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

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

Alberto Corcoba, João Miguel das Neves Duarte, Rolf Gruetter

Environmental stress can interact with genetic predisposition to increase the risk of developing psychopathology. In this work, we tested the hypothesis that social isolation stress interacts with impaired glutathione synthesis and have cumulative effects on the neurochemical profile of the frontal cortex. A mouse model with chronic glutathione deficit induced by knockout (-/-) of the glutamate-cysteine ligase modulatory subunit (Gclm) was exposed to social isolation stress from weaning to post-natal day 65. Using magnetic resonance methods at high-field (14.1 T), we analysed the neurochemical profile in the frontal cortex, brain size and ventricular volume of adult animals. Glutathione deficit was accompanied by elevated concentrations of N-acetylaspartate, alanine, and glutamine, as well as the ratio of glutamine to glutamate (Gln/Glu), and by a reduction in levels of myo-inositol and choline-containing compounds in the frontal cortex of -/- animals with respect to wild-type littermates. Although there was no significant interaction between social isolation stress and glutathione deficiency, mice reared in isolation displayed lower myo-inositol concentration (-8.4%, P

Wiley-Blackwell2017

Whole-brain structural connectivity in temporal lobe epilepsy: a Diffusion Spectrum Imaging study

Alessandro Daducci, Alessandra Griffa, François Lazeyras, Alia Lemkaddem, Jean-Philippe Thiran

Introduction: Medial Temporal Lobe Epilepsy (mTLE) with hippocampal sclerosis is the most frequent cause of drug-resistant focal epilepsy in adults. These patients suffer from widespread subtle white matter abnormalities and abnormal functional connectivity extending beyond the affected lobe, as revealed by Diffusion Tensor Imaging and functional MRI studies. Diffusion spectrum imaging (DSI) is a new diffusion imaging technique with high angular resolution for improving the mapping of white matter tracts [1]. In this study, we used DSI to investigate the whole brain effect of TLE as reflected by topological measures of the structural connectivity network. Methods: Eight patients with right-sided mTLE and hippocampal sclerosis and 25 controls underwent our DSI protocol at 3T using a 32 channel coil: DSI (voxel size 2.2x2.2x3mm; 44 slices, 257 diffusion directions; max b-value = 6400 s/mm2), 3D T1-weighted MPRAGE and 3D T2-weighted images. The analysis was performed using the Connectome Mapper. The cortical and subcortical grey matters were parcellated into 86 Regions of Interest (ROI) with anatomical landmarks using Freesurfer 5.0. The ROIs were coregistered to the diffusion data by using a nonlinear registration between T1 and T2, then T2 to the diffusion space. The Diffusion Tool Kit was used for the reconstruction of the diffusion Orientation Distribution Function in each voxel. Streamline fibre-tracking was then performed from each voxel in the white matter areas using an in-house streamline-based algorithm. Two scalar maps, the Fractional Anisotropy and the Generalized Fractional Anisotropy were calculated. For each patient, the connectivity between every region pair was estimated was used to construct a connectivity matrix (the adjacency matrix of the structural network). Finally we used topological measures in order to reduce the data and obtain whole-brain characteristics of the network [2]: characteristic Path Length (L), Clustering Coefficient (C) and Small Worldness (S) where S=(C/Crand)/(L/ Lrand) with Crand and Lrand are computed for a random network. Significant differences between the mTLE and control groups were assessed using a Wilcoxon rank-sum test. Results: In patients, we found a higher characteristic path length (0.0288), with a lower clustering coefficient (0.0079) and reduced small-worldness (p=0.000058) compared to controls. Network nodes that contributed significantly to these alterations were located within as well as outside the temporal lobe in both hemispheres, although with a predominance for the ipsilateral hemisphere and bilateral limbic structures. The pattern of significant nodes showed concordance with brain regions known to be involved in epileptic networks in patients with mTLE. Conclusions: Our results show a reduced efficiency of structural brain networks and altered connectivity patterns that are concordant with the mapping of functional epileptic networks [3] and altered functional connectivity [4] in patients with mTLE. Therefore, the network in mTLE is less segregated than in controls with reduced global interactions between the nodes and reduced specialised communities. Further studies are needed to establish the relevance of these findings with respect to the propagation of epileptic activity, cognitive deficits in mTLE and outcome of epilepsy surgery in individual patients.

2012

Therapeutic potential of glutathione-enhancers in stress-related psychopathologies

Fiona Hollis, Laia Morato Fornaguera, Eva Ramos Fernandez, Maria del Carmen Sandi Perez, Sarah Catherine Sonnay, Pascal Steiner, Ioannis Zalachoras

The mammalian brain has high energy demands, which may become higher in response to environmental challenges such as psychogenic stress exposure. Therefore, efficient neutralization of reactive oxygen species that are produced as a by-product of ATP synthesis is crucial for preventing oxidative damage and ensuring normal energy supply and brain function. Glutathione (GSH) is arguably the most important endogenous antioxidant in the brain. In recent years, aberrant GSH levels have been implicated in different psychiatric disorders, including stress-related psychopathologies. In this review, we examine the available data supporting a role for GSH levels and antioxidant function in the brain in relation to anxiety and stress-related psychopathologies. Additionally, we identify several promising compounds that could raise GSH levels in the brain by either increasing the availability of its precursors or the expression of GSH-regulating enzymes through activation of Nuclear factor erythroid-2-related factor 2 (Nrf2). Given the high tolerability and safety profile of these compounds, they may represent attractive new opportunities to complement existing therapeutic manipulations against stress-related psychopathologies.

2020

Whole-brain structural connectivity in temporal lobe epilepsy: a Diffusion Spectrum Imaging study

Alessandro Daducci, Alessandra Griffa, François Lazeyras, Alia Lemkaddem, Jean-Philippe Thiran

2012