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Cited by 304Schizophrenia research and treatmentNeuroscience and Neuropharmacology ResearchNeurotransmitter Receptor Influence on Behavior

Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis

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Hardingham, Giles E., Do, Kim Q.·2016·Nature Reviews Neuroscience
DOI 10.1038/nrn.2015.19
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Abstract

Molecular, genetic and pathological evidence suggests that deficits in GABAergic parvalbumin-positive interneurons contribute to schizophrenia pathophysiology through alterations in the brain's excitation-inhibition balance that result in impaired behaviour and cognition. Although the factors that trigger these deficits are diverse, there is increasing evidence that they converge on a common pathological hub that involves NMDA receptor hypofunction and oxidative stress. These factors have been separately linked to schizophrenia pathogenesis, but evidence now suggests that they are mechanistically interdependent and contribute to a common schizophrenia-associated pathology.

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Written from the paper’s full text.

TL;DR

This Perspective argues that diverse genetic and environmental risk factors for schizophrenia converge on a pathological hub of NMDA receptor hypofunction and oxidative stress/redox imbalance, especially during early development. It proposes that these two processes are reciprocally linked and preferentially impair parvalbumin-positive interneurons, contributing to excitation-inhibition imbalance and schizophrenia-relevant cognitive and behavioural deficits.

Key findings

  • NMDAR hypofunction and oxidative stress/GSH deficits are reciprocally linked: redox state regulates NMDAR activity, and even transient GSH deficits are sufficient to induce NMDAR hypofunction, while synaptic NMDAR activity boosts antioxidant gene expression and NMDAR hypofunction itself causes cortical oxidative stress and GSH deficits.
  • Parvalbumin-positive interneurons (PVIs) are selectively vulnerable during early development to both NMDAR hypofunction and oxidative stress. Early postnatal, but not adolescent, deletion of Grin1 in mouse forebrain interneurons reduced parvalbumin and GAD1 expression, caused cortical disinhibition and asynchrony, and induced schizophrenia-relevant phenotypes after adolescence; transient developmental GSH depletion between postnatal days 5 and 16 led to adult PVI abnormalities and cognitive and olfactory discrimination deficits.
  • Human evidence includes schizophrenia affecting 1% of the population with typical onset in late adolescence/early adulthood; post-mortem, CSF and MRS studies show lower GSH and altered antioxidant levels, and NMDAR antagonist administration mimics primary schizophrenia symptoms. Genetic evidence implicates NMDAR-related genes such as GRIN1, GRIN2A, GRIN2B and SRR, as well as GSH-system genes including GCLC and GST.
  • Neuroinflammation is proposed to interact with and potentiate the oxidative stress–NMDAR hypofunction hub, and antioxidant treatment with N-acetyl cysteine (NAC) prevents oxidative stress and the emergence of morphological, electrophysiological and behavioural deficits in a developmental rat model.

Methods

  • Design: Perspective/review article, not a primary experimental study; it synthesizes human, genetic, post-mortem, imaging and rodent-model evidence to build a mechanistic hypothesis.
  • Data or sample: no new sample is reported; the paper cites human studies of patients and high-risk groups, post-mortem brain, CSF, MRS, SPECT/PET and EEG/DTI approaches, plus animal models including NMDAR antagonist models and Grin1, Srr, Gclm, Gclc, DISC1 and G72 transgenic or knockout models.
  • Main analysis: narrative synthesis and mechanistic model building; no systematic review, meta-analysis or new quantitative analysis is described.

Limitations

  • Stated in the paper: further human data, especially longitudinal prospective studies of high-risk groups and patient-based imaging, are needed to establish the roles of oxidative stress and NMDAR hypofunction and any links between them; there is no single ideal mouse model of schizophrenia; the therapeutic window for antioxidant therapy remains an open question; the D-serine trial result in clinically high-risk patients needs confirmation in a larger cohort; and a glycine transporter antagonist recently failed in Phase III trials.
  • Evident from the text: as a Perspective/narrative review, it does not provide new primary data or a systematic quantitative synthesis, so causal claims rely on cross-species and model-based evidence.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/nrn.2015.19

Cites

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Statistics

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Claims the paper makes

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  • Premisecitation

    Autoimmune diseases associated with anti-NMDAR antibodies are associated with severe psychosis.

    “Recently, autoimmune diseases associated with anti-NMDAR antibodies were reported to be associated with severe psychosis 14 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Dalmau, J. et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 7, 1091–1098 (2008). source

      Not checked in the free run.

  • Premisecitation

    Behavioral, neurophysiological and functional imaging studies show that indicators of sensory dysfunction in patients with schizophrenia can be mimicked by treating healthy individuals with NMDAR antagonists.

    “Subsequent behavioral, neurophysiological and functional imaging studies have supported the NMDAR hypofunction hypothesis of schizophrenia, showing that indicators of sensory dysfunction in patients with schizophrenia -such as mismatch negativity (MMN) and changes in auditory and visual event-related potentials -can be mimicked by treating otherwise healthy individuals with NMDAR antagonists 12,15”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [12] Krystal, J. H. et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch. Gen. Psychiatry 51, 199–214 (1994). source

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    • cites [15] Javitt, D. C. et al. Translating glutamate: from pathophysiology to treatment. Sci. Transl Med. 3, 102mr2 (2011). source

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  • Interpretationreasoning
    § Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis

    Myelination defects together with PVI deficits may account for the emergence of schizophrenia pathophysiology and symptoms in early adulthood.

    “Together with myelination defects 4 , this may account for the emergence of schizophrenia pathophysiology and symptoms in early adulthood.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] Mighdoll, M. I., Tao, R., Kleinman, J. E. & Hyde, T. M. Myelin, myelin-related disorders, and psychosis. Schizophr. Res. 161, 85–93 (2015). source

      Not checked in the free run.

  • Premisecitation

    Exome sequencing revealed schizophrenia-linked de novo mutations in GRIN2A and GRIN2B.

    “Exome sequencing has revealed schizophrenia-linked de novo mutations in GRIN2A and GRIN2B [Tarabeux, 2011 #3386;Myers, 2011 #3486]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Tarabeux, 2011 #3386 source

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    • cites Myers, 2011 #3486 source

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  • Premisecitation
    § Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis

    Human epidemiological and animal model studies point to genetic and environmental factors that affect critical periods in early and adolescent brain development and that take place in advance of symptoms.

    “Both human epidemiological and animal model studies point to genetic and environmental factors that affect critical periods in early and adolescent brain development and that take place in advance of symptoms 1 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Brown, A. S. The environment and susceptibility to schizophrenia. Prog. Neurobiol. 93, 23–58 (2011). source

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  • May combine two claims. 42
  • Classified as probably not a substantial claim. 19

  • May combine two claims.

    Premisecitation
    § Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis

    Many diverse causes of schizophrenia and schizophrenia-like behaviours converge on aberrant function of fast-spiking parvalbumin-positive interneurons, which leads to altered excitation-inhibition balance.

    “Pathologically, many diverse causes of schizophrenia and schizophrenia-like behaviours appear to converge on a similar deficit: the aberrant function of fast-spiking parvalbumin-positive interneurons (PVIs) 2 , which leads to altered excitation-inhibition balance 3 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [2] Lewis, D. A., Curley, A. A., Glausier, J. R. & Volk, D. W. Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia. Trends Neurosci. 35, 57–67 (2012). source

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    • cites [3] Insel, T. R. Rethinking schizophrenia. Nature 468, 187–193 (2010). source

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  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    NMDARs are permeant to Ca2+, which mediates many consequences of NMDAR activity, including synaptic modification, learning and memory, activity-dependent development, and neuroprotective/homeostatic signaling.

    “They are permeant to Ca 2+ , which mediates many of the consequences of NMDAR activity, including synaptic modification, learning and memory, activity-dependent development, and neuroprotective/homeostatic signaling [6][7][8] .”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [6] Paoletti, P., Bellone, C. & Zhou, Q. NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat. Rev. Neurosci. 14, 383–400 (2013). source

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    • cites [7] Wyllie, D. J., Livesey, M. R. & Hardingham, G. E. Influence of GluN2 subunit identity on NMDA receptor function. Neuropharmacology 74, 4–17 (2013). source

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    • cites [8] Bell, K. F. & Hardingham, G. E. The influence of synaptic activity on neuronal health. Curr. Opin. Neurobiol. 21, 299–305 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis

    NMDAR hypofunction and oxidative stress are mechanistically interdependent and contribute to common schizophrenia-associated pathology.

    “These factors have been separately linked to schizophrenia pathogenesis, but evidence now suggests they are mechanistically interdependent and contribute to common schizophrenia-associated pathology.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    An NMDAR SPECT study pointed to lower NMDAR activity in unmedicated patients with schizophrenia, although this finding awaits confirmation with newer, more specific probes.

    “An NMDAR single-photon emission computed tomography (SPECT) study pointed to lower NMDAR activity in unmedicated patients with schizophrenia 19 , although this finding awaits confirmation with newer, more specific probes 20 .”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [19] Pilowsky, L. S. et al. First in vivo evidence of an NMDA receptor deficit in medication-free schizophrenic patients. Mol. Psychiatry 11, 118–119 (2006). source

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    • cites [20] Howes, O., McCutcheon, R. & Stone, J. Glutamate and dopamine in schizophrenia: an update for the 21st century. J. Psychopharmacol. 29, 97–115 (2015). source

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    Premisecitation

    Post-mortem studies of schizophrenia brains revealed lower GRIN1 expression, increases in kynurenate, and reductions in D-serine and D-serine racemase.

    “Post-mortem studies of the brain of patients with schizophrenia have revealed lower levels of expression of the obligate NMDAR subunit GRIN1 (glutamate receptor ionotropic, NMDA 1), increases in the expression of the endogenous NMDAR antagonist kynurenate, and a reduction in levels of the NMDAR co-agonist D-serine and the enzyme that catalyses its production, D-serine racemase 10,[16][17][18] .”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [10] Coyle, J. T., Basu, A., Benneyworth, M., Balu, D. & Konopaske, G. Glutamatergic synaptic dysregulation in schizophrenia: therapeutic implications. Handb. Exp. Pharmacol. 213, 267–295 (2012). source

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    • cites [16] Schwarcz, R. et al. Increased cortical kynurenate content in schizophrenia. Biol. Psychiatry 50, 521–530 (2001). source

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    • cites [17] Hashimoto, K. et al. Reduced D-serine to total serine ratio in the cerebrospinal fluid of drug naive schizophrenic patients. Prog. Neuropsychopharmacol. Biol. Psychiatry 29, 767–769 (2005). source

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    Premisecitation

    Proton MRS studies revealed hyperglutamatergic activity in patients with schizophrenia and groups at high risk of developing schizophrenia, which may be attributable to NMDAR hypofunction.

