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

Abstract

Schizophrenia pathophysiology implies both abnormal redox control and dysconnectivity of the prefrontal cortex, partly related to oligodendrocyte and myelin impairments. As oligodendrocytes are highly vulnerable to altered redox state, we investigated the interplay between glutathione and myelin. In control subjects, multimodal brain imaging revealed a positive association between medial prefrontal glutathione levels and both white matter integrity and resting-state functional connectivity along the cingulum bundle. In early psychosis patients, only white matter integrity was correlated with glutathione levels. On the other side, in the prefrontal cortex of peripubertal mice with genetically impaired glutathione synthesis, mature oligodendrocyte numbers, as well as myelin markers, were decreased. At the molecular levels, under glutathione-deficit conditions induced by short hairpin RNA targeting the key glutathione synthesis enzyme, oligodendrocyte progenitors showed a decreased proliferation mediated by an upregulation of Fyn kinase activity, reversed by either the antioxidant N-acetylcysteine or Fyn kinase inhibitors. In addition, oligodendrocyte maturation was impaired. Interestingly, the regulation of Fyn mRNA and protein expression was also impaired in fibroblasts of patients deficient in glutathione synthesis. Thus, glutathione and redox regulation have a critical role in myelination processes and white matter maturation in the prefrontal cortex of rodent and human, a mechanism potentially disrupted in schizophrenia.

Glutathione and glutamate in schizophrenia: a 7T MRS study

“…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].…”

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

“…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).…”

“…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).…”

“…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.…”

“…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.…”