Reduced number of satellite oligodendrocytes of pyramidal neurons in layer 5 of the prefrontal cortex in schizophrenia.

Neuroimaging, genetic and molecular biological studies have shown impaired intra-cortical myelination in patients with schizophrenia, particularly in the prefrontal cortex. Previously we reported a significant deficit of oligodendrocytes and oligodendrocyte clusters in layers 3 and 5 of the prefrontal cortex, Brodmann area 10 (BA10) in schizophrenia. In this current study, we investigate the number of oligodendrocyte satellites (Sat-Ol) per pyramidal neuron in layer 5 of BA10 in schizophrenia (n = 17) as compared to healthy controls (n = 20) in the same section collection as previously used to study the numerical density (Nv) of oligodendrocytes and oligodendrocyte clusters. We find a significant reduction (- 39%, p < 0.001) in the number of Sat-Ol per neuron in schizophrenia as compared to the control group. The number of Sat-Ol per neuron did not correlate with the Nv of oligodendrocytes or with the Nv of oligodendrocyte clusters. Our previous studies of the inferior parietal lobule (BA39 and BA40), demonstrated significant decrease of the number of Sat-Ol only in patient subgroups with poor and fair insight. Additionally, correlation pattern between number of Sat-Ol and Nv of oligodendrocytes and oligodendrocyte clusters was similar between the two functionally interconnected cortical areas, BA10 and BA40, whereas in BA39, strong significant correlations were revealed between the number of Sat-Ol and Nv of oligodendrocyte clusters (0.9 ≤ R ≥ 0.66; p < 0.001). These data suggest that that specific features of Sat-Ol alterations patterns may be associated with specific activity-driven plasticity of corresponding networks in the brain of people with schizophrenia.

Numerical density of oligodendrocytes and oligodendrocyte clusters in the anterior putamen in major psychiatric disorders.

There is increasing evidence to support the notion that oligodendrocyte and myelin abnormalities may contribute to the functional dysconnectivity found in the major psychiatric disorders. The putamen, which is an important hub in the cortico-striato-thalamo-cortical loop, has been implicated in a broad spectrum of psychiatric illnesses and is a central target of their treatments. Previously we reported a reduction in the numerical density of oligodendrocytes and oligodendrocyte clusters in the prefrontal and parietal cortex in schizophrenia. Oligodendrocyte clusters contain oligodendrocyte progenitors and are involved in functionally dependent myelination. We measured the numerical density (Nv) of oligodendrocytes and oligodendrocyte clusters in the putamen in schizophrenia, bipolar disorder (BPD) and major depressive disorder (MDD) as compared to healthy controls (15 cases per group). Optical disector was used to estimate the Nv of oligodendrocytes and oligodendrocyte clusters. A significant reduction in both the Nv of oligodendrocytes (- 34%; p < 0.01) and the Nv of oligodendrocyte clusters (- 41%; p < 0.05) was found in the schizophrenia group as compared to the control group. Sexual dimorphism for both measurements was found only within the control group. The Nv of oligodendrocytes was significantly lower in male schizophrenia cases as compared to the male control cases. However, the Nv of oligodendrocyte clusters was significantly lower in all male clinical cases as compared to the male control group. The data suggest that lowered density of oligodendrocytes and oligodendrocyte clusters may contribute to the altered functional connectivity in the putamen in subjects with schizophrenia.

Reduced oligodendrocyte density in layer 5 of the prefrontal cortex in schizophrenia.

