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