Journal article

Glutathione deficit affects the integrity and function of the fimbria/fornix and anterior commissure in mice: relevance for schizophrenia

BACKGROUND: Structural anomalies of white matter (WM) are found in various brain regions of patients with schizophrenia, bipolar and other psychiatric disorders, but the causes at 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 WM throughout the brain in a pre-clinical 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 WM structure, prefrontal neurochemical profile and ventricular volume. Electrophysiological recordings in the abnormal WM tracts identified by DTI were performed to characterize the functional consequences of fractional anisotropy (FA) alterations. RESULTS: Structural alterations observed at peri-pubertal age and adulthood in Gclm KO mice were restricted to the anterior commissure (AC) and fornix-fimbria (FF). Reduced FA in the AC (-7.5%+/-1.9, p<0.01) and FF (-4.5%+/-1.3, p<0.05) were accompanied by reduced conduction velocity in fast-conducting fibers of the posterior limb of the AC (-14.3%+/-5.1, p<0.05) and slow-conducting fibers of the FF (-8.6%+/-2.6, p<0.05). Ventricular enlargement was found at peri-puberty (+25%+/-8 p<0.05) but not in adult Gclm KO mice. CONCLUSIONS: Glutathione deficit in Gclm KO mice affects ventricular size and the integrity of the FF and AC. This suggests that redox dysregulation could contribute during neurodevelopment to the impaired WM and ventricle enlargement observed in schizophrenia and other psychiatric disorders.

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