title: 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.
authors.affiliation: 1] Center for Psychiatric Neuroscience, Centre Hospitalier Universitaire Vaudois and University of Lausanne (CHUV-UNIL), Prilly-Lausanne, Switzerland [2] Department of Psychiatry, Centre Hospitalier Universitaire Vaudois and University of Lausanne (CHUV-UNIL), Prilly-Lausanne, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Monin
authors.affiliation: 1] Center for Psychiatric Neuroscience, Centre Hospitalier Universitaire Vaudois and University of Lausanne (CHUV-UNIL), Prilly-Lausanne, Switzerland [2] Department of Psychiatry, Centre Hospitalier Universitaire Vaudois and University of Lausanne (CHUV-UNIL), Prilly-Lausanne, Switzerland [3] Service of General Psychiatry, Centre Hospitalier Universitaire Vaudois and University of Lausanne (CHUV-UNIL), Prilly-Lausanne, Switzerland.
authors.forename: P S
authors.initials: PS
authors.lastname: Baumann
authors.affiliation: 1] Signal Processing Laboratory, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland [2] Department of Radiology, Centre Hospitalier Universitaire Vaudois and University of Lausanne (CHUV-UNIL), Lausanne, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Griffa
authors.affiliation: Laboratory for Functional and Metabolic Imaging, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: L
authors.initials: L
authors.lastname: Xin
authors.affiliation: Physikalisch-Technische Bundesanstalt, Berlin, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Mekle
authors.affiliation: 1] Center for Psychiatric Neuroscience, Centre Hospitalier Universitaire Vaudois and University of Lausanne (CHUV-UNIL), Prilly-Lausanne, Switzerland [2] Department of Psychiatry, Centre Hospitalier Universitaire Vaudois and University of Lausanne (CHUV-UNIL), Prilly-Lausanne, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Fournier
authors.affiliation: 1] Center for Psychiatric Neuroscience, Centre Hospitalier Universitaire Vaudois and University of Lausanne (CHUV-UNIL), Prilly-Lausanne, Switzerland [2] Department of Psychiatry, Centre Hospitalier Universitaire Vaudois and University of Lausanne (CHUV-UNIL), Prilly-Lausanne, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Butticaz
authors.affiliation: 1] Center for Psychiatric Neuroscience, Centre Hospitalier Universitaire Vaudois and University of Lausanne (CHUV-UNIL), Prilly-Lausanne, Switzerland [2] Department of Psychiatry, Centre Hospitalier Universitaire Vaudois and University of Lausanne (CHUV-UNIL), Prilly-Lausanne, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Klaey
authors.affiliation: 1] Center for Psychiatric Neuroscience, Centre Hospitalier Universitaire Vaudois and University of Lausanne (CHUV-UNIL), Prilly-Lausanne, Switzerland [2] Department of Psychiatry, Centre Hospitalier Universitaire Vaudois and University of Lausanne (CHUV-UNIL), Prilly-Lausanne, Switzerland.
authors.forename: J H
authors.initials: JH
authors.lastname: Cabungcal
authors.affiliation: 1] Center for Psychiatric Neuroscience, Centre Hospitalier Universitaire Vaudois and University of Lausanne (CHUV-UNIL), Prilly-Lausanne, Switzerland [2] Department of Psychiatry, Centre Hospitalier Universitaire Vaudois and University of Lausanne (CHUV-UNIL), Prilly-Lausanne, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Steullet
authors.affiliation: 1] Center for Psychiatric Neuroscience, Centre Hospitalier Universitaire Vaudois and University of Lausanne (CHUV-UNIL), Prilly-Lausanne, Switzerland [2] Department of Psychiatry, Centre Hospitalier Universitaire Vaudois and University of Lausanne (CHUV-UNIL), Prilly-Lausanne, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Ferrari
authors.affiliation: 1] Center for Psychiatric Neuroscience, Centre Hospitalier Universitaire Vaudois and University of Lausanne (CHUV-UNIL), Prilly-Lausanne, Switzerland [2] Department of Psychiatry, Centre Hospitalier Universitaire Vaudois and University of Lausanne (CHUV-UNIL), Prilly-Lausanne, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Cuenod
authors.affiliation: 1] Department of Radiology, Centre Hospitalier Universitaire Vaudois and University of Lausanne (CHUV-UNIL), Lausanne, Switzerland [2] Laboratory for Functional and Metabolic Imaging, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Gruetter
authors.affiliation: 1] Signal Processing Laboratory, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland [2] Department of Radiology, Centre Hospitalier Universitaire Vaudois and University of Lausanne (CHUV-UNIL), Lausanne, Switzerland.
authors.forename: J P
authors.initials: JP
authors.lastname: Thiran
authors.affiliation: 1] Signal Processing Laboratory, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland [2] Department of Radiology, Centre Hospitalier Universitaire Vaudois and University of Lausanne (CHUV-UNIL), Lausanne, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Hagmann
authors.affiliation: 1] Department of Psychiatry, Centre Hospitalier Universitaire Vaudois and University of Lausanne (CHUV-UNIL), Prilly-Lausanne, Switzerland [2] Service of General Psychiatry, Centre Hospitalier Universitaire Vaudois and University of Lausanne (CHUV-UNIL), Prilly-Lausanne, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Conus
authors.affiliation: 1] Center for Psychiatric Neuroscience, Centre Hospitalier Universitaire Vaudois and University of Lausanne (CHUV-UNIL), Prilly-Lausanne, Switzerland [2] Department of Psychiatry, Centre Hospitalier Universitaire Vaudois and University of Lausanne (CHUV-UNIL), Prilly-Lausanne, Switzerland.
authors.forename: K Q
authors.initials: KQ
authors.lastname: Do
mesh_terms: D000328:Adult; D000818:Animals; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000172:deficiency*; D006801:Humans; D008297:Male; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000473:pathology / Q000502:physiology; D009836:Oligodendroglia / Q000473:pathology* / Q000502:physiology*; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism; D017208:Rats, Wistar; D012559:Schizophrenia / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology*; D066127:White Matter / Q000473:pathology / Q000503:physiopathology; D055815:Young Adult
chemical_list: D051076:Proto-Oncogene Proteins c-fyn; C560749:GCLM protein, mouse; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione