskins RG. Oxygen metabolism in schizophrenia. Archives of Neurology and Psychiatry. 1937;38(6):1261–70. [Google Scholar]
  • 4.Paschos A, Pandya R, Duivenvoorden WC, et al. Oxidative stress in prostate cancer: changing research concepts towards a novel paradigm for prevention and therapeutics. Prostate Cancer Prostatic Dis. 2013;16(3):217–25. doi: 10.1038/pcan.2013.13. [DOI] [PubMed] [Google Scholar]
  • 5.Elnakish MT, Hassanain HH, Janssen PM, et al. Emerging role of oxidative stress in metabolic syndrome and cardiovascular diseases: important role of Rac/NADPH oxidase. J Pathol. 2013;231(3):290–300. doi: 10.1002/path.4255. [DOI] [PubMed] [Google Scholar]
  • 6.Simonian NA, Coyle JT. Oxidative stress in neurodegenerative diseases. Annu Rev Pharmacol Toxicol. 1996;36:83–106. doi: 10.1146/annurev.pa.36.040196.000503. [DOI] [PubMed] [Google Scholar]
  • 7.Behrens MM, Ali SS, Dao DN, et al. Ketamine-induced loss of phenotype of fast-spiking interneurons is mediated by NADPH-oxidase. Science. 2007;318(5856):1645–7. doi: 10.1126/science.1148045. [DOI] [PubMed] [Google Scholar]
  • 8.Brennand KJ, Landek-Salgado MA, Sawa A. Modeling Heterogeneous Patients with a Clinical Diagnosis of Schizophrenia with Induced Pluripotent Stem Cells. Biol Psychiatry. 2013 doi: 10.1016/j.biopsych.2013.10.025. [Epub ahead of print] **This review provides evidence for the potential of iPS cells to study schizophrenia, a heterogenous mental condition.
  • 9.Cascella NG, Takaki M, Lin S, et al. Neurodevelopmental involvement in schizophrenia: the olfactory epithelium as an alternative model for research. J Neurochem. 2007;102(3):587–94. doi: 10.1111/j.1471-4159.2007.04628.x. [DOI] [PubMed] [Google Scholar]
  • 10.Mackay-Sim A. Concise review: Patient-derived olfactory stem cells: new models for brain diseases. Stem Cells. 30(11):2361–5. doi: 10.1002/stem.1220. [DOI] [PubMed] [Google Scholar]
  • 11.Horiuchi Y, Kano S, Ishizuka K, et al. Olfactory cells via nasal biopsy reflect the developing brain in gene expression profiles: utility and limitation of the surrogate tissues in research for brain disorders. Neurosci Res. 2013;77(4):247–50. doi: 10.1016/j.neures.2013.09.010. *The characterization of various cells is useful in understanding their properties, and has implications on biospecimen chosen for study of a brain disorder.
  • 12.Gillard JH, Waldman AD, Barker PB. Clinical MR neuroimaging : physiological and functional techniques. 2nd ed Cambridge University Press; New York: 2009. [Google Scholar]
  • 13.Flatow J, Buckley P, Miller BJ. Meta-analysis of oxidative stress in schizophrenia. Biol Psychiatry. 2013;74(6):400–9. doi: 10.1016/j.biopsych.2013.03.018. **This meta-analysis is a thorough example of what is needed to interpret contradicting results from human biospecimens on oxidative stress and schizophrenia.
  • 14.McGorry P, Johanessen JO, Lewis S, et al. Early intervention in psychosis: keeping faith with evidence-based health care. Psychol Med. 2010;40(3):399–404. doi: 10.1017/S0033291709991346. [DOI] [PubMed] [Google Scholar]
  • 15.Valko M, Leibfritz D, Moncol J, et al. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 2007;39(1):44–84. doi: 10.1016/j.biocel.2006.07.001. [DOI] [PubMed] [Google Scholar]
  • 16.Robicsek O, Karry R, Petit I, et al. Abnormal neuronal differentiation and mitochondrial dysfunction in hair follicle-derived induced pluripotent stem cells of schizophrenia patients. Mol Psychiatry. 2013;18(10):1067–76. doi: 10.1038/mp.2013.67. **This study reports possible involvement of oxidative stress in schizophrenia with iPS cells from patients.
  • 17.Kano S, Colantuoni C, Han F, 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(7):740–2. doi: 10.1038/mp.2012.120. **Using olfactory cells from patients with schizophrenia, this study elucidates a series of pathways that are altered in the disease, including a redox pathway.
