Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients

Monin, Aline; Baumann, Philipp; Griffa, Alessandra; Xin, Lijing; Mekle, Ralf; Fournier, Margot; Butticaz, Christophe; Klaey, Magali; Cabungcal, Jan-Harry; Steullet, Pascal; Ferrari, Carina; Cuénod, Michel; Gruetter, Rolf; Thiran, Jean-Philippe; Hagmann, Patric; Conus, Philippe; Q., Kim

doi:10.1038/mp.2014.88

Cited by 100 publications

(102 citation statements)

References 72 publications

(84 reference statements)

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“…Another recent study reported reduced glutathione only in schizophrenia patients carrying a risk variant of the gene coding for the ratelimiting enzyme in glutathione synthesis [22]. Four other studies reported no statistically significant differences in glutathione levels in the posterior medial frontal cortex [23], mPFC [24] or anterior cingulate cortex (ACC) [25,26]. However, two out of the four found a trend toward reduced glutathione in schizophrenia [24,25] and in one, lowered levels of glutathione were associated with negative symptoms [24].…”

Section: Introductionmentioning

confidence: 95%

Glutathione and glutamate in schizophrenia: a 7T MRS study

et al. 2018

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In schizophrenia, abnormal neural metabolite concentrations may arise from cortical damage following neuroinflammatory processes implicated in acute episodes. Inflammation is associated with increased glutamate, whereas the antioxidant glutathione may protect against inflammation-induced oxidative stress. We hypothesized that patients with stable schizophrenia would exhibit a reduction in glutathione, glutamate, and/or glutamine in the cerebral cortex, consistent with a post-inflammatory response, and that this reduction would be most marked in patients with "residual schizophrenia", in whom an early stage with positive psychotic symptoms has progressed to a late stage characterized by long-term negative symptoms and impairments. We recruited 28 patients with stable schizophrenia and 45 healthy participants matched for age, gender, and parental socio-economic status. We measured glutathione, glutamate and glutamine concentrations in the anterior cingulate cortex (ACC), left insula, and visual cortex using 7T proton magnetic resonance spectroscopy (MRS). Glutathione and glutamate were significantly correlated in all three voxels. Glutamine concentrations across the three voxels were significantly correlated with each other. Principal components analysis (PCA) produced three clear components: an ACC glutathione-glutamate component; an insula-visual glutathione-glutamate component; and a glutamine component. Patients with stable schizophrenia had significantly lower scores on the ACC glutathione-glutamate component, an effect almost entirely leveraged by the sub-group of patients with residual schizophrenia. All three metabolite concentration values in the ACC were significantly reduced in this group. These findings are consistent with the hypothesis that excitotoxicity during the acute phase of illness leads to reduced glutathione and glutamate in the residual phase of the illness.

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Section: Introductionmentioning

confidence: 95%

Glutathione and glutamate in schizophrenia: a 7T MRS study

et al. 2018

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“…112,113 In SZ patients, a direct role for redox control of myelin is seen in the positive correlation between prefrontal GSH levels and functional anisotropy along the cingulum bundle, which connects the ACC to limbic structures. 114 The importance of redox control for white matter integrity and oligodendrocyte development is further supported by animal models and in vitro research. Redox state controls oligodendrocyte maturation as well as the switch between proliferation (reduced state) and differentiation (oxidized state).…”

Section: Oligodendrocyte Sensitivity To Redox Statementioning

confidence: 99%

“…Redox state controls oligodendrocyte maturation as well as the switch between proliferation (reduced state) and differentiation (oxidized state). 114,115 Abnormal redox control would interfere with oligodendrocyte development. Consistent with this, Gclm-KO mice bearing a 70% GSH deficit within brain and increased oxidative stress marks in the PFC and ventral hippocampus 85,87 have lower levels of mature oligodendrocytes and myelin in the peripubertal period 114 (figure 2).…”

Section: Oligodendrocyte Sensitivity To Redox Statementioning

confidence: 99%

“…114,115 Abnormal redox control would interfere with oligodendrocyte development. Consistent with this, Gclm-KO mice bearing a 70% GSH deficit within brain and increased oxidative stress marks in the PFC and ventral hippocampus 85,87 have lower levels of mature oligodendrocytes and myelin in the peripubertal period 114 (figure 2). Although myelination reaches similar levels in adult Gclm-KO and wild-type mice, DTI reveals persistent impairment of white matter integrity and reduced conduction velocity in the fornix and anterior commissure.…”