    “Proton magnetic resonance spectroscopy (MRS studies) revealed hyperglutamatergic activity in patients with schizophrenia and groups at high risk of developing schizophrenia, which may be attributable to NMDAR hypofunction 20 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Howes, O., McCutcheon, R. & Stone, J. Glutamate and dopamine in schizophrenia: an update for the 21st century. J. Psychopharmacol. 29, 97–115 (2015). source

      Not checked in the free run.

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    Premisecitation

    Genetic evidence points to disturbed NMDAR signaling in schizophrenia: a GWAS implicated SRR and GRIN2A as risk genes and other genes functionally up- and downstream of NMDAR activity.

    “A recent genome-wide association study (GWAS) implicated serine racemase (SRR) and GRIN2A as risk genes for schizophrenia 21 as well as other genes functionally up-and downstream of NMDAR activity 21,22 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [21] Group, S. W. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427 (2014). source

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    • cites [22] Balu, D. T. & Coyle, J. T. The NMDA receptor 'glycine modulatory site' in schizophrenia: D-serine, glycine, and beyond. Curr. Opin. Pharmacol. 20, 109–115 (2015). source

      Not checked in the free run.

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    Premisecitation

    GSH levels are lower in chronic schizophrenia as measured in CSF, post-mortem brain, and by MRS-based in vivo imaging, and the GSH system enzymes GPX and GR are dysregulated.

    “GSH levels have been shown to be lower in chronic schizophrenia, as measured in the CSF and post-mortem brain, and by MRS-based in vivo imaging 41,42 and the GSH system enzymes glutathione peroxidase (GPX) and glutathione reductase (GR) are also dysregulated 36 .”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [41] Coughlin, J. M. et al. Marked reduction of soluble superoxide dismutase-1 (SOD1) in cerebrospinal fluid of patients with recent-onset schizophrenia. Mol. Psychiatry 18, 10–11 (2013). source

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    • cites [42] Martins-de-Souza, D., Harris, L. W., Guest, P. C. & Bahn, S. The role of energy metabolism dysfunction and oxidative stress in schizophrenia revealed by proteomics. Antioxid. Redox Signal. 15, 2067–2079 (2011). source

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    • cites [36] Fernandez-Fernandez, S., Almeida, A. & Bolanos, J. P. Antioxidant and bioenergetic coupling between neurons and astrocytes. Biochem. J. 443, 3–11 (2012). source

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    Premisecitation

    NAC treatment prevents PVI abnormalities in the NVHL model and blocking superoxide overproduction by NADPH oxidase prevents the PVI impairment induced by social isolation.

    “Evidence causally linking oxidative stress to PVI deficits in other schizophrenia models also exists: NAC treatment prevents PVI abnormalities in the NVHL model 56 and blocking superoxide overproduction by NADPH oxidase (NOX) prevents the PVI impairment induced by social isolation 64 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [56] Filiou, M. D., Teplytska, L., Otte, D. M., Zimmer, A. & Turck, C. W. Myelination and oxidative stress alterations in the cerebellum of the G72/G30 transgenic schizophrenia mouse model. J. Psychiatr. Res. 46, 1359–1365 (2012). source

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    • cites [64] Greenhill, S. D. et al. Adult cortical plasticity depends on an early postnatal critical period. Science 349, 424–427 (2015). source

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    Premisecitation

    Mice deficient in the GCL regulatory subunit Gclm have reduced brain GSH levels and exhibit schizophrenia-relevant behavioural and cognitive deficits.

    “Mice deficient in the GCL regulatory subunit Gclm have reduced brain GSH levels and exhibit schizophrenia-relevant behavioural and cognitive deficits, including altered stress responses, amphetamine responses, social behaviour, prepulse inhibition (PPI) and learning 46,47 ,.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [46] Gysin, R. et al. Impaired glutathione synthesis in schizophrenia: convergent genetic and functional evidence. Proc. Natl Acad. Sci. USA 104, 16621–16626 (2007). source

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    • cites [47] Rodriguez-Santiago, B. et al. Association of common copy number variants at the glutathione S-transferase genes and rare novel genomic changes with schizophrenia. Mol. Psychiatry 15, 1023–1033 (2010). source

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    Premisecitation

    Neuron-specific reduction of selenoproteins selectively impaired PVI development, which was also observed in the prefrontal and ventral hippocampal regions in Gclm-deficient mice.

    “For example, neuron-specific reduction of the levels of selenoproteins (a group of proteins that include several antioxidants) selectively impaired PVI development 58 , which was also observed in the prefrontal and ventral hippocampal regions in Gclm-deficient mice 46,59,60 .”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [58] Cabungcal, J. H. et al. Juvenile antioxidant treatment prevents adult deficits in a developmental model of schizophrenia. Neuron 83, 1073–1084 (2014). source

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    • cites [46] Gysin, R. et al. Impaired glutathione synthesis in schizophrenia: convergent genetic and functional evidence. Proc. Natl Acad. Sci. USA 104, 16621–16626 (2007). source

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    • cites [59] Otte, D. M. et al. N-acetyl cysteine treatment rescues cognitive deficits induced by mitochondrial dysfunction in G72/G30 transgenic mice. Neuropsychopharmacology 36, 2233–2243 (2011). source

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    Premisecitation

    Early postnatal, but not adolescent, deletion of Grin1 in mouse forebrain interneurons reduced parvalbumin and GAD1 expression and caused cortical disinhibition and asynchrony.