  • 18.Gawryluk JW, Wang JF, Andreazza AC, et al. Decreased levels of glutathione, the major brain antioxidant, in post-mortem prefrontal cortex from patients with psychiatric disorders. Int J Neuropsychopharmacol. 2011;14(1):123–30. doi: 10.1017/S1461145710000805. [DOI] [PubMed] [Google Scholar]
  • 19.Yao JK, Leonard S, Reddy RD. Increased nitric oxide radicals in postmortem brain from patients with schizophrenia. Schizophr Bull. 2004;30(4):923–34. doi: 10.1093/oxfordjournals.schbul.a007142. [DOI] [PubMed] [Google Scholar]
  • 20.Evans DR, Parikh VV, Khan MM, et al. Red blood cell membrane essential fatty acid metabolism in early psychotic patients following antipsychotic drug treatment. Prostaglandins Leukot Essent Fatty Acids. 2003;69(6):393–9. doi: 10.1016/j.plefa.2003.08.010. [DOI] [PubMed] [Google Scholar]
  • 21.Coughlin JM, Ishizuka K, Kano SI, et al. Marked reduction of soluble superoxide dismutase-1 (SOD1) in cerebrospinal fluid of patients with recent-onset schizophrenia. Mol Psychiatry. 2013;18(1):10–1. doi: 10.1038/mp.2012.6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Martinez-Cengotitabengoa M, Mac-Dowell KS, Leza JC, et al. Cognitive impairment is related to oxidative stress and chemokine levels in first psychotic episodes. Schizophr Res. 2012;137(1-3):66–72. doi: 10.1016/j.schres.2012.03.004. [DOI] [PubMed] [Google Scholar]
  • 23.Raffa M, Mechri A, Othman LB, et al. Decreased glutathione levels and antioxidant enzyme activities in untreated and treated schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33(7):1178–83. doi: 10.1016/j.pnpbp.2009.06.018. [DOI] [PubMed] [Google Scholar]
  • 24.Raffa M, Atig F, Mhalla A, et al. Decreased glutathione levels and impaired antioxidant enzyme activities in drug-naive first-episode schizophrenic patients. BMC Psychiatry. 2011;11:124. doi: 10.1186/1471-244X-11-124. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Borgmann-Winter KE, Rawson NE, Wang HY, et al. Human olfactory epithelial cells generated in vitro express diverse neuronal characteristics. Neuroscience. 2009;158(2):642–53. doi: 10.1016/j.neuroscience.2008.09.059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Paulsen S, de Moraes Maciel R, Galina A, et al. Altered oxygen metabolism associated to neurogenesis of induced pluripotent stem cells derived from a schizophrenic patient. Cell Transplant. 2012;21(7):1547–59. doi: 10.3727/096368911X600957. [DOI] [PubMed] [Google Scholar]
  • 27.Trabesinger AH, Weber OM, Duc CO, et al. Detection of glutathione in the human brain in vivo by means of double quantum coherence filtering. Magn Reson Med. 1999;42(2):283–9. doi: 10.1002/(sici)1522-2594(199908)42:2<283::aid-mrm10>3.0.co;2-q. [DOI] [PubMed] [Google Scholar]
  • 28.Schwerk A, Alves FD, Pouwels PJ, et al. Metabolic alterations associated with schizophrenia: a critical evaluation of proton magnetic resonance spectroscopy studies. J Neurochem. 128(1):1–87. doi: 10.1111/jnc.12398. **This study shows the strength of magnetic resonance spectroscopy in the study of schizophrenia.
