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

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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.

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Acknowledgements

This work was supported by the Swiss National Science Foundation (Grant Nos. 310030_135736/1 to KQD and PS, 320030_122419 to PC and KQD and 130090 to PH) and the National Center of Competence in Research (NCCR) ‘SYNAPSY—The Synaptic Bases of Mental Diseases’ (Grant No. 51AU40_125759). We thank the Brazilian Swiss Joint Research Program (BSJRP), the ‘Loterie Romande’, Damm-Etienne Foundation, Avina Foundation and Alamaya Foundation. PH was financially supported by Leenaards Foundation. We are grateful for technical assistance to Hélène Moser and Adeline Cottier. We also thank Dr Mehdi Gholam for advices on statistics, Dr Portia Vliet for the GCLC antibody and Dr Ibro Ambeskovic for advices on OPC culture and in vitro experiments. We extend thanks to Ying Chen for providing us with the GCLM-KO breeders. Most of all, we express our gratitude to all patients and healthy volunteers for their enduring participation.

Author Contributions

AM wrote the manuscript, designed and carried out the rodent experiments and performed human fibroblast culture. PSB wrote the manuscript and performed the patient recruitment and skin biopsy and analyzed DSI. AG performed DSI/fMRI acquisition and analyzed the data. LX and RM performed MRS acquisition and analyzed the data. MF wrote the manuscript, designed and performed human fibroblast culture and evaluated data from Stanley database. CB designed and prepared shRNA. MK established OPC culture. J-HC contributed to morphology analysis of GCLM-KO mice and editing the manuscript. PS designed and contributed to experiments in rodents and to the manuscript writing. CF recruited control subjects and early psychosis patients and performed psychiatric evaluations. MC contributed to the overall study concept and to the manuscript writing. RG supervised MRS study. J-PT supervised DSI/fMRI analysis. PH designed, analyzed and supervised DSI/fMRI study. PC contributed to the overall concept, and planned and coordinated the recruitment in human study. KQD conceived and directed the whole study, and contributed to the writing. All authors reviewed and edited the manuscript.

Author contributions

AM wrote the manuscript, designed and carried out the rodent experiments and performed human fibroblast culture. PSB wrote the manuscript and performed the patient recruitment and skin biopsy and analyzed DSI. AG performed DSI/fMRI acquisition and analyzed the data. LX and RM performed MRS acquisition and analyzed the data. MF wrote the manuscript, designed and performed human fibroblast culture and evaluated data from Stanley database. CB designed and prepared shRNA. MK established OPC culture. J-HC contributed to morphology analysis of GCLM-KO mice and editing the manuscript. PS designed and contributed to experiments in rodents and to the manuscript writing. CF recruited control subjects and early psychosis patients and performed psychiatric evaluations. MC contributed to the overall study concept and to the manuscript writing. RG supervised MRS study. J-PT supervised DSI/fMRI analysis. PH designed, analyzed and supervised DSI/fMRI study. PC contributed to the overall concept, and planned and coordinated the recruitment in human study. KQD conceived and directed the whole study, and contributed to the writing. All authors reviewed and edited the manuscript.

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Monin, A., Baumann, P., Griffa, A. et al. Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients. Mol Psychiatry 20, 827–838 (2015). https://doi.org/10.1038/mp.2014.88

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