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.

Deficit of pericapillary oligodendrocytes in the prefrontal cortex in schizophrenia.

OBJECTIVE: Our previous studies have shown a significant decrease of numerical density of oligodendrocytes in the prefrontal cortex in postmortem schizophrenic brains. Deficit of oligodendrocytes was associated with loss of oligodendroglial satellites of pyramidal neurons. In this study we tested the hypothesis that there might be a deficit and loss of pericapillary oligodendrocytes in the prefrontal cortex in schizophrenia. METHOD: Autopsy samples from the prefrontal cortex (BA 10) were obtained from 12 normal controls and 12 chronic schizophrenic cases. Capillaries and oligodendrocytes were viewed in paraffin sections stained with a Luxol-fast blue and cresyl violet. Electron microscopy was applied to study the ultrastructure of oligodendrocytes. For morphometric analysis, an average of 100 rectilinear capillary segments from layer V was sampled for each individual. The number of oligodendrocytes visible along rectilinear segments was expressed as the number of oligodendrocytes per 0.01 mm of capillary length. RESULTS: Subjects with schizophrenia had a significantly lower (-23%; P < 0.005) number of pericapillary oligodendrocytes compared to controls. Prominent ultrastructural dystrophic and degenerative alterations of pericapillary oligodendrocytes have been revealed in schizophrenic brains. CONCLUSION: The present study provides evidence that there is a prominent reduction, damage and loss of pericapillary oligodendrocytes in the prefrontal cortex in schizophrenia. These changes may contribute to the pathophysiological basis for altered blood-brain barrier and lowered metabolic rates in subjects with schizophrenia.

Deficit of perineuronal oligodendrocytes in the prefrontal cortex in schizophrenia and mood disorders.

OBJECTIVE: A deficit of oligodendrocytes has been reported in the prefrontal cortex (PFC) in schizophrenia (SCH), bipolar disorder (BPD) and major depression (MDD). Also, a decreased size of pyramidal neurons has been detected in layer III in SCH and in mood disorders. Since oligodendrocytes have a trophic influence on neurons, reduced neuronal size reported in these disorders might be associated with the deficit in subpopulation of perineuronal oligodendrocytes. We hypothesized that deficit of perineuronal oligodendrocytes might occur in SCH and mood disorders. METHOD: We estimated the number of oligodendroglial satellites of pyramidal neurons and the size of pyramidal neurons in layer III (Brodmann's area 9) in Nissl stained sections in SCH, BPD, MDD and normal controls. The Stanley Foundation Neuropathology Consortium brain collection consisted of 15 cases in each of four groups was used. RESULTS: We detected a prominent and significant reduction in the number of perineuronal oligodendrocytes in the sublayers IIIa, IIIb and IIIc in SCH, BPD and MDD as compared to controls. The BPD group differed significantly from SCH group and from MDD group. There were no significant differences in somal sizes of pyramidal neurons in the sublayers IIIa, IIIb, IIIc between each of the psychiatric groups and the control group. Only BPD group showed significantly smaller neuronal size in sublayer IIIc as compared to controls. CONCLUSIONS: Our data provide evidence for a deficit of perineuronal oligodendrocytes in severe mental disorders that may play a key role in the pathophysiology of SCH, BPD and MDD.

Decreased numerical density of CA3 hippocampal mossy fiber synapses in schizophrenia.

The CA3 region of the hippocampus is unique in its connectivity, its role in cognitive maintenance, and its great vulnerability in schizophrenia. The down regulation of the expression and binding activity of glutamate receptors was revealed in the CA3 hippocampal region and may be attributed to cognitive disturbances in schizophrenia. Our previous study demonstrated that only schizophrenics with predominantly positive (but not predominantly negative) symptoms had smaller-sized branched spines (thorny excrescences) of CA3 pyramidal neurons and fewer synaptic contacts formed by dentate mossy fiber terminals (MFT-synapses). In the present study, we used an unbiased stereological physical dissector method to verify whether the numerical density of MFT-synapses is altered in schizophrenia. A morphometric study was performed in 10 normal controls and eight age-matched cases with chronic schizophrenia, including five cases with predominantly positive and three with predominantly negative symptoms. Schizophrenic cases had a significantly reduced numerical density of MFT-synapses (-25%, P < 0.01) compared with the control group. The decrease was similar in schizophrenic subgroups with predominantly positive and predominantly negative symptoms. No effects of postmortem delay, age, duration of disease, and neuroleptic exposure were found. Taken together with our previous results, the data suggest that the decrease of numerical density of MFT-synapses may be the result of different mechanisms in schizophrenics with predominantly positive and predominantly negative symptoms.

The ultrastructure of lymphocytes in schizophrenia.

