[Microglia-neuron interactions in the caudate nucleus in different course of schizophrenia]. / Vzaimodeistviya mikroglii i neironov v khvostatom yadre pri raznykh tipakh techeniya shizofrenii.

OBJECTIVE: To study the ultrastructure of microglia and neurons in contact with each other in the head of the caudate nucleus in continuous schizophrenia (CS) and paroxysmal-progressive schizophrenia (PPS) as compared to controls and to analyze correlations between the parameters of microglia and neurons in the control and schizophrenia groups. MATERIAL AND METHODS: Post-mortem electron microscopic morphometric study of microglia and neurons in contact with each other was performed in the head of the caudate nucleus in 9 cases of CS, 10 cases of PPS and 20 controls without mental pathology. Group comparisons were made using analysis of covariance and Pearson correlation analysis. RESULTS: The PPS group showed increased numerical density of microglia in young (≤50 years old) patients compared to elderly (>50 years old) controls and increased area of endoplasmic reticulum vacuoles in microglia in young patients compared to young controls. Decreased numerical density of microglia was found in the CS group compared to the PPS group (p<0.05), and increased volume fraction (Vv) and the number of lipofuscin granules in microglia were found in the CS group in elderly patients compared with young and elderly controls. In this group, negative correlations were revealed between the numerical density of microglia, microglia nuclear area and the duration of disease (r= -0.72, p=0.03; r= -0.8; p=0.01). Decreased Vv and the number of mitochondria in microglia and increased area and perimeter of neurons were revealed in both groups compared to the control group. In neurons, increased vacuole area was found in the PPS group and mitochondrial area in the NTS group compared to the control group. Correlation violations were found between the parameters of mitochondria in microglia and neurons in both PPS and CS groups and between the area of mitochondria in neurons and the area of vacuoles in microglia in the CS group compared to the control group. CONCLUSION: Disturbed interactions between microglia and neurons in the caudate nucleus are associated with the types of course of schizophrenia and with microglial reactivity. They might be caused by the damage of energy metabolism in microglia in both types of schizophrenia course and by stress of endoplasmic reticulum in microglia in CS.

Microglia-neuron interactions in prefrontal gray matter in schizophrenia: a postmortem ultrastructural morphometric study.

This study addressed the question of whether the interaction between neurons and satellite microglia (SatMg) is abnormal in schizophrenia. SatMg-neuron communication at direct contacts between neuronal soma is essential for neuroplasticity as SatMg can regulate neuronal activity. A postmortem ultrastructural morphometric study was performed to investigate SatMg and adjacent neurons in layer 5 of the prefrontal cortex in 21 cases of schizophrenia and 20 healthy controls. Density of SatMg was significantly higher in the young schizophrenia group and in the group with illness duration ≤ 26 years as compared to controls. We found lower volume fraction (Vv) and the number (N) of mitochondria and higher Vv and N of lipofuscin granules and vacuoles in endoplasmic reticulum in SatMg in the schizophrenia compared to the control brain. These changes progressed with age and illness duration. A significantly higher soma area and Vv of vacuoles of endoplasmic reticulum were revealed in neurons in schizophrenia as compared to controls. Negative significant correlations between N of vacuoles in neurons and N of mitochondria in SatMg were found in the control group but not in the schizophrenia group. Area of vacuole in neurons was significantly positively correlated with Vv and area of mitochondria in SatMg in the control group and negatively in the schizophrenia group. Correlation coefficients between these parameters differed significantly between the groups. These results indicate disturbed SatMg-neuron interactions in the schizophrenia brain and suggest a key role of mitochondrial abnormalities in SatMg in these disturbances.

[Specific interactions between microglia and oligodendrocytes in white matter in continuous schizophrenia]. / Osobennosti vzaimodeistviya mikroglii i oligodendrotsitov v belom veshchestve pri nepreryvnotekushchei shizofrenii.

