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.
Key Words
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Article Info
Publication History
Published online: September 27, 2011
Accepted:
July 29,
2011
Received in revised form:
July 11,
2011
Received:
March 23,
2011
Footnotes
Authors JMdND and AK contributed equally to this work.
Identification
Copyright
© 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
