18
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

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

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          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.

          Related collections

          Most cited references80

          • Record: found
          • Abstract: found
          • Article: not found

          Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia.

          Neuropathological and brain imaging studies suggest that schizophrenia may result from neurodevelopmental defects. Cytoarchitectural studies indicate cellular abnormalities suggestive of a disruption in neuronal connectivity in schizophrenia, particularly in the dorsolateral prefrontal cortex. Yet, the molecular mechanisms underlying these findings remain unclear. To identify molecular substrates associated with schizophrenia, DNA microarray analysis was used to assay gene expression levels in postmortem dorsolateral prefrontal cortex of schizophrenic and control patients. Genes determined to have altered expression levels in schizophrenics relative to controls are involved in a number of biological processes, including synaptic plasticity, neuronal development, neurotransmission, and signal transduction. Most notable was the differential expression of myelination-related genes suggesting a disruption in oligodendrocyte function in schizophrenia.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress.

            The etiology and pathophysiology of schizophrenia remain unknown. A parallel transcriptomics, proteomics and metabolomics approach was employed on human brain tissue to explore the molecular disease signatures. Almost half the altered proteins identified by proteomics were associated with mitochondrial function and oxidative stress responses. This was mirrored by transcriptional and metabolite perturbations. Cluster analysis of transcriptional alterations showed that genes related to energy metabolism and oxidative stress differentiated almost 90% of schizophrenia patients from controls, while confounding drug effects could be ruled out. We propose that oxidative stress and the ensuing cellular adaptations are linked to the schizophrenia disease process and hope that this new disease concept may advance the approach to treatment, diagnosis and disease prevention of schizophrenia and related syndromes.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Meta-analysis of diffusion tensor imaging studies in schizophrenia.

              The objective of the study was to identify whether there are consistent regional white matter changes in schizophrenia. A systematic search was conducted for voxel-based diffusion tensor imaging fractional anisotropy studies of patients with schizophrenia (or related disorders) in relation to comparison groups. The authors carried out meta-analysis of the co-ordinates of fractional anisotropy differences. For the meta-analysis they used the Activation Likelihood Estimation (ALE) method hybridized with the rank approach used in Genome Scan Meta-Analysis (GSMA). This system detects three-dimensional conjunctions of co-ordinates from multiple studies and permits the weighting of studies in relation to sample size. Fifteen articles were identified for inclusion in the meta-analysis, including a total of 407 patients with schizophrenia and 383 comparison subjects. The studies reported fractional anisotropy reductions at 112 co-ordinates in schizophrenia and no fractional anisotropy increases. Over all studies, significant reductions were present in two regions: the left frontal deep white matter and the left temporal deep white matter. The first region, in the left frontal lobe, is traversed by white matter tracts interconnecting the frontal lobe, thalamus and cingulate gyrus. The second region, in the temporal lobe, is traversed by white matter tracts interconnecting the frontal lobe, insula, hippocampus-amygdala, temporal and occipital lobe. This suggests that two networks of white matter tracts may be affected in schizophrenia, with the potential for 'disconnection' of the gray matter regions which they link.
                Bookmark

                Author and article information

                Journal
                Int J Neuropsychopharmacol
                Int. J. Neuropsychopharmacol
                ijnp
                ijnp
                International Journal of Neuropsychopharmacology
                Oxford University Press (US )
                1461-1457
                1469-5111
                March 2016
                3 October 2015
                : 19
                : 3
                : pyv110
                Affiliations
                Laboratory for Functional and Metabolic Imaging, École Polytechnique Fédérale de Lausanne , Lausanne, Switzerland (Mr Corcoba, and Drs Duarte, Van de Looij, and Gruetter); Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital , CHUV, Lausanne, Switzerland (Mr Corcoba, Drs Steullet, Monin, Cuenod, and Do); Division of Child Growth & Development, University of Geneva , Geneva, Switzerland (Dr Van de Looij); Department of Radiology, University Hospital , Lausanne, Switzerland (Dr Gruetter); Department of Radiology, University Hospital , Geneva, Switzerland (Dr Gruetter).
                Author notes
                Correspondence: Kim Q. Do, Center for Psychiatric Neuroscience, Site de Cery, 1008 Prilly, Switzerland ( kim.do@ 123456chuv.ch ).
                Article
                10.1093/ijnp/pyv110
                4815475
                26433393
                3dbda900-9f74-46fb-940b-d2b780cb0201
                © The Author 2015. Published by Oxford University Press on behalf of CINP.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 12 June 2015
                : 21 September 2015
                : 24 September 2015
                Page count
                Pages: 11
                Categories
                Research Article

                Pharmacology & Pharmaceutical medicine
                schizophrenia,anterior commissure,fimbria-fornix,oxidative stress,glutathione

                Comments

                Comment on this article