OBJECTIVE: To study the ultrastructure of microglia adjacent to oligodendrocytes in white matter of the prefrontal cortex in continuous schizophrenia (CSch) as compared to controls and attack-like schizophrenia (ASch) and to perform correlation analysis between the parameters of microglia and adjacent oligodendrocytes previously detected in both clinical types of schizophrenia. MATERIAL AND METHODS: Electron microscopic morphometric study of microglia adjacent to oligodendrocytes was performed in postmortem white matter of the prefrontal cortex (BA10) in 9 cases of CSch, 8 cases of ASch and 20 healthy controls. Group comparisons were made by ANCOVA and Pearson correlation analyses. RESULTS: The reduction of volume fraction (Vv) and the number of mitochondria in microglia was found in elderly subjects (>50 y.o.) as compared to young controls (60%, p<0.05), and the increase in these parameters of lipofuscin granules were detected in elderly subjects as compared to elderly controls in CSch (470%, 606%, p<0.001). Vv and the number of mitochondria in microglia correlated negatively with area of heterochromatin in microglia (r≥-0.7, p<0.05), and area of lipofuscin correlated positively with area of heterochromatin in microglia (r=0.76, p<0.05) and with illness duration (r=0.7, p<0.05) only in the CSch group. The numerical density of microglia was not changed in both schizophrenia groups. Area of heterochromatin was increased in both groups as compared to controls (p<0.05) and correlated negatively with the numerical density of microglia in the CSch group. The number of mitochondria in oligodendrocytes (reduced in CSch) correlated positively with the number of mitochondria in microglia and negatively with Vv of lipofuscin granules in microglia and with area of microglial nucleus only in the CSch group. CONCLUSION: Specific features of CSch as compared to ASch might be associated with the disturbances of mitochondrial and lipid metabolism in microglia, dysfunction of nucleus and accelerated aging of microglia that might lead to alterations of mitochondrial metabolism in oligodendrocytes.

Abnormal microglial reactivity in gray matter of the prefrontal cortex in schizophrenia.

Microglial activation has been proposed to contribute to the pathogenesis of schizophrenia. The present study addressed the questions of whether microglial reactivity is involved in the course of schizophrenia and is associated with aging. Transmission electron microscopy and morphometry were applied to estimate microglial density and ultrastructural parameters in layer 5 of the prefrontal cortex (BA10) in postmortem 21 chronic schizophrenia and 20 healthy control cases. A significant increase in microglial density was found in the schizophrenia group (+20 %), in young group (≤50 y.o.), in shorter duration of disease (≤26 yrs.) group, in early age at onset of disease (≤ 21 y.o.) group as compared to controls (p < 0.05) and in young schizophrenia group as compared to both young and elderly (>50 y.o.) controls (p < 0.05). Volume fraction (Vv) of mitochondria was significantly lower and area of lipofuscin granules was significantly higher in young and elderly schizophrenia groups as compared to young and elderly controls. Vv of lipofuscin granules strongly positively correlated with age and duration of disease in the schizophrenia group. Vv and the number (N) of lipofuscin granules were higher in longer duration (>26 yrs.) group as compared to shorter duration group (p < 0.01). Vv and N of vacuoles were increased in longer duration group as compared to controls (p < 0.01). The study provides evidence for microgliosis associated with age, duration of disease and age at onset of disease, progressive dystrophy and accelerated aging of microglia in gray matter of the prefrontal cortex in schizophrenia.

[Ultrastructural pathology of oligodendrocytes in white matter in continuous attack-like schizophrenia and a role for microglia]. / Ul'trastrukturnaia patologiia oligodendrotsitov v belom veshchestve pri pristupoobrazno-progredientnoi shizofrenii i rol' mikroglii.