  • 29.Do KQ, Trabesinger AH, Kirsten-Kruger M, et al. Schizophrenia: glutathione deficit in cerebrospinal fluid and prefrontal cortex in vivo. Eur J Neurosci. 2000;12(10):3721–8. doi: 10.1046/j.1460-9568.2000.00229.x. [DOI] [PubMed] [Google Scholar]
  • 30.Terpstra M, Vaughan TJ, Ugurbil K, et al. Validation of glutathione quantitation from STEAM spectra against edited 1H NMR spectroscopy at 4T: application to schizophrenia. MAGMA. 2005;18(5):276–82. doi: 10.1007/s10334-005-0012-0. [DOI] [PubMed] [Google Scholar]
  • 31.Matsuzawa D, Obata T, Shirayama Y, et al. Negative correlation between brain glutathione level and negative symptoms in schizophrenia: a 3T 1H-MRS study. PLoS One. 2008;3(4):e1944. doi: 10.1371/journal.pone.0001944. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Wood SJ, Berger GE, Wellard RM, et al. Medial temporal lobe glutathione concentration in first episode psychosis: a 1H-MRS investigation. Neurobiol Dis. 2009;33(3):354–7. doi: 10.1016/j.nbd.2008.11.018. [DOI] [PubMed] [Google Scholar]
  • 33.Terpstra M, Henry PG, Gruetter R. Measurement of reduced glutathione (GSH) in human brain using LCModel analysis of difference-edited spectra. Magn Reson Med. 2003;50(1):19–23. doi: 10.1002/mrm.10499. [DOI] [PubMed] [Google Scholar]
  • 34.Gonzalez-Burgos G, Lewis DA. NMDA receptor hypofunction, parvalbumin-positive neurons, and cortical gamma oscillations in schizophrenia. Schizophr Bull. 2012;38(5):950–7. doi: 10.1093/schbul/sbs010. *This review introduces the importance of NMDA receptor, parvalbumin interneurons, and gamma oscillations in SZ.
  • 35.Benes FM, Berretta S. GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology. 2001;25(1):1–27. doi: 10.1016/S0893-133X(01)00225-1. [DOI] [PubMed] [Google Scholar]
  • 36.Akbarian S, Kim JJ, Potkin SG, et al. Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics. Arch Gen Psychiatry. 1995;52(4):258–66. doi: 10.1001/archpsyc.1995.03950160008002. [DOI] [PubMed] [Google Scholar]
  • 37.Lodge DJ, Behrens MM, Grace AA. A loss of parvalbumin-containing interneurons is associated with diminished oscillatory activity in an animal model of schizophrenia. J Neurosci. 2009;29(8):2344–54. doi: 10.1523/JNEUROSCI.5419-08.2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Uhlhaas PJ, Singer W. Abnormal neural oscillations and synchrony in schizophrenia. Nat Rev Neurosci. 2010;11(2):100–13. doi: 10.1038/nrn2774. [DOI] [PubMed] [Google Scholar]
  • 39.Johnson AW, Jaaro-Peled H, Shahani N, et al. Cognitive and motivational deficits together with prefrontal oxidative stress in a mouse model for neuropsychiatric illness. Proc Natl Acad Sci U S A. 2013;110(30):12462–7. doi: 10.1073/pnas.1307925110. *Transgenic mice expressing a putative dominant-negative DISC1 are studied by linking oxidative stress and behavioral deficits relevant to major mental illness.
  • 40.Schiavone S, Sorce S, Dubois-Dauphin M, et al. Involvement of NOX2 in the development of behavioral and pathologic alterations in isolated rats. Biol Psychiatry. 2009;66(4):384–92. doi: 10.1016/j.biopsych.2009.04.033. [DOI] [PubMed] [Google Scholar]
  • 41.Cabungcal JH, Steullet P, Kraftsik R, et al. Early-life insults impair parvalbumin interneurons via oxidative stress: reversal by N-acetylcysteine. Biol Psychiatry. 2012;73(6):574–82. doi: 10.1016/j.biopsych.2012.09.020. **The present work demonstrates the significance of antioxidant treatment on interneuron deficits in a mouse model that shows behavioral abnormalities relevant to mental illness.
