title: N-acetylcysteine normalizes neurochemical changes in the glutathione-deficient schizophrenia mouse model during development.
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.
authors.affiliation: Laboratory for Functional and Metabolic Imaging, Center for Biomedical Imaging, Ecole Polytechnique Federale, University Hospital Lausanne, Switzerland. kim.do@chuv.ch
authors.forename: Joao Miguel
authors.initials: JM
authors.lastname: das Neves Duarte
authors.forename: Anita
authors.initials: A
authors.lastname: Kulak
authors.forename: Mehdi Mohammad
authors.initials: MM
authors.lastname: Gholam-Razaee
authors.forename: Michel
authors.initials: M
authors.lastname: Cuenod
authors.forename: Rolf
authors.initials: R
authors.lastname: Gruetter
authors.forename: Kim Quang
authors.initials: KQ
authors.lastname: Do
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000409:Alanine / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005721:Glutamate-Cysteine Ligase / Q000235:genetics*; D018698:Glutamic Acid / Q000187:drug effects / Q000378:metabolism; D005973:Glutamine / Q000187:drug effects / Q000378:metabolism; D005978:Glutathione / Q000172:deficiency*; D007294:Inositol / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D008137:Longitudinal Studies; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D018345:Mice, Knockout; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism
chemical_list: D016166:Free Radical Scavengers; D005973:Glutamine; D001224:Aspartic Acid; D019344:Lactic Acid; D018698:Glutamic Acid; D007294:Inositol; C000179:N-acetylaspartate; C560749:GCLM protein, mouse; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D000409:Alanine; D000111:Acetylcysteine