AIM: Previously the authors have reported the ultrastructural pathology and deficits of oligodendrocytes in gray and white matter of the prefrontal cortex in continuous paranoid schizophrenia. The aim of the present work was to study the effects of microglia on the ultrastructure of oligodendrocytes in white matter underlying the prefrontal cortex (BA10) in attack-like schizophrenia. MATERIAL AND METHODS: Postmortem morphometric electron microscopic study of oligodendrocytes in close apposition to microglia was performed in white matter underlying the prefrontal cortex (BA10). Nine cases of chronic attack-like schizophrenia and 20 normal controls were studied. Areas of oligodendrocytes, volume density (Vv) and the number of mitochondria, vacuoles of endoplasmic reticulum and lipofuscin granules were estimated. Group comparison was performed using ANCOVA. RESULTS: The schizophrenia group differed from the control group by paucity of ribosomes in cytoplasm of oligodendrocytes, cytoplasm swelling, a significant increase in Vv and number of vacuoles and lipofuscin granules. Significant correlations between the parameters of vacuoles and lipofuscin granules and mitochondria were found only in the schizophrenia group. CONCLUSION: Dystrophic alterations of oligodendrocytes apposed microglial cells were found in the white matter of the prefrontal cortex in chronic schizophrenia as compared to controls. Microglia might contribute to abnormalities of lipid and protein metabolism of oligodendrocytes.

[Ultrastructural pathology of oligodendrocytes in the white matter in continuous paranoid schizophrenia: a role for microglia]. / Ul'trastrukturnaia patologiia oligodendrotsitov v belom veshchestve pri nepreryvnotekushchei paranoidnoi shizofrenii: rol' mikroglii.

AIM: Previously the authors have reported the ultrastructural pathology and deficit of oligodendrocytes in gray and white matter of the prefrontal cortex in schizophrenia. The aim of the study was to determine of the effects of microglia on the ultrastructure of oligodendrocytes in the white matter underlying the prefrontal cortex in continuous schizophrenia. MATERIAL AND METHODS: Postmortem morphometric electron microscopic study of oligodendrocytes in close apposition to microglia was performed in white matter underlying the prefrontal cortex (BA10). Eleven cases of chronic continuous schizophrenia and 11 normal controls were studied. Areas of oligodendrocytes, of their nuclei and cytoplasm, volume density (Vv) and the number of mitochondria, vacuoles of endoplasmic reticulum and lipofuscin granules were estimated. Group comparison was performed using ANCOVA. RESULTS: The schizophrenia group differed from the control group by paucity of ribosomes in the cytoplasm of oligodendrocytes, a significant decrease in Vv and the number of mitochondria and increase in the number of lipofuscin granules. Significant correlations between the parameters of lipofuscin granules, mitochondria and vacuoles were found only in the schizophrenia group. The number of lipofuscin granules were correlated positively with the illness duration. CONCLUSION: Dystrophic alterations of oligodendrocytes attached to microglial cells were found in the white matter of the prefrontal cortex in chronic paranoid schizophrenia as compared to controls. The data obtained suggest that microglia might contribute to abnormalities of energy, lipid and protein metabolism of oligodendrocytes in schizophrenia.

[Ultrastructural changes of myelinated fibers in the brain in continuous and attack-like paranoid schizophrenia]. / Ul'trastrukturnye izmeneniya mielinovykh volokon v golovnom mozge pri nepreryvnotekushchei i pristupoobraznoi paranoidnoi shizofrenii.

AIM: Previously the authors have reported the ultrastructural pathology of myelinated fibers (MF) in the brain in schizophrenia. The aim of the present study was to compare the effect of disease course on ultrastructural changes of MF. MATERIAL AND METHODS: Postmortem electron microscopic morphometric study of MF was performed in the prefrontal cortex, caudate nucleus and hippocampus in 19 cases of paranoid schizophrenia. Fourteen cases of continuous schizophrenia, 5 cases of attack-like schizophrenia and 25 normal matched control cases were studied. The proportion (percentage) of pathological MF was estimated in the prefrontal cortex, layer 5, CA3 area of hippocampus, pyramidal layer, and in the head of the caudate nucleus. RESULTS: The percentage of MF having axonal atrophy and swelling of periaxonal oligodendrocyte process was significantly higher in both continuous and attack-like schizophrenia in all brain structures studied as compared to the control group. In the hippocampus and caudate nucleus, this parameter was increased significantly in attack-like schizophrenia as compared to continuous schizophrenia. In the prefrontal cortex. The percentage of the pathological MF having signs of deformation and destruction of myelin sheaths increased significantly only in continuous schizophrenia as compared to the control group. CONCLUSION: MF pathology is similar in attack-like and continuous paranoid schizophrenia but differ by the degree of severity of pathological MF. Abnormalities in MF contribute to the disconnectivity between the prefrontal cortex, caudate nucleus and hippocampus.

