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

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.

Ultrastructural pathology of oligodendrocytes adjacent to microglia in prefrontal white matter in schizophrenia.

Microglial activation has been proposed to be involved in the pathophysiology of schizophrenia (SCZ). We hypothesized that dystrophic alterations of oligodendrocytes previously reported in the prefrontal white matter in SCZ might be associated with microglial activation in the acute state of SCZ. White matter of the prefrontal cortex (BA10) was studied in post-mortem brain tissue from 21 SCZ cases and 20 normal controls. The SCZ group included 12 subjects with predominantly positive symptoms and 9 subjects with predominantly negative symptoms. Electron microscopy was applied to estimate cell density, size, volume fraction (Vv) and the number (N) of organelles in oligodendrocytes adjacent to microglia and in oligodendrocytes adjacent to myelin, neurons and capillaries and not adjacent to microglia. Cell density of oligodendrocytes was not changed in the SCZ group as compared to controls. Vv and N of mitochondria were significantly decreased, while Vv of vacuoles of endoplasmic reticulum and lipofuscin granules were significantly increased in oligodendrocytes adjacent to either microglia or myelin in the SCZ group and in patients displaying predominantly positive symptoms as compared to the control group. There were no significant differences between oligodendrocytes adjacent to microglia and to myelin. Vv and N of lipofuscin were also increased in peri-capillary oligodendrocytes. There was no effect of clinical subgroups on the parameters of peri-capillary and peri-neuronal oligodendrocytes. Though many ameboid and dystrophic microglia adjacent to oligodendrocytes were found in the SCZ samples, we provide no quantitative evidence that oligodendrocyte dystrophy is associated with microglial activation in white matter in SCZ.

Ultrastructural alterations of myelinated fibers and oligodendrocytes in the prefrontal cortex in schizophrenia: a postmortem morphometric study.

Schizophrenia is believed to result from altered neuronal connectivity and impaired myelination. However, there are few direct evidence for myelin abnormalities in schizophrenia. We performed electron microscopic study of myelinated fibers and oligodendrocytes and morphometric study of myelinated fibers in the prefrontal cortex in gray and white matters in schizophrenia and normal controls. Six types of abnormal fibers and ultrastructural alterations of oligodendrocytes were found in schizophrenia. No significant group differences in area density of myelinated fibers were found. Frequency of pathological fibers was increased significantly in gray matter in young and elderly schizophrenia patients and in patients with predominantly positive symptoms. In contrast, in white matter, frequency of altered fibers was increased significantly in elderly patients, in patients with predominantly negative symptoms, and correlated with illness duration. Progressive alterations of myelinated fibers in white matter might be followed by alterations of myelinated fibers in gray matter in schizophrenia.

Ultrastructural damage of capillaries in the neocortex in schizophrenia.

OBJECTIVES: Neuroimaging studies showed lowered blood flow, glucose metabolic rates and hypoactivation of the prefrontal cortex (PFC) in patients with schizophrenia. The aim of the study was to clear up whether there are abnormalities in the microvasculature in the neocortex in schizophrenia. METHODS: Capillaries were studied in PFC (BA 10) and visual cortex (VC) (BA 17) by electron microscopy and morphometry in 26 schizophrenia cases and 26 normal controls. Capillary diameter and areas of capillaries and of pericapillary astrocytic end-feet were estimated in layers I-II of the prefrontal and visual cortices. RESULTS: Ultrastructural abnormalities of capillaries in schizophrenia included thickening, deformation of basal lamina, vacuolation of cytoplasm of endothelial cells, basal lamina and astrocytic end-feet, swelling of astrocytic end-feet, of pericapillary oligodendrocytes and signs of activation of microglial cells in both PFC and VC. Capillary diameter and area did not differ significantly between the groups. Area of astrocytic end-feet was significantly higher in PFC (+49%, P<0.001) and in VC (+29%, P<0.01) in schizophrenic group and in different clinical subgroups as compared to controls. CONCLUSIONS: Ultrastructural abnormalities of capillaries and of pericapillary cellular environment found suggest that blood-brain barrier dysfunction might contribute to the pathogenesis of cortical lesions in schizophrenia.

The role of oligodendrocyte pathology in schizophrenia.

Neuroimaging and microarray studies provide evidence for myelin and oligodendrocyte abnormalities in schizophrenia (SZ). Electron microscopy demonstrated dystrophy, necrosis and apoptosis of oligodendrocytes, the most severely affected cells in SZ. The proportion of myelinated fibres with atrophy of axon and swelling of periaxonal oligodendrocyte processes increased significantly in the prefrontal cortex (PFC), caudate nucleus and hippocampus in SZ compared to controls. Morphometry showed a deficit of oligodendrocytes in the PFC and in adjacent white matter, lower number of oligodendroglial satellites of pyramidal neurons and a loss of pericapillar oligodendrocytes in the PFC in SZ compared to normal controls. A lowered number of oligodendrocytes in the PFC was also found in mood disorders. These data provide evidence for altered oligodendrocyte-axon, oligodendrocyte-neuron and oligodendrocyte-capillar interactions in SZ brains suggesting a key role of damage and loss of oligodendrocytes in altered neuronal connectivity and in atrophy of neurons in SZ.