title: Glutathione Deficit Affects the Integrity and Function of the Fimbria/Fornix and Anterior Commissure in Mice: Relevance for Schizophrenia.
abstract: BACKGROUND
  Structural anomalies of white matter are found in various brain regions of patients with schizophrenia and bipolar and other psychiatric disorders, but the causes at the cellular and molecular levels remain unclear. Oxidative stress and redox dysregulation have been proposed to play a role in the pathophysiology of several psychiatric conditions, but their anatomical and functional consequences are poorly understood. The aim of this study was to investigate white matter throughout the brain in a preclinical model of redox dysregulation.
  
  
  METHODS
  In a mouse model with impaired glutathione synthesis (Gclm KO), a state-of-the-art multimodal magnetic resonance protocol at high field (14.1 T) was used to assess longitudinally the white matter structure, prefrontal neurochemical profile, and ventricular volume. Electrophysiological recordings in the abnormal white matter tracts identified by diffusion tensor imaging were performed to characterize the functional consequences of fractional anisotropy alterations.
  
  
  RESULTS
  Structural alterations observed at peri-pubertal age and adulthood in Gclm KO mice were restricted to the anterior commissure and fornix-fimbria. Reduced fractional anisotropy in the anterior commissure (-7.5% ± 1.9, P<.01) and fornix-fimbria (-4.5% ± 1.3, P<.05) were accompanied by reduced conduction velocity in fast-conducting fibers of the posterior limb of the anterior commissure (-14.3% ± 5.1, P<.05) and slow-conducting fibers of the fornix-fimbria (-8.6% ± 2.6, P<.05). Ventricular enlargement was found at peri-puberty (+25% ± 8 P<.05) but not in adult Gclm KO mice.
  