    “Early post-natal, but not adolescent, deletion of Grin1 in mouse forebrain interneurons reduced their expression of parvalbumin and glutamate decarboxylase 1 (GAD1, also known as GAD67), and caused cortical disinhibition and asynchrony 30,31 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [30] Ikonomidou, C. et al. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 283, 70–74 (1999). source

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    • cites [31] Wang, X., Pinto-Duarte, A., Sejnowski, T. J. & Behrens, M. M. How Nox2-containing NADPH oxidase affects cortical circuits in the NMDA receptor antagonist model of schizophrenia. Antioxid. Redox Signal. 18, 1444–1462 (2013). source

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    Premisecitation

    A correlation exists between PFC GSH levels and white matter integrity in the cingulum bundle in both control and early psychosis patients, which may reflect the role of GSH in controlling oligodendrocyte progenitor proliferation and differentiation.

    “A correlation exists between PFC GSH levels and white matter integrity in the cingulum bundle in both control and early psychosis patients, which may reflect the role of GSH in controlling oligodendrocyte progenitor proliferation and differentiation 66 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] Schiavone, S. et al. Involvement of NOX2 in the development of behavioral and pathologic alterations in isolated rats. Biol. Psychiatry 66, 384–392 (2009). source

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    Premisecitation

    Evidence for oxidative stress has been found in patients with schizophrenia, including increased lipid and protein oxidation in blood, CSF and post-mortem tissue, altered plasma antioxidants, and altered CSF superoxide dismutase-1 levels.

    “Evidence for oxidative stress has been found in patients with schizophrenia, including increased lipid and protein oxidation in blood, cerebrospinal fluid (CSF) and post-mortem tissue 36,37 , as well as altered levels of plasma antioxidants (such as vitamins C and E, catalase, GSH and GSH-peroxidase) 36,38 and CSF superoxide dismutase-1 levels 39 .”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [36] Fernandez-Fernandez, S., Almeida, A. & Bolanos, J. P. Antioxidant and bioenergetic coupling between neurons and astrocytes. Biochem. J. 443, 3–11 (2012). source

      Not checked in the free run.

    • cites [37] Kennedy, K. A., Sandiford, S. D., Skerjanc, I. S. & Li, S. S. Reactive oxygen species and the neuronal fate. Cell. Mol. Life Sci. 69, 215–221 (2012). source

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    • cites [38] Yao, J. K. & Keshavan, M. S. Antioxidants, redox signaling, and pathophysiology in schizophrenia: an integrative view. Antioxid. Redox Signal. 15, 2011–2035 (2011). source

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  • May combine two claims.

    Interpretationcitation

    Aberrant NMDAR function during development particularly affects PVIs, and these effects are sufficient to induce long-lasting delayed behavioural and cognitive abnormalities in the adult.

    “Thus, studies suggest that aberrant NMDAR function during development particularly affects PVIs and that these effects are sufficient to induce long-lasting delayed behavioural and cognitive abnormalities in the adult.”
    Quote in the paperSubstantial claim

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    Premisecitation

    The NMDAR is regulated by redox state: GRIN1 and GRIN2A possess pairs of redox-sensitive cysteine residues whose disulfide bond formation decreases NMDAR currents, while an overlapping group of cysteine residues are subject to inhibitory S-nitrosylation which facilitates disulfide bond formation.

    “The NMDAR is regulated by redox state: both GRIN1 and GRIN2A possess pairs of redox-sensitive cysteine residues whose disulfide bond formation decreases NMDAR currents 67,68 , while an overlapping group of cysteine residues are subject to inhibitory Snitrosylation which facilitates disulfide bond formation 67 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [67] Back, S. A. & Rosenberg, P. A. Pathophysiology of glia in perinatal white matter injury. Glia 62, 1790–1815 (2014). source

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    • cites [68] Monin, A. et al. Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients. Mol. Psychiatry 20, 827–838 (2015). source

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    Premisecitation

    An allelic variant of GCLC is associated with schizophrenia and with reduced induction of GSH, GCL activity, and GCLC expression in schizophrenia patient-derived fibroblasts.

    “An allelic variant of the GCLC gene, which encodes the catalytic subunit of GSH biosynthetic enzyme glutamate-cysteine ligase (GCL) is associated with schizophrenia.This polymorphism is associated with reduced induction of GSH, GCL activity, and GCLC expression in schizophrenia patient-derived fibroblasts 44 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Gawryluk, J. W., Wang, J. F., Andreazza, A. C., Shao, L. & Young, L. T. Decreased levels of glutathione, the major brain antioxidant, in post-mortem prefrontal cortex from patients with psychiatric disorders. Int. J. Neuropsychopharmacol. 14, 123–130 (2011). source

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  • May combine two claims.

    Interpretationreasoning

    There are clear similarities between the impact of developmental NMDAR hypofunction and that of oxidative stress on the adult rodent: both cause a selective impairment in PVI function and similar behavioural and cognitive disturbances.

    “There are clear similarities between the impact of developmental NMDAR hypofunction and that of oxidative stress on the adult rodent: both cause a selective impairment in PVI function and similar behavioural and cognitive disturbances.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Juvenile antioxidant treatment using N-acetyl cysteine prevents oxidative stress in a developmental rat model of schizophrenia (neonatal ventral hippocampal lesion) and inhibits the emergence of morphological, electrophysiological and behavioural deficits.

    “The causal relevance of oxidative stress was further strengthened by the demonstration that juvenile antioxidant treatment using N-Acetyl cysteine (NAC) prevents oxidative stress in a developmental rat model of schizophrenia (neonatal ventral hippocampal lesion (NVHL)) and, in doing so, inhibits the emergence of morphological, electrophysiological and behavioural deficits 56 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] Filiou, M. D., Teplytska, L., Otte, D. M., Zimmer, A. & Turck, C. W. Myelination and oxidative stress alterations in the cerebellum of the G72/G30 transgenic schizophrenia mouse model. J. Psychiatr. Res. 46, 1359–1365 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Targeted deletion of Gclc in PVIs triggers oxidative stress, impairs their development, and causes a delay and prolongation in the critical period of cortical plasticity resulting in a failure to stabilise cortical circuits.

