Abstract
BackgroundRecent neuroimaging studies have shown altered brain connectivity in patients with schizophrenia, associated with disturbed myelination in different fiber tracts and disruptions of white matter (WM) integrity, including prefrontal WM. We aimed to perform a qualitative and morphometric study of the ultrastructure of oligodendrocytes, myelin-forming cells, in prefrontal WM in schizophrenia and normal controls.MethodsWM of the prefrontal cortex (Brodmann’s area 10) was studied by transmission electron microscopy and morphometry. Size, volume density (Vv) and the number (N) of organelles in oligodendrocytes were estimated in 21 patients with schizophrenia and 20 normal matched controls. Pearson correlation analysis was performed to assess possible correlations between the parameters measured and age, post-mortem interval, neuroleptic treatment and duration of the disease. ANCOVA tests were used for group comparisons.ResultsQualitative study showed swelling, vacuolation, paucity of ribosomes and mitochondria and accumulation of lipofuscin granules in oligodendrocytes in schizophrenia as compared to controls. Morphometry detected lowered Vv and N of mitochondria and higher Vv and N of lipofuscin granules and vacuoles in oligodendrocytes in the schizophrenic group as compared to the control group (all p<0.01).DiscussionAltered metabolism of oligodendrocytes, previously reported reduced number of oligodendrocytes, disrupted myelin/axon integrity, damage and progressive degeneration of myelin sheaths in prefrontal WM in schizophrenia may lead to disturbances in myelination, deficiency of nerve impulses propagation and contribute to network dysfunctions in schizophrenia. Oligodendrocyte and myelin abnormalities may be a target to prevent or restore WM abnormalities and dysfunction of neuronal connectivity in schizophrenia.
Highlights
Recent neuroimaging studies have shown altered brain connectivity in patients with schizophrenia, associated with disturbed myelination in different fiber tracts and disruptions of white matter (WM) integrity, including prefrontal WM
Proteomic studies in postmortem brain by Daniel Martins-de-Souza have suggested a schizophrenia-related energy metabolism dysfunction in oligodendrocytes. These findings have been followed up using oligodendroglia cell lines and induced pluripotent stem cell-derived cerebral organoids, supporting the notion that alterations in glycolysis in oligodendrocytes are pivotal to the overall energy dysfunction in schizophrenia brains
Twenty-nine schizophrenia patients and twenty controls participated in this 3T imaging study where we used Diffusion tensor imaging (DTI) and tract-based spatial statistics (TBSS) to assess white matter integrity of the cingulum bundle and magnetic resonance spectroscopy (MRS) to quantify NAA and glutamate in the anterior cingulate cortex (ACC) and hippocampus, i.e. in cortico-limbic regions connected by the cingulum bundle
Summary
We present human post-mortem and in-vivo imaging studies on the pivotal role of oligedondrocyte loss and dysfunction with consecutive impairments of brain connectivity in schizophrenia. Natalya Uranova will show morphometric data on ultrastructural alterations of oligodendrocytes, myelin damage and degeneration and disturbed oligodendrocyte-axon interactions in post-mortem prefrontal white matter in schizophrenia. Adrienne Lahti will report diffusion tensor imaging data suggesting impaired axonal and myelin integrity. Proteomic studies in postmortem brain by Daniel Martins-de-Souza have suggested a schizophrenia-related energy metabolism dysfunction in oligodendrocytes. These findings have been followed up using oligodendroglia cell lines and induced pluripotent stem cell-derived cerebral organoids, supporting the notion that alterations in glycolysis in oligodendrocytes are pivotal to the overall energy dysfunction in schizophrenia brains. Enhancing oligodendrocyte generation and myelin repair by FDA-approved compounds, like quetiapine (an APD) or clemastine (a histamine antagonist) successfully reversed the above phenotype
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