  
  CONCLUSIONS
  Glutathione deficit in Gclm KO mice affects ventricular size and the integrity of the fornix-fimbria and anterior commissure. This suggests that redox dysregulation could contribute during neurodevelopment to the impaired white matter and ventricle enlargement observed in schizophrenia and other psychiatric disorders.
authors.affiliation: Laboratory for Functional and Metabolic Imaging, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland (Mr Corcoba, and Drs Duarte, Van de Looij, and Gruetter); Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, CHUV, Lausanne, Switzerland (Mr Corcoba, Drs Steullet, Monin, Cuenod, and Do); Division of Child Growth & Development, University of Geneva, Geneva, Switzerland (Dr Van de Looij); Department of Radiology, University Hospital, Lausanne, Switzerland (Dr Gruetter); Department of Radiology, University Hospital, Geneva, Switzerland (Dr Gruetter).
authors.forename: Alberto
authors.initials: A
authors.lastname: Corcoba
authors.affiliation: Laboratory for Functional and Metabolic Imaging, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland (Mr Corcoba, and Drs Duarte, Van de Looij, and Gruetter); Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, CHUV, Lausanne, Switzerland (Mr Corcoba, Drs Steullet, Monin, Cuenod, and Do); Division of Child Growth & Development, University of Geneva, Geneva, Switzerland (Dr Van de Looij); Department of Radiology, University Hospital, Lausanne, Switzerland (Dr Gruetter); Department of Radiology, University Hospital, Geneva, Switzerland (Dr Gruetter).
authors.forename: Pascal
authors.initials: P
authors.lastname: Steullet
authors.affiliation: Laboratory for Functional and Metabolic Imaging, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland (Mr Corcoba, and Drs Duarte, Van de Looij, and Gruetter); Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, CHUV, Lausanne, Switzerland (Mr Corcoba, Drs Steullet, Monin, Cuenod, and Do); Division of Child Growth & Development, University of Geneva, Geneva, Switzerland (Dr Van de Looij); Department of Radiology, University Hospital, Lausanne, Switzerland (Dr Gruetter); Department of Radiology, University Hospital, Geneva, Switzerland (Dr Gruetter).
authors.forename: João M N
authors.initials: JM
authors.lastname: Duarte
authors.affiliation: Laboratory for Functional and Metabolic Imaging, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland (Mr Corcoba, and Drs Duarte, Van de Looij, and Gruetter); Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, CHUV, Lausanne, Switzerland (Mr Corcoba, Drs Steullet, Monin, Cuenod, and Do); Division of Child Growth & Development, University of Geneva, Geneva, Switzerland (Dr Van de Looij); Department of Radiology, University Hospital, Lausanne, Switzerland (Dr Gruetter); Department of Radiology, University Hospital, Geneva, Switzerland (Dr Gruetter).
authors.forename: Yohan
authors.initials: Y
authors.lastname: Van de Looij
authors.affiliation: Laboratory for Functional and Metabolic Imaging, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland (Mr Corcoba, and Drs Duarte, Van de Looij, and Gruetter); Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, CHUV, Lausanne, Switzerland (Mr Corcoba, Drs Steullet, Monin, Cuenod, and Do); Division of Child Growth & Development, University of Geneva, Geneva, Switzerland (Dr Van de Looij); Department of Radiology, University Hospital, Lausanne, Switzerland (Dr Gruetter); Department of Radiology, University Hospital, Geneva, Switzerland (Dr Gruetter).
authors.forename: Aline
authors.initials: A
authors.lastname: Monin
authors.affiliation: Laboratory for Functional and Metabolic Imaging, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland (Mr Corcoba, and Drs Duarte, Van de Looij, and Gruetter); Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, CHUV, Lausanne, Switzerland (Mr Corcoba, Drs Steullet, Monin, Cuenod, and Do); Division of Child Growth & Development, University of Geneva, Geneva, Switzerland (Dr Van de Looij); Department of Radiology, University Hospital, Lausanne, Switzerland (Dr Gruetter); Department of Radiology, University Hospital, Geneva, Switzerland (Dr Gruetter).
authors.forename: Michel
authors.initials: M
authors.lastname: Cuenod
authors.affiliation: Laboratory for Functional and Metabolic Imaging, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland (Mr Corcoba, and Drs Duarte, Van de Looij, and Gruetter); Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, CHUV, Lausanne, Switzerland (Mr Corcoba, Drs Steullet, Monin, Cuenod, and Do); Division of Child Growth & Development, University of Geneva, Geneva, Switzerland (Dr Van de Looij); Department of Radiology, University Hospital, Lausanne, Switzerland (Dr Gruetter); Department of Radiology, University Hospital, Geneva, Switzerland (Dr Gruetter).
authors.forename: Rolf
authors.initials: R
authors.lastname: Gruetter
authors.affiliation: Laboratory for Functional and Metabolic Imaging, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland (Mr Corcoba, and Drs Duarte, Van de Looij, and Gruetter); Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, CHUV, Lausanne, Switzerland (Mr Corcoba, Drs Steullet, Monin, Cuenod, and Do); Division of Child Growth & Development, University of Geneva, Geneva, Switzerland (Dr Van de Looij); Department of Radiology, University Hospital, Lausanne, Switzerland (Dr Gruetter); Department of Radiology, University Hospital, Geneva, Switzerland (Dr Gruetter). kim.do@chuv.ch.
authors.forename: Kim Q
authors.initials: KQ
authors.lastname: Do
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000254:growth & development / Q000473:pathology / Q000503:physiopathology*; D056324:Diffusion Tensor Imaging; D004195:Disease Models, Animal; D005721:Glutamate-Cysteine Ligase / Q000172:deficiency / Q000235:genetics; D005978:Glutathione / Q000172:deficiency*; D008297:Male; D018345:Mice, Knockout; D009929:Organ Size; D011758:Pyrroles; D012559:Schizophrenia; D046509:Tissue Culture Techniques; D066127:White Matter / Q000000981:diagnostic imaging / Q000254:growth & development / Q000473:pathology / Q000503:physiopathology
chemical_list: D011758:Pyrroles; C572041:longmide B; C560749:GCLM protein, mouse; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione
keywords: Schizophrenia; anterior commissure; fimbria-fornix; glutathione; oxidative stress