    “Targeted deletion of Gclc in PVIs triggers oxidative stress, impairs their development and causes a delay and prolongation in the critical period of cortical plasticity resulting in a failure to stabilise cortical circuits 61 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [61] Cabungcal, J. H., Steullet, P., Kraftsik, R., Cuenod, M. & Do, K. Q. Early-life insults impair parvalbumin interneurons via oxidative stress: reversal by N-acetylcysteine. Biol. Psychiatry 73, 574–582 (2013). source

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    Premisecitation

    Transient pharmacological depletion of brain GSH early in development (between postnatal days 5 and 16) leads to PVI abnormalities in the adult anterior cingulate cortex as well as cognitive and olfactory discrimination deficits.

    “Moreover, transient pharmacological depletion of brain GSH early in development (between postnatal days 5 and 16) leads to PVI abnormalities in the adult anterior cingulate cortex as well as cognitive and olfactory discrimination deficits 49 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [49] Kulak, A., Cuenod, M. & Do, K. Q. Behavioral phenotyping of glutathione-deficient mice: relevance to schizophrenia and bipolar disorder. Behav. Brain Res. 226, 563–570 (2012). source

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    Premisecitation

    A milder NMDAR antagonism regime caused long-lasting behavioural changes and a specific long-lasting decrease in cortical PVI numbers, mimicking a key pathological feature of schizophrenia.

    “A milder antagonism regime caused long-lasting behavioural changes and a specific longlasting decrease in cortical PVI numbers 29 , mimicking a key pathological feature of schizophrenia 2 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [29] Stefani, M. R. & Moghaddam, B. Transient N-methyl-D-aspartate receptor blockade in early development causes lasting cognitive deficits relevant to schizophrenia. Biol. Psychiatry 57, 433–436 (2005). source

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    • cites [2] Lewis, D. A., Curley, A. A., Glausier, J. R. & Volk, D. W. Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia. Trends Neurosci. 35, 57–67 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The deleterious consequences of neuroinflammation may be mediated in part by oxidative stress, and so be mechanistically coupled to the oxidative stress-NMDAR hypofunction hub of schizophrenia etiology.

    “The deleterious consequences of neuroinflammation may in any case be mediated in part by oxidative stress, and so be mechanistically coupled to the oxidative stress-NMDAR hypofunction hub of schizophrenia etiology (Figure 3).”
    Quote in the paperSubstantial claim

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    Premisecitation

    Persistent activation of astrocytic NMDARs can activate NFE2L2-dependent gene expression, raising the possibility that synaptic activity can control the NFE2L2 pathway in astrocytes.

    “Moreover, a recent study has shown that persistent activation of astrocytic NMDARs can activate NFE2L2-dependent gene expression, raising the possibility that synaptic activity can control the NFE2L2 pathway in astrocytes 83 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [83] Bell, K. F. et al. Neuronal development is promoted by weakened intrinsic antioxidant defences due to epigenetic repression of Nrf2. Nat. Commun. 6, 7066 (2015). source

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    Premisecitation

    The mechanism underlying the proposed loss of PVI phenotype involves cortical disinhibition leading to neuronal IL-6 production and consequent activation of NADPH oxidase, which generates H2O2.

    “The mechanism underlying this proposed loss of PVI phenotype involves cortical disinhibition leading to neuronal IL-6 production and consequent activation of NADPH oxidase, which generates H 2 O 2 29 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] Stefani, M. R. & Moghaddam, B. Transient N-methyl-D-aspartate receptor blockade in early development causes lasting cognitive deficits relevant to schizophrenia. Biol. Psychiatry 57, 433–436 (2005). source

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    Interpretationreasoning

    Inflammation and oxidative stress are closely interacting and potentiate each other.

    “Altogether, inflammation and oxidative stress are closely interactin and potentiate each other.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Maternal infection in mice is sufficient to induce long-term PPI and social behavioural changes in the offspring, changes that are attributable to inflammation.

    “Epidemiological evidence points to maternal infection being a risk factor in schizophrenia 1 and maternal infection in mice is sufficient to induce long-term PPI and social behavioural changes in the offspring, changes that are attributable to inflammation 89 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89] Lewerenz, J. et al. Phosphoinositide 3-kinases upregulate system xc− via eukaryotic initiation factor 2α and activating transcription factor 4 — a pathway active in glioblastomas and epilepsy. Antioxid. Redox Signal. 20, 2907–2922 (2014). source

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    Premisecitation

    NFE2L2 is epigenetically repressed in cortical neurons early in development and what little NFE2L2 exists is highly unstable, leading to reduced intrinsic antioxidant defences.

    “NFE2L2 is epigenetically repressed in cortical neurons early in development and what little NFE2L2 exists is highly unstable, leading to reduced intrinsic antioxidant defences 81,83 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [81] Moghaddam, B. & Krystal, J. H. Capturing the angel in “angel dust”: twenty years of translational neuroscience studies of NMDA receptor antagonists in animals and humans. Schizophr. Bull. 38, 942–949 (2012). source

      Not checked in the free run.