Impaired monocyte activation in schizophrenia: ultrastructural abnormalities and increased IL-1ß production.

Monocyte activation is consistently reported in patients with schizophrenia (SZ). We aimed to study the ultrastructure of monocytes and monocyte production of IL-1ß in drug-free patients with SZ and controls. Monocytes from young (18-30 y.o.) healthy and SZ men in relapse were studied. Electron microscopy and morphometry were applied to estimate areas of monocytes, volume density (Vv), areas, and number of organelles. The production IL-1ß by monocytes was estimated by the ELISA method. Group differences were examined using ANCOVA. Pearson's correlation coefficients were used to examine the effects of possible confounding variables. Correlation analyses were applied to detect the relationships between the parameters of monocytes measured and between the parameters measured and the IL-1ß production. Area of nucleolus, Vv and area of mitochondria and lysosomes, and the number of lysosomes were significantly increased in patients as compared to controls. Area of mitochondria was correlated significantly with Vv and area of lysosomes, and the number of lysosomes was significantly correlated with area of monocyte and Vv of vacuoles only in the control group. The production of IL-1ß by monocytes was higher in patients than in controls (p = 0.01) and was correlated with Vv of lysosomes (r = 0.68, p = 0.04) and area of lysosomes (r = 0.78, p = 0.013). The data provide new evidence for over activation of monocytes in SZ and disturbed metabolic relationships between lysosomes, mitochondria, and vacuoles.

Differences in Monoamine Oxidase Activity in the Brain of Wistar and August Rats with High and Low Locomotor Activity: A Cytochemical Study.

Monoamine oxidase activity was quantitatively assessed by cytochemical method in brain structures (layers III and V of the sensorimotor cortex, caudate nucleus, nucleus accumbens, hippocampal CA3 field) of rats of August line and Wistar population with high and low locomotor activity in the open fi eld test. Monoamine oxidase activity (substrate tryptamine) predominated in the nucleus accumbens of Wistar rats with high motor activity in comparison with rats with low locomotor activity. In August rats, enzyme activity (substrates tryptamine and serotonin) predominated in the hippocampus of animals with high motor activity. Comparison of August rats with low locomotor activity and Wistar rats with high motor activity (i.e. animals demonstrating maximum differences in motor function) revealed significantly higher activity of the enzyme (substrates tryptamine and serotonin) in the hippocampus of Wistar rats. The study demonstrates clear-cut morphochemical specificity of monoaminergic metabolism based on the differences in the cytochemical parameter "monoamine oxidase activity", in the studied brain structures, responsible for the formation and realization of goal-directed behavior in Wistar and August rats.

Ultrastructural alterations of oligodendrocytes in prefrontal white matter in schizophrenia: A post-mortem morphometric study.

OBJECTIVE: Neuroimaging studies showed abnormalities in frontal white matter (WM) in schizophrenia that were associated with clinical symptoms. Previously, we reported ultrastructural alterations of myelinated fibers and reduction in the numerical density of oligodendrocytes in BA 10 WM in patients with schizophrenia. We aimed to perform a qualitative and morphometric study of the ultrastructure of oligodendrocytes in BA 10 WM in schizophrenia and in normal controls. METHODS: The study was performed using electron microscopy and morphometry. Size, volume density (Vv) and the number (N) of organelles of oligodendrocytes were estimated in 21 patients with schizophrenia and 20 normal controls. The data were examined using the Kolmogorov-Smirnov test for normality. Pearson correlation analysis was performed to assess possible correlations between the parameters measured and age, post-mortem interval, neuroleptic treatment and duration of the disease. Comparisons between the schizophrenia patients and controls were performed using ANCOVA tests. RESULTS: We found oligodendrocyte swelling, vacuolation, paucity of ribosomes and mitochondria and accumulation of lipofuscin granules in schizophrenia as compared to controls. Morphometry detected a significant reduction in Vv and N of mitochondria and the increase in Vv and N of lipofuscin granules and vacuoles in oligodendrocytes in the schizophrenic group as compared to controls. CONCLUSION: Alterations of oligodendrocytes in schizophrenia provide evidence for the disturbance of their energy, lipid and protein metabolism in prefrontal WM. Oligodendrocyte abnormalities might disturb axonal integrity and circuitry and contribute to the pathophysiology of schizophrenia.