Section: Oligodendrocyte Sensitivity To Redox Statementioning

confidence: 99%

“…116 At the cellular level, GSH deficiency in oligodendrocyte progenitors leads to cell-cycle arrest and reduces proliferation which can be reversed by the antioxidant NAC. 114,115 At a molecular level, the switch from proliferation to early differentiation is controlled by the platelet-derived growth factor receptor (PDGFR-Fyn) pathway. 114,117 Nonreceptor tyrosine kinase, Fyn, is activated by redox dysregulation, 117 and interestingly, is impaired in early psychosis patients associated with a vulnerability to redox dysregulation.…”

Section: Oligodendrocyte Sensitivity To Redox Statementioning

confidence: 99%

See 2 more Smart Citations

Targeting Oxidative Stress and Aberrant Critical Period Plasticity in the Developmental Trajectory to Schizophrenia

Q.¹,

Cuénod²,

Hensch

2015

SCHBUL

138

113

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Schizophrenia is a neurodevelopmental disorder reflecting a convergence of genetic risk and early life stress. The slow progression to first psychotic episode represents both a window of vulnerability as well as opportunity for therapeutic intervention. Here, we consider recent neurobiological insight into the cellular and molecular components of developmental critical periods and their vulnerability to redox dysregulation. In particular, the consistent loss of parvalbumin-positive interneuron (PVI) function and their surrounding perineuronal nets (PNNs) as well as myelination in patient brains is consistent with a delayed or extended period of circuit instability. This linkage to critical period triggers (PVI) and brakes (PNN, myelin) implicates mistimed trajectories of brain development in mental illness. Strategically introduced antioxidant treatment or later reinforcement of molecular brakes may then offer a novel prophylactic psychiatry.

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Cystine/glutamate antiporter blockage induces myelin degeneration

Soria

Zabala

Pampliega

et al. 2016

Glia

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The cystine/glutamate antiporter is a membrane transport system responsible for the uptake of extracellular cystine and release of intracellular glutamate. It is the major source of cystine in most cells, and a key regulator of extrasynaptic glutamate in the CNS. Because cystine is the limiting factor in the biosynthesis of glutathione, and glutamate is the most abundant neurotransmitter, the cystine/glutamate antiporter is a central player both in antioxidant defense and glutamatergic signaling, two events critical to brain function. However, distribution of cystine/glutamate antiporter in CNS has not been well characterized. Here, we analyzed expression of the catalytic subunit of the cystine/glutamate antiporter, xCT, by immunohistochemistry in histological sections of the forebrain and spinal cord. We detected labeling in neurons, oligodendrocytes, microglia, and oligodendrocyte precursor cells, but not in GFAP(+) astrocytes. In addition, we examined xCT expression and function by qPCR and cystine uptake in primary rat cultures of CNS, detecting higher levels of antiporter expression in neurons and oligodendrocytes. Chronic inhibition of cystine/glutamate antiporter caused high toxicity to cultured oligodendrocytes. In accordance, chronic blockage of cystine/glutamate antiporter as well as glutathione depletion caused myelin disruption in organotypic cerebellar slices. Finally, mice chronically treated with sulfasalazine, a cystine/glutamate antiporter inhibitor, showed a reduction in the levels of myelin and an increase in the myelinated fiber g-ratio. Together, these results reveal that cystine/glutamate antiporter is expressed in oligodendrocytes, where it is a key factor to the maintenance of cell homeostasis. GLIA 2016. GLIA 2016;64:1381-1395.

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Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients

Cited by 100 publications

References 72 publications

Glutathione and glutamate in schizophrenia: a 7T MRS study

Glutathione and glutamate in schizophrenia: a 7T MRS study

Targeting Oxidative Stress and Aberrant Critical Period Plasticity in the Developmental Trajectory to Schizophrenia

Cystine/glutamate antiporter blockage induces myelin degeneration

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