    • cites [83] Bell, K. F. et al. Neuronal development is promoted by weakened intrinsic antioxidant defences due to epigenetic repression of Nrf2. Nat. Commun. 6, 7066 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GABAergic interneuron-specific deletion of Grin1 leads to increased ROS levels which are exacerbated by post-weaning social isolation, in association with down-regulation of PPARGC1A/PGC-1α.

    “Moreover, GABAergic interneuron-specific deletion of Grin1 has been show to lead to increased ROS levels which are exacerbated by post-weaning social isolation, in association with down-regulation of peroxisome proliferative activated receptor-γ, coactivator 1α (PPARGC1A, also known as PGC-1α), a regulator of mitochondrial energy metabolism and antioxidant defences 78 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [78] Hardingham, G. E. & Bading, H. Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat. Rev. Neurosci. 11, 682–696 (2010). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Both circuit and cellular-level effects could combine to exacerbate oxidative stress.

    “One can envisage that both circuit and cellular-level effects could combine to exacerbate oxidative stress (Figure 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Many antioxidant genes transcriptionally controlled by synaptic activity in neurons are known NFE2L2 target genes, but are induced via NFE2L2-independent routes (e.g. AP-1 and ATF4), suggesting that activity-dependent signaling may act as a substitute for an absent NFE2L2 pathway.

    “Interestingly, many of the antioxidant genes transcriptionally controlled by synaptic activity in neurons are known NFE2L2 target genes, but are induced via NFE2L2independent routes (e.g. via activator protein 1 (AP-1) family and activating transcription factor 4 (ATF4)), suggesting that activity-dependent signaling may act as a substitute for an absent NFE2L2 pathway 73,86,87 .”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [73] Guidi, M., Kumar, A. & Foster, T. C. Impaired attention and synaptic senescence of the prefrontal cortex involves redox regulation of NMDA receptors. J. Neurosci. 35, 3966–3977 (2015). source

      Not checked in the free run.

    • cites [86] Bell, K. F. et al. Mild oxidative stress activates Nrf2 in astrocytes, which contributes to neuroprotective ischemic preconditioning. Proc. Natl Acad. Sci. USA 108, E1–E2; author reply E3–E4 (2011). source

      Not checked in the free run.

    • cites [87] Bell, K. F., Fowler, J. H., Al-Mubarak, B., Horsburgh, K. & Hardingham, G. E. Activation of Nrf2-regulated glutathione pathway genes by ischemic preconditioning. Oxid. Med. Cell Longev. 2011, 689524 (2011).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Age-associated shifts in intracellular redox state to a pro-oxidizing environment are linked to reduced NMDAR activity via the redox regulation of CaMKII, and can be rescued by intracellular GSH.

    “Ageassociated shifts in intracellular redox state to a pro-oxidizing environment have been linked to reduced NMDAR activity via the redox regulation of calcium/ calmodulin-dependent protein kinase type II (CaMKII), and can be rescued by intracellular GSH 72 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [72] Steullet, P., Neijt, H. C., Cuenod, M. & Do, K. Q. Synaptic plasticity impairment and hypofunction of NMDA receptors induced by glutathione deficit: relevance to schizophrenia. Neuroscience 137, 807–819 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NMDAR hypofunction itself leads to cortical oxidative stress and GSH deficits.

    “Critically, there is also a reciprocal relationship: NMDAR hypofunction itself leads to cortical oxidative stress and GSH defcits 73,74 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [73] Guidi, M., Kumar, A. & Foster, T. C. Impaired attention and synaptic senescence of the prefrontal cortex involves redox regulation of NMDA receptors. J. Neurosci. 35, 3966–3977 (2015). source

      Not checked in the free run.

    • cites [74] Bodhinathan, K., Kumar, A. & Foster, T. C. Intracellular redox state alters NMDA receptor response during aging through Ca2+/calmodulin-dependent protein kinase II. J. Neurosci. 30, 1914–1924 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A recent trial with clinically high risk patients showed that D-serine induced an improvement in negative symptoms, a promising result that needs to be confirmed in a larger cohort.

    “A recent trial with clinically high risk patients (scored high on the Scale of Prodromal Symptoms (SOPS)) showed that D-serine induced an improvement in negative symptoms, a promising result that needs to be confirmed in a larger cohort 98 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [98] Pan, H., Wang, H., Wang, X., Zhu, L. & Mao, L. The absence of Nrf2 enhances NF-κB-dependent inflammation following scratch injury in mouse primary cultured astrocytes. Mediators Inflamm. 2012, 217580 (2012).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Antioxidant therapy with NAC reduces the pathological and behavioural consequences of maternal LPS treatment and reduces foetal proinflammatory cytokine production.

    “Activated innate immune cells both produce and are activated by ROS: antioxidant therapy with NAC reduces the pathological and behavioural consequences of maternal LPS treatment and reduces foetal proinflammatory cytokine production 92,93 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [92] Giovanoli, S. et al. Stress in puberty unmasks latent neuropathological consequences of prenatal immune activation in mice. Science 339, 1095–1099 (2013). source

      Not checked in the free run.

    • cites [93] Ibi, D. et al. Combined effect of neonatal immune activation and mutant DISC1 on phenotypic changes in adulthood. Behav. Brain Res. 206, 32–37 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The GSH deficit induced by NMDAR blockade in the developing mouse is associated with transcriptional downregulation of Gclc and reduced GCL activity, which contributes to the deleterious effects observed in vivo.

