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Cited by 103Schizophrenia research and treatmentRedox biology and oxidative stressTryptophan and brain disorders

Potential Roles of Redox Dysregulation in the Development of Schizophrenia

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Perkins, Diana O., Jeffries, Clark D., Do, Kim Q.·2020·Biological Psychiatry
DOI 10.1016/j.biopsych.2020.03.016PMC PMC7395886
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Abstract

Converging evidence implicates redox dysregulation as a pathological mechanism driving the emergence of psychosis. Increased oxidative damage and decreased capacity of intracellular redox modulatory systems are consistent findings in persons with schizophrenia as well as in persons at clinical high risk who subsequently developed frank psychosis. Levels of glutathione, a key regulator of cellular redox status, are reduced in the medial prefrontal cortex, striatum, and thalamus in schizophrenia. In humans with schizophrenia and in rodent models recapitulating various features of schizophrenia, redox dysregulation is linked to reductions of parvalbumin containing gamma-aminobutyric acid (GABA) interneurons and volumes of their perineuronal nets, white matter abnormalities, and microglia activation. Importantly, the activity of transcription factors, kinases, and phosphatases regulating diverse aspects of neurodevelopment and synaptic plasticity varies according to cellular redox state. Molecules regulating interneuron function under redox control include NMDA receptor subunits GluN1 and GluN2A as well as KEAP1 (regulator of transcription factor NRF2). In a rodent schizophrenia model characterized by impaired glutathione synthesis, the Gclm knockout mouse, oxidative stress activated MMP9 (matrix metalloprotease 9) via its redox-responsive regulatory sites, causing a cascade of molecular events leading to microglia activation, perineural net degradation, and impaired NMDA receptor function. Molecular pathways under redox control are implicated in the etiopathology of schizophrenia and are attractive drug targets for individualized drug therapy trials in the contexts of prevention and treatment of psychosis.

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  • There is converging evidence pointing at a role of redox dysregulation as a possible mechanism involved in the aetiopathogenesis of both ASD and psychosis.

    “There is converging evidence pointing at a role of redox dysregulation as a possible mechanism involved in the aetiopathogenesis of both ASD (Bjørklund et al., 2020) and psychosis (Perkins, Jeffries, & Do, 2020).”

    From Can epigenetics shine a light on the biological pathways underlying major mental disorders? (2022) · cites this paper as Perkins, Jeffries, & Do, 2020

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Cited by

Sorted by citations

Authors
Perkins, D. O., Jeffries, C. D., & Do, K. Q.
Affiliations
University of North Carolina at Chapel Hill (US)
Corresponding author
Perkins, Diana O.
ORCID
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2020-08
Volume
88
Issue
4
Pages
326-336
ISSN
0006-3223 (ISSN-L)
DOI
10.1016/j.biopsych.2020.03.016
PMC
PMC7395886
OpenAlex
W3014338844
Cited by
103
References
27
Citations by year
2026: 14 · 2025: 18 · 2024: 12 · 2023: 17 · 2022: 10 · 2021: 26 · 2020: 6
FWCI
2.44
Type
journal article
Language
en
Open access
Licence
Locations
  • Biological Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
  • IRIS (submittedVersion)
  • SERVAL (Université de Lausanne) (submittedVersion)
  • UNC Libraries
Funders
National Institute of Mental Health
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Keywords
schizophrenia, redox dysregulation, oxidative stress, glutathione, glutathione synthesis, NMDA receptor, GluN1, GluN2A, Keap1, Nrf2, MMP-9, microglial activation, parvalbumin interneurons, perineuronal nets, white matter abnormalities, synaptic plasticity, psychosis, clinical high risk, therapeutic target
MeSH terms
Kelch-Like ECH-Associated Protein 1, Animals, Oxidation-Reduction, Parvalbumins, Schizophrenia, NF-E2-Related Factor 2, Mice

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