Neuroimaging and post-mortem studies have implicated altered myelin integrity and oligodendrocyte abnormalities in the dysfunction of neuronal network in schizophrenia, including the prefrontal cortex, Brodmann area (BA) 10. Pyramidal neurons in layer 5 of BA10 are the important link of reciprocal frontal cortical-basal ganglia-thalamic circuits altered in schizophrenia. Previously, we found ultrastructural dystrophic and degenerative alterations of oligodendrocytes in layer 5 of BA10 in schizophrenia. The aim of the study was to estimate the numerical density (Nv) of oligodendrocytes in layer 5 of BA10 in schizophrenia as compared to normal controls. 17 chronic schizophrenia subjects and 22 healthy matched controls were studied in Nissl-stained sections using optical disector method. Group differences were analyzed using ANCOVA followed by post hoc Duncan's test. The Nv of oligodendrocytes was significantly lower (- 32%, p < 0.001) in the schizophrenia group as compared to the control group. Young controls (age < 50 years old) showed significantly higher Nv of oligodendrocytes as compared to elderly controls (age > 50 years old). Young and elderly schizophrenia subgroups did not differ significantly. Both control subgroups have significantly higher Nv of oligodendrocytes as compared to the schizophrenia subgroups. Decreased Nv of oligodendrocytes found in layer 5 of BA10 may be the result of dystrophic and destructive alterations and/or disrupted development of oligodendrocytes in schizophrenia.

Oligodendrocyte abnormalities in layer 5 inthe inferior parietal lobule are associated with lackof insight in schizophrenia: A postmorte mmorphometric study

Background and Objectives: Previously we reported in layer 3 of the inferior parietal lobule a reduction in the numerical density of oligodendrocytes (Nv Ol), oligodendrocyte clusters (Nv OlC) in BA 39, and in the number of perineuronal oligodendrocytes(N PnOl) in BA 39/40 areas in schizophrenia. These changes were associatedwith lack of insight. We hypothesized that similar abnormalities might occur in layer 5 inBA 39/40, and they might be associated with lack of insight. Methods: We estimated the Nv Ol, the Nv OlC by optical disector method and the NPnOl in layer 5 in BA 39/40 in Nissl stained sections from 24 males with schizophrenia and 24 normal male controls from the Stanley Parietal Collection. The schizophrenia group was divided into three subgroups based on level of insight: poor, fair or good. Results: We found a significant deficit in the parameters measured in BA 39 in the schizophrenia group and in the subgroup of subjects having poor insight as compared to the control group. In BA 40 the Nv Ol and the Nv OlC were significantly lower in the schizophrenia group compared to controls, and the N PnOl was not changed. Each insight subgroup showed a decreased the Nv Ol and the Nv OlC compared to controls. There were no subgroup differences in BA 39/40. Conclusions: Schizophrenia is characterized by the reduction in the Nv Ol and the NvOlC in layer 5 of BA 39/40. Oligodendrocyte abnormalities in BA 39 are associated with poor insight in schizophrenia (AU)

Deficit of perineuronal oligodendrocytes in the inferior parietal lobule is associated with lack of insight in schizophrenia

Background and Objectives: Previously we reported a significant reduction in the numerical density of oligodendrocytes and oligodendrocyte clusters in the inferior parietal lobule (IPL) in schizophrenia that was associated with lack of insight. We also found a significant decrease in the number of perineuronal oligodendrocytes (PnOl) in the prefrontal cortex in schizophrenia and therefore we hypothesized that there may also be a deficit of PnOl in the IPL in schizophrenia and that it could be associated with poor insight. Methods: We estimated the number of PnOl adjacent to pyramidal neurons in layer 3 of BA39 and BA40 in Nissl stained sections from 24 males with schizophrenia and 24 normal male controls from the Stanley Parietal Collection. The schizophrenia group was divided into three subgroups based on level of insight: poor, fair or good.Results: We found a significant deficit of PnOl in layer 3 of BA39 and BA40 in the schizophrenia group as compared to the control group (p<0.01). In the control group but not in the schizophrenia group in BA39 the number of PnOl was significantly higher in the left hemisphere compared to the right hemisphere. In schizophrenia, in BA39 the number of PnOl was decreased in the subgroup with poor insight vs. controls. In BA40 the subgroups with both poor and fair insight were decreased vs. controls (p<0.01). In BA40 the subjects with fair insight also differed from those with good insight (p<0.01). Conclusions: The reduction of PnOl in the IPL in schizophrenia is associated with impaired insight and lack of hemispheric asymmetry (AU)

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Abnormalities in oligodendrocyte clusters inthe inferior parietal cortex in schizophreniaare associated with insight

