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.

Social isolation stress and chronic glutathione deficiency have a common effect on the glutamine‐to‐glutamate ratio and myo‐inositol concentration in the mouse frontal cortex

“…; Corcoba et al . ). The magnitude of each significant metabolic modification caused by the Gclm genotype in the frontal cortex is shown in Table .…”

“…Consistent with the results reported previously (Corcoba et al . ; Duarte et al . ), we found an increase in glutamine (and Gln/Glu) in the frontal cortex of Gclm −/− with respect to +/+ and +/− mice.…”

“…Brain and ventricular volumes were assessed by manual segmentation of these anatomical images using FSLview (FMRIB'S Software Tools, Oxford, UK), as described previously (Corcoba et al . ).…”

“…; Corcoba et al . ). Field homogeneity in the VOI was achieved with FAST(EST)MAP (Gruetter and Tkác ).…”

“…; Corcoba et al . ). Furthermore, early‐life insults inducing oxidative stress in Gclm −/− mice are detrimental to immature parvalbumin‐immunoreactive interneurons and have consequences for anterior cingulate cortex functioning in adulthood (Cabungcal et al .…”