  • 42.Konat GW, Wiggins RC. Effect of reactive oxygen species on myelin membrane proteins. J Neurochem. 1985;45(4):1113–8. doi: 10.1111/j.1471-4159.1985.tb05530.x. [DOI] [PubMed] [Google Scholar]
  • 43.Takahashi N, Sakurai T, Davis KL, et al. Linking oligodendrocyte and myelin dysfunction to neurocircuitry abnormalities in schizophrenia. Prog Neurobiol. 2011;93(1):13–24. doi: 10.1016/j.pneurobio.2010.09.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Martins-de-Souza D, Gattaz WF, Schmitt A, et al. Alterations in oligodendrocyte proteins, calcium homeostasis and new potential markers in schizophrenia anterior temporal lobe are revealed by shotgun proteome analysis. J Neural Transm. 2009;116(3):275–89. doi: 10.1007/s00702-008-0156-y. [DOI] [PubMed] [Google Scholar]
  • 45.Paintlia MK, Paintlia AS, Khan M, et al. Modulation of peroxisome proliferator-activated receptor-alpha activity by N-acetyl cysteine attenuates inhibition of oligodendrocyte development in lipopolysaccharide stimulated mixed glial cultures. J Neurochem. 2008;105(3):956–70. doi: 10.1111/j.1471-4159.2007.05199.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Tristan C, Shahani N, Sedlak TW, et al. The diverse functions of GAPDH: views from different subcellular compartments. Cell Signal. 2011;23(2):317–23. doi: 10.1016/j.cellsig.2010.08.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Gysin R, Kraftsik R, Sandell J, et al. Impaired glutathione synthesis in schizophrenia: convergent genetic and functional evidence. Proc Natl Acad Sci U S A. 2007;104(42):16621–6. doi: 10.1073/pnas.0706778104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Yang Y, Dieter MZ, Chen Y, et al. Initial characterization of the glutamatecysteine ligase modifier subunit Gclm(−/−) knockout mouse. Novel model system for a severely compromised oxidative stress response. J Biol Chem. 2002;277(51):49446–52. doi: 10.1074/jbc.M209372200. [DOI] [PubMed] [Google Scholar]
  • 49.Steullet P, Cabungcal JH, Kulak A, et al. Redox dysregulation affects the ventral but not dorsal hippocampus: impairment of parvalbumin neurons, gamma oscillations, and related behaviors. J Neurosci. 2010;30(7):2547–58. doi: 10.1523/JNEUROSCI.3857-09.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Kulak A, Cuenod M, Do KQ. Behavioral phenotyping of glutathione-deficient mice: relevance to schizophrenia and bipolar disorder. Behav Brain Res. 2012;226(2):563–70. doi: 10.1016/j.bbr.2011.10.020. [DOI] [PubMed] [Google Scholar]
  • 51.Chen Y, Curran CP, Nebert DW, et al. Effect of chronic glutathione deficiency on the behavioral phenotype of Gclm−/− knockout mice. Neurotoxicol Teratol. 2012;34(4):450–7. doi: 10.1016/j.ntt.2012.04.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.das Neves Duarte JM, Kulak A, Gholam-Razaee MM, et al. N-acetylcysteine normalizes neurochemical changes in the glutathione-deficient schizophrenia mouse model during development. Biol Psychiatry. 2012;71(11):1006–14. doi: 10.1016/j.biopsych.2011.07.035. [DOI] [PubMed] [Google Scholar]
  • 53.Brandon NJ, Sawa A. Linking neurodevelopmental and synaptic theories of mental illness through DISC1. Nat Rev Neurosci. 2011;12(12):707–22. doi: 10.1038/nrn3120. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Hikida T, Jaaro-Peled H, Seshadri S, et al. Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans. Proc Natl Acad Sci U S A. 2007;104(36):14501–6. doi: 10.1073/pnas.0704774104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Hara MR, Agrawal N, Kim SF, et al. S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding. Nat Cell Biol. 2005;7(7):665–74. doi: 10.1038/ncb1268. [DOI] [PubMed] [Google Scholar]
  • 56.Sen N, Hara MR, Kornberg MD, et al. Nitric oxide-induced nuclear GAPDH activates p300/CBP and mediates apoptosis. Nat Cell Biol. 2008;10(7):866–73. doi: 10.1038/ncb1747. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Aoyama K, Suh SW, Hamby AM, et al. Neuronal glutathione deficiency and age-dependent neurodegeneration in the EAAC1 deficient mouse. Nat Neurosci. 2006;9(1):119–26. doi: 10.1038/nn1609. [DOI] [PubMed] [Google Scholar]
  • 58.Myles-Worsley M, Tiobech J, Browning SR, et al. Deletion at the SLC1A1 glutamate transporter gene co-segregates with schizophrenia and bipolar schizoaffective disorder in a 5-generation family. Am J Med Genet B Neuropsychiatr Genet. 2013;162B(2):87–95. doi: 10.1002/ajmg.b.32125. [DOI] [PubMed] [Google Scholar]
  • 59.Horiuchi Y, Iida S, Koga M, et al. Association of SNPs linked to increased expression of SLC1A1 with schizophrenia. Am J Med Genet B Neuropsychiatr Genet. 2012;159B(1):30–7. doi: 10.1002/ajmg.b.31249. [DOI] [PubMed] [Google Scholar]
  • 60.Hara MR, Thomas B, Cascio MB, et al. Neuroprotection by pharmacologic blockade of the GAPDH death cascade. Proc Natl Acad Sci U S A. 2006;103(10):3887–9. doi: 10.1073/pnas.0511321103. [DOI] [PMC free article] [PubMed] [Google Scholar]

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