OBJECTIVE: Replicated abnormalities in schizophrenia include decreased cellular immunity. The aim of the study was to verify whether there are some abnormalities in the ultrastructure of lymphocytes in drug-free schizophrenic patients. METHOD: Fifty-nine in-patients with paranoid schizophrenia (DSM-IV 295.30) and 31 normal controls were used. Psychosis severity was assessed by the PANSS psychotic cluster. Electron microscopy and morphometric methods were applied to estimate the frequency and ultrastructural parameters of small, large, large activated lymphocytes (LAL) (containing 10 and more mitochondria) and of atypical lymphocytes (lymphoblasts, LB). RESULTS: The frequency of small lymphocytes in schizophrenic patients was lower and that of large lymphocytes, LAL and LB was higher than in controls (all p= < 0.01). The volume density (Vv) of mitochondria in LAL in individuals with schizophrenia was lower than in controls (p<0.05), correlated negatively with the frequency of LB, Vv and number of lysosomes in LB (all p<0.01) and with the psychosis severity (p<0.05). In schizophrenic patients a trend towards positive correlations between the frequency of LB and psychosis severity were found (p<0.07). CONCLUSION: The data suggest that the excess of LB in schizophrenic patients is associated with the dysfunction of energy metabolism in LAL, and these abnormalities are related to 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.

Ultrastructural alterations in hippocampal mossy fiber synapses in schizophrenia: a postmortem morphometric study.

Synapses formed between mossy fibers, the axons of hippocampal dentate granular cells, and the dendrites of CA3 pyramidal neurons are important links within the trisynaptic circuitry. Abnormalities in this circuitry are associated with the failure of schizophrenics to integrate affective experience with higher cognitive function, and with disturbances in memory and spatial learning processes. The abnormalities include reduced size and altered dendritic arborization of CA3 pyramidal neurons. In addition, decreased expression and binding activity of glutamate receptors have been reported, predominantly in the CA3 region of the hippocampus. These findings suggest that there are disturbed neuronal processes and connections in the hippocampus of schizophrenics. An electron microscope morphometric study of synaptic contacts between mossy fiber axon terminals (MFT) and branched dendritic spines of pyramidal neurons in stratum lucidum of the CA3 region of the hippocampus was performed in 10 normal controls and 9 age-matched chronic schizophrenics (postmortem delay 3-9 h). Schizophrenic cases with predominantly positive symptoms had a significantly reduced volume fraction of spines (-35%, P < 0.05), total number of invaginated spines (-47%, P < 0.01), and number of spines forming synapses (-32%, P < 0.05) per MFT compared with the control group. No effects of postmortem delay, age, duration of disease, or neuroleptic exposure were found. These data may reflect decreased efficacy of mossy fiber synapses in the CA3 hippocampal region in schizophrenics with predominantly positive symptoms. These data are in line with the neurodevelopmental hypothesis of schizophrenia.

Pathology of layer V pyramidal neurons in the prefrontal cortex of patients with schizophrenia.

OBJECTIVE: Morphological indications of abnormal circuitry have been detected in the prefrontal neuropil of patients with schizophrenia. The authors tested the hypothesis that schizophrenia is associated with smaller dendritic field size in layer V pyramidal neurons in the prefrontal cortex. METHOD: Tissue from area 10 with a mean postmortem interval of 5.7 hours was obtained from 15 subjects with chronic schizophrenia and 18 normal comparison subjects. After Golgi impregnation, basilar dendritic field size was estimated for layer V pyramidal neurons by ring intersection analysis. RESULTS: The schizophrenia subjects had 40% fewer total ring intersections per neuron than comparison subjects. Smaller basilar dendritic field size was evident in proximal and distal branches. CONCLUSIONS: These results indicate that abnormal dendritic outgrowth or maintenance contributes to reduced neuropil and prefrontal connectivity in schizophrenia. Short postmortem intervals and resulting high tissue quality suggest that these dystrophic changes reflect schizophrenia pathology rather than postmortem artifact.

Oligodendroglial density in the prefrontal cortex in schizophrenia and mood disorders: a study from the Stanley Neuropathology Consortium.

Our previous electron microscopic study of the prefrontal cortex (PFC) demonstrated ultrastructural signs of apoptosis and necrosis of oligodendroglial cells in schizophrenia (SCH) and bipolar disorder (BPD). Using optical dissector methodology, we have now conducted a morphometric study of numerical density (Nv) of oligodendroglial cells in layer VI and in adjacent white matter of Brodmann area 9 (BA 9) of the Stanley Foundation Neuropathology Consortium (SFNC). The SFNC consists of 15 cases in each of four groups: schizophrenia, bipolar disorder, major depression (MDD) and unaffected controls. A significant reduction in Nv of oligodendroglial cells was found in layer VI of subjects with schizophrenia (-25%), bipolar disorder (-29%) and major depression (-19%) as compared to controls. In adjacent white matter, there were no significant differences between groups. The data suggest that lowered density of oligodendroglial cells that occurs in schizophrenia and mood disorders could contribute to the atrophy of neurones that has been described in the prefrontal cortex of subjects with severe mental illness.