    “Of note, the GSH deficit induced by NMDAR blockade in the developing mouse is associated with transcriptional downregulation of Gclc and reduced GCL activity, which contributes to the deleterious effects observed in vivo 77 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] Bell, K. F. & Hardingham, G. E. CNS peroxiredoxins and their regulation in health and disease. Antioxid. Redox Signal. 14, 1467–1477 (2011). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Activity-dependent induction of GCLC increases the capacity of the rate-limiting step in GSH biosynthesis.

    “Activity-dependent induction of GCLC, which encodes the catalytic subunit of GCL (glutamate-cysteine ligase), increases the capacity of the rate-limiting step in GSH biosynthesis”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    The consequences of oxidative stress and GSH deficits during development can include impaired development and maturation of parvalbumin-expressing interneurons (PVIs, leading to E/I imbalance) and white matter abnormalities, which collectively may lead to altered cognition, behaviour and sensory processing in schizophrenia.

    “The consequences of oxidative stress and GSH deficits during development can include impaired development and maturation of parvablumin-expressing interneurons (PVIs, leading to excitation/inhibition (E/I) imbalance) and white matter abnormalities, which collectively may lead to altered cognition, behaviour and sensory processing in schizophrenia.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    The NFE2L2 pathway regulates dozens (if not hundreds) of genes controlling antioxidant and detoxification processes.

    “A more holistic approach to rebalancing the brain's redox status may be to target the NFE2L2 pathway, which regulates dozens (if not hundreds) of genes controlling antioxidant and detoxification processes (Figure 5).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Environmental and genetic factors have the capacity to influence NMDAR function, antioxidant defences, and inflammation.

    “Moreover, environmental and genetic factors have the capacity to influence NMDAR function, antioxidant defences, and inflammation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Both NMDAR hypofunction-induced cellular effects and circuit-level disinhibition have the capacity to lead to oxidative stress and GSH depletion, which in turn can further repress NMDAR activity.

    “Both of these events have the capacity to lead to oxidative stress and glutathione (GSH) depletion, which in turn can further repress NMDAR activity.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    BG-12 is licensed for the relapsing remitting phase of multiple sclerosis.

    “BG-12 (also known as Tecfidera or dimethyl fumarate) is licensed for the relapsing remitting phase of multiple sclerosis”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [107] Amminger, G. P., Schafer, M. R., Schlogelhofer, M., Klier, C. M. & McGorry, P. D. Longer-term outcome in the prevention of psychotic disorders by the Vienna omega-3 study. Nat. Commun. 6, 7934 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Schizophrenia-associated NMDA receptor hypofunction may be either milder or more temporally or spatially restricted than that caused by genome-level subunit ablation.

    “This suggests that schizophreniaassociated NMDA receptor hypofunction may be either milder or more temporally or spatially restricted than that caused by genome-level subunit ablation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Synaptic activity boosts the capacity of neuronal antioxidant systems.

    “Synaptic activity boosts the capacity of neuronal antioxidant systems.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Neuroinflammation can act both up- and down-stream of ROS and inflammatory cytokine (such as IL6) production.

    “neuroinflammation can act both up-and down-stream of ROS and inflammatory cytokine (such as interleukin-6 (IL6)) production.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    In response to oxidative stress, astrocytic GSH is released through MRP1 and broken down to Cys-Gly by γGT.

    “In response to oxidative stress, this GSH is released through the the multidrug resistance protein (MRP1) and broken down to the Cys-Gly dipeptide by γ-glutamyl transpeptidase (γGT).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Mitochondrial dysfunction can be both up- and down-stream of oxidative stress.

    “Mitochondrial dysfunction can also be both up-and down-stream of oxidative stress.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisereasoning

    Transcriptional induction of glutathione peroxidase (GPX) activity enhances the ability of the GSH system to reduce cellular peroxides; however, as a result of increased GR and GCL activity, neuronal levels of GSH can be sustained.

    “Transcriptional induction of glutathione peroxidase (GPX) activity enhances the ability of the GSH system to reduce cellular peroxides; however, as a result of increased GR and GCL activity, neuronal levels of GSH can be sustained.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Induction of glutathione reductase GR boosts recycling capacity (reducing oxidized GSSG back to GSH).

    “whereas the induction of glutathione reductase GR boosts recycling capacity (reducing oxidized GSSG back to GSH).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    The astrocytic NFE2L2 pathway boosts the brain's antioxidant defences.

    “The astrocytic NFE2L2 pathway boosts the brain's antioxidant defences.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Under normal conditions, NFE2L2 is targeted for ubiquitin-mediated degradation by KEAP1.

    “Under normal conditions, Nuclear factor erythroid 2-related factor 2 (NFE2L2) is targeted for ubiquitin-mediated degradation by KEAP1 (Kelch-Like ECH-Associated Protein 1).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationcitation

    The potential for juvenile NAC treatment to prevent the emergence of electrophysiological and behavioural deficits in a rodent developmental model of schizophrenia suggests that prophylactic treatment for high-risk groups may be effective.

    “The potential for juvenile NAC treatment to prevent the emergence of electrophysiological and behavioural deficits in a rodent developmental model of schizophrenia 56 suggests that prophylactic treatment for high-risk groups may be effective, particularly with a drug or dietary supplement with a good safety profile like NAC or polyunsaturated fatty acids such as omega 3s 105 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [56] Filiou, M. D., Teplytska, L., Otte, D. M., Zimmer, A. & Turck, C. W. Myelination and oxidative stress alterations in the cerebellum of the G72/G30 transgenic schizophrenia mouse model. J. Psychiatr. Res. 46, 1359–1365 (2012). source

      Not checked in the free run.

