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.
The postnatal maturation of the human prefrontal cortex is associated with substantial increase of number of oligodendrocytes. Previously, we reported decreased numerical density of oligodendrocytes in the prefrontal cortex in schizophrenia and mood disorders. To gain further understanding of the role oligodendrocytes in pathogenesis of schizophrenia and mood disorders, we examined the effect of the age on the number of oligodendrocytes in the prefrontal cortex in schizophrenia, bipolar disorder, and major depressive disorder. We revealed the age-related increase in numerical density of oligodendrocytes in layer VI and adjacent white matter of BA10 and BA 9 in normal controls but not in schizophrenia, bipolar disorder, and major depressive disorder. The absence of normal increase in the number of oligodendrocytes in gray and white matter with age in schizophrenia and mood disorders suggests that age-related process of oligodendrocyte increase is dysregulated in schizophrenia and mood disorders.
A morphometric study of the synapses on dendritic shafts and spines was performed in the rat caudate nucleus and the CAI area of the hippocampus under chronic haloperidol treatment. In the nucleus caudatus, the synaptic density on dendritic shafts increased by 83% and those on spines by 53%. Most of the parameters measured in axospinous synapses were significantly increased: the area of presynaptic axon terminals (20%), the number of mitochondria per axon terminal (51%), the length of active zone (11%), the area of postsynaptic density (23%), and the perimeter of postsynaptic density (12.5%). The area of postsynaptic spines showed no changes. In the synapses on dendritic shafts, the area of presynaptic terminals decreased (31%), the area of mitochondria per terminal decreased (40%), the length of active zone increased (14%), and other parameters were unchanged. There were no significant differences in the same parameters measured in the hippocampus. The data are discussed as morphological correlates of behavioral supersensitivity and dopamine D2 receptor up-regulation.
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.
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