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Glutathione Deficit Affects the Integrity and Function of the Fimbria/Fornix and Anterior Commissure in Mice : Relevance for Schizophrenia

Corcoba, Alberto; Steullet, Pascal; Duarte, João M N LU ; Van de Looij, Yohan; Monin, Aline; Cuenod, Michel; Gruetter, Rolf and Do, Kim Q (2016) In International Journal of Neuropsychopharmacology 19(3).
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... (More)

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.

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publishing date
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Contribution to journal
publication status
published
keywords
Animals, Brain, Diffusion Tensor Imaging, Disease Models, Animal, Glutamate-Cysteine Ligase, Glutathione, Male, Mice, Knockout, Organ Size, Pyrroles, Schizophrenia, Tissue Culture Techniques, White Matter, Journal Article, Research Support, Non-U.S. Gov't
in
International Journal of Neuropsychopharmacology
volume
19
issue
3
pages
11 pages
publisher
Cambridge University Press
external identifiers
  • scopus:85016925395
ISSN
1469-5111
DOI
10.1093/ijnp/pyv110
language
English
LU publication?
no
id
186ac2ae-9df4-47d0-8f2a-8bfc3d7d40f5
date added to LUP
2017-10-19 15:17:59
date last changed
2017-11-12 04:36:03
@article{186ac2ae-9df4-47d0-8f2a-8bfc3d7d40f5,
  abstract     = {<p>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.</p><p>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.</p><p>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&lt;.01) and fornix-fimbria (-4.5% ± 1.3, P&lt;.05) were accompanied by reduced conduction velocity in fast-conducting fibers of the posterior limb of the anterior commissure (-14.3% ± 5.1, P&lt;.05) and slow-conducting fibers of the fornix-fimbria (-8.6% ± 2.6, P&lt;.05). Ventricular enlargement was found at peri-puberty (+25% ± 8 P&lt;.05) but not in adult Gclm KO mice.</p><p>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.</p>},
  author       = {Corcoba, Alberto and Steullet, Pascal and Duarte, João M N and Van de Looij, Yohan and Monin, Aline and Cuenod, Michel and Gruetter, Rolf and Do, Kim Q},
  issn         = {1469-5111},
  keyword      = {Animals,Brain,Diffusion Tensor Imaging,Disease Models, Animal,Glutamate-Cysteine Ligase,Glutathione,Male,Mice, Knockout,Organ Size,Pyrroles,Schizophrenia,Tissue Culture Techniques,White Matter,Journal Article,Research Support, Non-U.S. Gov't},
  language     = {eng},
  number       = {3},
  pages        = {11},
  publisher    = {Cambridge University Press},
  series       = {International Journal of Neuropsychopharmacology},
  title        = {Glutathione Deficit Affects the Integrity and Function of the Fimbria/Fornix and Anterior Commissure in Mice : Relevance for Schizophrenia},
  url          = {http://dx.doi.org/10.1093/ijnp/pyv110},
  volume       = {19},
  year         = {2016},
}