Background and Objectives: Deficits in oligodendrocytes have been consistentlyreported in the brains of patients with schizophrenia and include alterations in theclustering pattern of oligodendrocytes. Recently it has been shown that oligodendrocyteprogenitors proliferate in the adult mammalian brain to form oligodendrocyte clusters(OlC). We previously found a deficit of oligodendrocytes in layer 3 of the inferior parietallobule (IPL) in subjects with schizophrenia with poor insight into disorder. We hypothesizedthat the number of OlC might be reduced in schizophrenia subjects with poor insight.Methods: Nissl-stained sections from the Stanley “Parietal Collection” from maleschizophrenia subjects (n = 24) that have poor, fair, or good insight into their disorder andnormal matched controls (n = 24) were studied. The numerical density (Nv) of OlC wasestimated in layer 3 of BA 39 and BA 40 by optical disector method.Results: The Nv of OlC was 23% lower in BA 39 and 30% lower in BA40 in the schizophreniagroup compared to the control group (p<0.01). Normal hemispheric differences inthe Nv of OlC in BA 39 were absent in the schizophrenia group. The Nv of OlC was significantlydecreased in BA39 in the subgroup with poor insight and in BA40 in the subgroupswith fair and good insight as compared to controls. In BA40 lower Nv of OlC (-40%,p<0.01) was found in the subgroup with adolescent onset of disease as compared to controls.Conclusions: The deficit of OlC may be associated with altered proliferation and/ormaturation of oligodendrocyte progenitors in schizophrenia (AU)

Reduced oligodendroglial density in the inferiorparietal lobule and lack of insight in schizophrenia

Background and Objectives: Alterations and deficits of oligodendrocytesreported in the grey and white matter in schizophrenia may contribute to neuronal disconnectivity. Prefrontal-parietal functional disconnections have been implicated in diverseclinical symptoms of schizophrenia, including poor insight. We studied the effects ofschizophrenia diagnosis and insight on numerical density (Nv) of oligodendrocytes in the inferior parietal lobule (IPL).Methods: Nissl-stained sections from the Stanley “Parietal Collection” from male schizophrenia subjects (n = 24) having poor, fair, or good insight and healthy matched controls(n = 24) were examined. The Nv of oligodendrocytes was estimated in layer 3 of BA 39 and BA 40 of the IPL and in white matter underlying layer 6 by optical dissector method. Results: In BA 39 we found a significant 15% decrease in the Nv of oligodendrocytesin layer 3 in the schizophrenia group. Nv of oligodendrocytes in the poor+fair insight subgroup was 20% lower compared to controls (p< 0.05) and to good insight subgroup (p =0.055). Nv of oligodendrocytes in the good insight subgroup did not differ from the control group. A significant lateralization of oligodendrocyte density was detected in layer 3(L>R) only in the control group. There were no significant group differences in the Nv ofoligodendrocytes in BA 40 or in the white matter underlying BA 39/40 areas. Conclusions: Lack of insight in schizophrenia may be associated with a deficit ofoligodendroglia in the grey matter of IPL (AU)

Ultrastructural abnormalities of astrocytes in the hippocampus in schizophrenia and duration of illness: a postortem morphometric study.

There is a lot of evidence of astrocytic dysfunction in schizophrenia. We performed an electron microscopic morphometric study of astrocytes in the CA3 hippocampal region in 19 cases of schizophrenia and 16 normal controls. No significant group differences were found in cell size, volume fraction (Vv) and area density (Na) of mitochondria and lipofuscin granules. Young control subjects (<50 years old) had significantly lower area of cell, nucleus and cytoplasm and higher Vv and Na of mitochondria than old controls (>50 years old), and young and old schizophrenic cases. No significant differences between young and old schizophrenic subgroups were found. Vv and Na of mitochondria correlated negatively (r=-0.66, r=-0.72, P<0.01) and Vv of lipofuscin granules correlated positively (r=0.72, P=0.001) with duration of illness. These parameters did not correlate with age in controls and in schizophrenic subjects. Both Vv and Na of mitochondria were significantly lower in the subgroup of cases with duration of disease of>21 years. than in the control group and in the subgroup of cases with duration of illness of<21 years (P<0.01). The data suggest progressive disturbances of astrocyte function due to the deficit of mitochondria in schizophrenia.

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 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.