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, myoInositol, 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: Glutathione, MRS, N-acetylcysteine, neurochemical profile, oxidative stress, schizophrenia O xidative stress and impaired redox-regulation occur in neurodegenerative diseases such as Parkinson's (1), Alzheimer's (2), and Huntington disease (3), as well as in psychiatric pathologies including bipolar disorder (4) and schizophrenia (5). Whereas redox-dysregulation in neurodegenerative diseases is likely a downstream consequence of other primary causes, compelling data suggest that redox-dysregulation is a primary risk factor for schizophrenia (5). Indeed, glutathione (GSH), the major cellular redox-regulator and antioxidant, is decreased in cerebrospinal fluid, medial prefrontal cortex (6,7) and postmortem striatum (8) of schizophrenia patients. Furthermore, the two genes coding for the key GSH-synthesizing enzyme, glutamate-cysteine ligase catalytic (GCLC) and modifier (GCLM) subunits, are associated with schizophrenia (9,10). Polymorphisms of trinucleotide repeats on the GCLC gene are accompanied by reduced enzyme activity, decreased GSH levels, and higher risk for the disease (10). Moreover, the response to an oxidative stress challenge in patient fibroblasts is depressed (10), indicating a deficit in GSH regulation. Thus, in combination with environmental insults that generate oxidative stress, this redox dysregulation may play a central role in schizophrenia (5,11).To investigate the link between redox imbalance and the disease, we study mice with genetic deletion (knockout) of the GCLM gene (KO) (12), which display a sustained...

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BackgroundOxidative stress, coupled with dysregulation of inflammation, NMDAR and dopamine, is involved in schizophrenia (SZ) pathophysiology. Earlier add-on clinical trials showed in chronic SZ patients that NAC, a precursor of glutathione (GSH), an important cerebral antioxidant, improved negative symptoms, mismatch negativity and local synchronization. We hypothesized that NAC at an earlier stage of illness would have a greater impact.MethodsEarly psychosis patients (EP, less than 5 years of illness, N=63; NAC=32, placebo=31) were supplemented with NAC (2.7g/day, 6 months) in a double-blind randomized placebo-controlled trial. Outcome measures: PANSS and neurocognition (MATRICS Consensus Cognitive Battery; n=36); quantification of medial prefronfal cortex glutathione (GSHmPFC) by 1H-magnetic-resonance-spectroscopy, of white matter diffusion properties estimated by generalized fractional anisotropy (gFA) computed from diffusion spectrum imaging (DSI), of blood cells GSH (GSHBC) and GSH peroxidase activity (GPxBC) at start and end of trialResultsWhile PANSS negative and positive were not affected by NAC, NAC improved Processing Speed (NAC > Placebo; F(1, 30)=5.849, p=.022), favoring 2 of 3 processing speed tasks (Trail Making A, F(1, 30)=4.279, p=.048 & Verbal Fluency, F(1, 30)=5.749, p=.023). GSHmPFC (+23%, p=0.005) and GSHBC (+19%, p=0.05) were increased following NAC treatment. In patients with high-baseline GPxBC (>22.3U/gHb), subgroup explorations revealed an improvement of PANSS positive compared to placebo (p=0.02). The change of PANSS positive correlated negatively with that of GPxBC activity, showing that the improvement paralleled the restoration of redox status. NAC group showed 11% increase in fornix white matter integrity as measured by gFA, correlating with an increase in GSHmPFC over the 6-months period.DiscussionThis is the first clinical trial assessing the impact of NAC treatment in a sample of EP and the potential predictive role of peripheral biomarkers of redox dysregulation. The hypothesis that NAC would be beneficial to negative symptoms in EP was not confirmed in this small sample, most likely in reason of their very low level at baseline. The NAC induced GSHmPFC increase demonstrates its target engagement. NAC improved Processing Speed showing a therapeutic enhancement of cognitive functions. Most importantly, NAC improved fornix integrity, in association with brain GSH elevation, demonstrating for the first time that a redox regulator can enhance structural connectivity. Peripheral redox status allows identifying a subgroup of patients with improved positive symptoms. Future biomarker guided antioxidant interventions in larger EP samples should replicate these findings.