Dystrophy of Oligodendrocytes and Adjacent Microglia in Prefrontal Gray Matter in Schizophrenia

Abstract

Background: Some evidence support the notion that microglia activation in acute state of schizophrenia might contribute to damage of oligodendrocytes and myelinated fibers. Previously we found dystrophic changes of oligodendrocytes in prefrontal white matter in schizophrenia subjects displaying predominantly positive symptoms as compared to controls. The aim of the study was to verify whether microglial activation might contribute to dystrophic changes of oligodendrocytes in prefrontal gray matter in this clinical subgroup. Methods: Transmission electron microscopy and morphometry of microglia and adjacent oligodendrocytes were performed in layer 5 of the prefrontal cortex (BA10) in the schizophrenia subjects displaying predominantly positive symptoms (SPPS, n = 12), predominantly negative symptoms (SPNS, n = 9) and healthy controls (n = 20). Results: Qualitative study showed microglial activation and dystrophic alterations of microglia and oligodendrocytes adjacent to each other in both subgroups as compared to controls. A significant reduction in volume density (Vv) and the number (N) of mitochondria and an increase in N of lipofuscin granules were found in oligodendrocytes and adjacent microglia in both subgroups. Vv of lipofuscin granules, Vv and N of vacuoles of endoplasmic reticulum in microglia were increased significantly in the SPPS subgroup as compared to controls. In the SPPS subgroup Vv and N of mitochondria in microglia were correlated with N of vacuoles in microglia (r =-0.61, p < 0.05) and with Vv (r = 0.79, p < 0.01) and N (r = 0.59, p < 0.05) of mitochondria in oligodendrocytes. Vv of mitochondria in microglia was also correlated with Vv and N of vacuoles in oligodendrocytes in the SPPS subgroup (r = 0.76, p < 0.01). Area of nucleus of microglial cells was correlated negatively with age (r =-0.76, p < 0.01) and age at illness onset (r =-0.65, p < 0.05) in the SPPS subgroup. In the SPNS subgroup N of mitochondria in microglia was correlated with Vv of lipofuscin granules in oligodendrocytes (r =-0.9, p < 0.01). There were no significant correlations between these parameters in the control group. Discussion: Microglial dystrophy might contribute to oligodendrocyte dystrophy in the schizophrenia subjects with predominantly positive symptoms during relapse. Mitochondria in microglia and oligodendrocytes may be a target for treatment strategy of schizophrenia.

Caught in vicious circles: a perspective on dynamic feed-forward loops driving oxidative stress in schizophrenia

“…Interestingly, these hub regions which process large amounts of information have high metabolic requirements, are characterized by the co-expression of genes regulating oxidative metabolism, and might be particularly sensitive to OxS [161]. WM abnormalities typically result from dystrophic alterations of oligodendrocytes at the ultrastructural, genetic, epigenetic and molecular levels [162][163][164]. Similarly to PV neurons, oligodendrocytes have a high metabolism to build and maintain the myelin sheets around the axons [165] and express elevated antioxidant enzymes (catalase and GPx) to prevent lipid peroxidation [166].…”

The Inflamed Brain in Schizophrenia: The Convergence of Genetic and Environmental Risk Factors That Lead to Uncontrolled Neuroinflammation

“…These complex cells contribute to normal brain development and function by supporting the neuronal circuitry through synapse addition, elimination, maintenance, and plasticity (Hammond et al, 2018;Bohlen et al, 2019). Despite variability in the findings of several studies, there is evidence of microglial dysfunction in SCZ (Bayer et al, 1999;Hercher et al, 2014;Bloomfield et al, 2016;Trépanier et al, 2016;De Picker et al, 2017;Sellgren et al, 2019;Uranova et al, 2020). A key element to understand the pathogenesis of SCZ is to discern how genetic and environmental risk factors intersect to alter microglial function given.…”

Microglia activation in postmortem brains with schizophrenia demonstrates distinct morphological changes between brain regions

“…In cases of SCZ, Uranova et al, found that in the prefrontal white matter region, microglia activation contributed to dystrophic changes of oligodendrocytes ( 31 ). Furthermore, other studies show that in cases of SCZ, oligodendrocytes have lysed cytoplasm and form vacuoles in the surrounding tissue when they are found in close proximity to amoeboid microglia in cortical gray matter ( 54 ). These studies suggest that both cortical and WM activated microglia contribute to an inability to modulate normal brain function, which is exaggerated in cases of SCZ.…”