    • cites [105] Farokhnia, M. et al. N-acetylcysteine as an adjunct to risperidone for treatment of negative symptoms in patients with chronic schizophrenia: a randomized, double-blind, placebo-controlled study. Clin. Neuropharmacol. 36, 185–192 (2013). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    NMDAR hypofunction triggers both cellular effects (downregulation of antioxidant genes) and circuit-level disinhibition of cortical networks that leads to ROS generation through activation of NADPH oxidase (NOX).

    “NMDAR hypofunction triggers both cellular effects (the downregulation of antioxidant genes) and circuit level disinhibition of cortical networks that leads to reactive oxygen species (ROS) generation through activation of NADPH oxidase (NOX).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Both oxidative stress and certain small molecules (often electrophiles) interfere with NFE2L2 degradation, enabling NFE2L2 to accumulate, translocate to the nucleus and drive transcription of genes with AREs.

    “Both oxidative stress and certain small molecules (often electrophiles (e.g.tBHQ and BG12) interfere with this degradation, enabling NFE2L2 to accumulate, translocate to the nucleus and drive the transcription of genes whose promoters contain antioxidant response elements (AREs).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisereasoning

    The capacity of neurons to produce, utilize, and recycle glutathione (GSH) is enhanced by synaptic activity.

    “The capacity of neurons to produce, utilize, and recycle glutathione (GSH) is enhanced by synaptic activity.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Synaptic activity induces expression of Srxn1 and represses expression of Txnip, an inhibitor of thioredoxin.

    “Synaptic activity induces expression of Srxn1, and represses expression of Txnip, an inhibitor of thioredoxin.”
    Quote in the paperNot a substantial claim
56 of 56

  • The paper relies on this without support.

    The first two postnatal weeks in rodents correspond to the developmental window of sensitivity in humans for schizophrenia.

    “In supporting of this notion, NMDAR antagonism during an equivalent period in rodents (first 2 post-natal weeks) induces long-lasting behavioural and cognitive disturbances that are relevant to the schizophrenia phenotype and which extend into adolescence and adulthood 10,27 .”

  • The paper relies on this without support.

    Findings from animal models of NMDAR hypofunction and oxidative stress can be generalized to human schizophrenia pathophysiology.

    “Animal studies suggest that brain GSH deficits and oxidative stress are sufficient to induce schizophrenia-like behaviour.”

  • The paper relies on this without support.

    NAC's principal mechanism of action is the supply of increased cysteine for GSH biosynthesis.

    “its principal modus operandus -the supply of increased cysteine for GSH biosynthesis -is of limited help unless the brain can use it to produce, recycle and utilise GSH.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Some of these biological processes participate in disease pathogenesis in parallel, such as the redox system and glutamatergic/GABAergic imbalance, or the immune system and the stress response.

    “It is important to take into account that some of these processes participate in disease pathogenesis in a parallel manner, such as via the redox system and through the glutamatergic/GABAergic imbalance (Hardingham & Do, 2016); or the immune system and the stress response (Pariante, 2017).”

    From Can epigenetics shine a light on the biological pathways underlying major mental disorders? (2022) · cites this paper as Hardingham & Do, 2016

    The paper’s Figure 3 discussion links redox imbalance, NMDAR hypofunction and excitation–inhibition imbalance to schizophrenia pathogenesis. It describes reciprocal effects between these processes, however, rather than establishing that the redox and glutamatergic/GABAergic processes act in parallel. The immune-system and stress-response example is attributed to a different citation and is not assessed here. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • These asymmetries can be explained with a Bayesian model if agents are allowed to derive utility from their beliefs.

    “These asymmetries can be explained with a Bayesian model, if we allow agents to derive utility from their beliefs (114).”

    From The Predictive Coding Account of Psychosis (2018) · cites this paper as [114]

    The passages from “Making the link” and “Future prospects” discuss NMDAR hypofunction, oxidative stress, and schizophrenia, not Bayesian explanations of asymmetries. Searches for agents deriving utility from beliefs and for belief-dependent utility found no passage addressing the claim; page numbers are unavailable in our copy. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Figure 2 legend says two peroxide sources but lists three

    Minor

    The legend states that two sources of cellular peroxide are shown, then names superoxide dismutation, monoamine oxidase metabolism, and NADPH oxidase-three sources.

1 of 1

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Authors
Hardingham, G. E., & Do, K. Q.
Affiliations
University of Edinburgh (GB)
Corresponding author
Hardingham, Giles E.
ORCID
Hardingham, Giles E.
Venue
Nature Reviews Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2016-01-14
Volume
17
Issue
2
Pages
125-134
ISSN
  • 1471-003X (ISSN-L)
  • 1471-0048
DOI
10.1038/nrn.2015.19
OpenAlex
W2234053937
Cited by
304
References
119
Citations by year
2026: 17 · 2025: 16 · 2024: 18 · 2023: 30 · 2022: 29 · 2021: 49 · 2020: 27 · 2019: 32 · 2018: 33 · 2017: 37 · 2016: 16
FWCI
5.63
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature reviews. Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • IRIS (submittedVersion)
  • SERVAL (Université de Lausanne) (submittedVersion, other-oa)
Funders
  • National Science Foundation
  • Biogen
  • Wellcome Trust
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (125759, 320,030_122,419, 116689)
  • Medical Research Council
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
schizophrenia, NMDA receptor hypofunction, oxidative stress, parvalbumin interneurons, GABAergic interneurons, excitation-inhibition balance, early life development, schizophrenia pathogenesis
MeSH terms
Animals, Brain, Humans, Schizophrenia, Receptors, N-Methyl-D-Aspartate, Oxidative Stress

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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