Cited by 124Schizophrenia research and treatmentSulfur Compounds in BiologyAmino Acid Enzymes and Metabolism

N-acetylcysteine normalizes neurochemical changes in the glutathione-deficient schizophrenia mouse model during development

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das Neves Duarte, Joao Miguel, Kulak, Anita, Gholam-Razaee, Mehdi Mohammad, Cuenod, Michel, Gruetter, Rolf, Do, Kim Quang·2012·Biological Psychiatry

Abstract

Background Glutathione (GSH) is the major cellular redox-regulator and antioxidant. Redox-imbalance due to genetically impaired GSH synthesis is among the risk factors for schizophrenia. Here we used a mouse model with chronic GSH deficit induced by knockout (KO) of the key GSH-synthesizing enzyme, glutamate-cysteine ligase modulatory subunit (GCLM).Methods With high-resolution magnetic resonance spectroscopy at 14.1 T, we determined the neurochemical profile of GCLM-KO, heterozygous, and wild-type mice in anterior cortex throughout development in a longitudinal study design.Results Chronic GSH deficit was accompanied by an elevation of glutamine (Gln), glutamate (Glu), Gln/Glu, N-acetylaspartate, myo-Inositol, lactate, and alanine. Changes were predominantly present at prepubertal ages (postnatal days 20 and 30). Treatment with N-acetylcysteine from gestation on normalized most neurochemical alterations to wild-type level.Conclusions Changes observed in GCLM-KO anterior cortex, notably the increase in Gln, Glu, and Gln/Glu, were similar to those reported in early schizophrenia, emphasizing the link between redox imbalance and the disease and validating the model. The data also highlight the prepubertal period as a sensitive time for redox-related neurochemical changes and demonstrate beneficial effects of early N-acetylcysteine treatment. Moreover, the data demonstrate the translational value of magnetic resonance spectroscopy to study brain disease in preclinical models.

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Crossref · 10.1016/j.biopsych.2011.07.035

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  1. Hedrich H, Bullock G, Petrusz P (2008): The Handbook of Experimental Animals: The Laboratory Mouse. Oxford, England: Academic Press.

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Authors
das Neves Duarte, J. M., Kulak, A., Gholam-Razaee, M. M., Cuenod, M., Gruetter, R., & Do, K. Q.
Affiliations
Centre Hospitalier Universitaire Vaudois (CH)
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2012-06
Volume
71
Issue
11
Pages
1006-1014
ISSN
0006-3223 (ISSN-L)
OpenAlex
W2171650204
Cited by
124
References
76
Citations by year
2026: 2 · 2025: 4 · 2024: 7 · 2023: 9 · 2022: 10 · 2021: 10 · 2020: 6 · 2019: 10 · 2018: 4 · 2017: 11 · 2016: 13 · 2015: 7 · 2014: 7 · 2013: 11 · 2012: 9
FWCI
6.77
Type
journal article
Language
en
Open access
Locations
  • Biological Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
  • Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
  • IRIS (submittedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
  • SERVAL (Université de Lausanne) (submittedVersion)
Funders
  • National Science Foundation (310030)
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (135736, 310030)
  • Université de Genève
  • Université de Lausanne
  • Centre d'Imagerie BioMédicale
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
Keywords
N-acetylcysteine, glutathione deficiency, schizophrenia, redox imbalance, neurochemical changes, glutamine, glutamate, N-acetylaspartate, myo-inositol, lactate, prepubertal development, anterior cortex, early treatment, mouse model
MeSH terms
Acetylcysteine, Alanine, Animals, Aspartic Acid, Cerebral Cortex, Disease Models, Animal, Glutamate-Cysteine Ligase, Glutamine, Glutathione, Inositol, Longitudinal Studies, Magnetic Resonance Spectroscopy, Schizophrenia, Free Radical Scavengers, Mice, Knockout, Glutamic Acid, Lactic Acid, Mice

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