[Ultrastructural changes of lymphocytes in patients with schizophrenia treated with olanzapine]. / Ul'trastrukturnye izmeneniya limfotsitov u bol'nykh shizofreniei pri lechenii olanzapinom.

OBJECTIVE: to study the effect of olanzapine on the ultrastructure of different populations of lymphocytes and lymphoblasts in patients with schizophrenia. MATERIAL AND METHODS: Authors performed a morphometric study using electron microscopy of lymphocytes in 56 patients with schizophrenia treated for 8 weeks with olanzapine and 49 patients treated for 28 weeks with olanzapine before and after treatment. Authors estimated the frequency and ultrastructural parameters of small, large, large activated lymphocytes and lymphoblasts. RESULTS: The frequency of small lymphocytes in patients treated with olanzapine increased and that of large lymphocytes decreased in treated patients as compared to the patients before treatment. The volume fraction of lysosomes increased significantly in small, large and large activated lymphocytes after treatment as compared to the patients before treatment. CONCLUSION: The increased lysosome content in different lymphocyte subpopulations might contribute to the mechanism of olanzapine efficacy.

Brain acetylcholinesterase activity in Wistar and August rats with low and high motor activity (a cytochemical study).

Acetylcholinesterase activity was quantitatively evaluated by cytochemical method in brain structures (layers III and V of the sensorimotor cortex, caudate nucleus, nucleus accumbens, hippocampus CA3 field) of August and Wistar rats demonstrating high and low motor activity in the open field test. In August rats, acetylcholinesterase activity in the analyzed brain structures prevailed in animals with high motor activity in comparison with rats with low motor activity. In Wistar rats, the differences between the animals demonstrating high and low motor activity were less pronounced, but varied depending on the experimental series of studies. Comparisons of August rats with low motor activity and Wistar rats with high motor activity (maximum difference of motor function in these animals) revealed significant excess of acetylcholinesterase activity in layer III of the sensorimotor cortex in August rats and no differences in other brain structures of the examined animals.

[Ultrastructural changes in platelets and their relationship with serotonin metabolism in patients with schizophrenia treated with olanzapine].

An aim of the study was to investigate the effect of olanzapine treatment on platelet ultrastructure and to search for its association with serotonin metabolism in patients with schizophrenia. Platelets of 59 patients with chronic (attack-like schizophrenia) treated with olanzapine and 31 health people were explored. Based on the data on the platelet ultrastructure, authors studied the content of functionally activated vacuolated platelets (VP) and less active granular platelets (GP) as well of platelet serotonin (PS). VP content was higher in patients compared to the control group (+57%, p<0.001). After treatment for 8 and 28 weeks with olanzapine, it decreased and reached the control level (52% and 57%, respectively). There were significant negative correlations between % VP and PS before treatment (r= -0.30, p=0.02) and 8 week after treatment (r= -0.29, p<0.04) and a positive correlation between the decrease in % VP and increase in the PS levels during 8-week treatment (r=0.34, p=0.008). The association between increased platelet vacuolization and decreased PS content in schizophrenia was demonstrated for the first time. This association disappeared after treatment that led to the normalization of % VP and PS levels.

[Ultrastructural changes in platelets of schizophrenia patients: a link with serotonin metabolism and therapeutic efficacy].

OBJECTIVE: To investigate the effect of olanzapine treatment on the ultrastructure of granulated platelets (GP) and vacuolated platelets (VP) and to find their association with platelet serotonin (PS) content and treatment efficacy in patients with schizophrenia. MATERIALS AND METHODS: Platelets of 49 patients with attack-like schizophrenia treated with olanzapine and 31 healthy people were explored. Electron microscopic morphometry of GP and VP was performed to estimate the ultrastructural parameters of platelets. Microfluorimetry was used to measure PS content. RESULTS; The number of pseudopodies in GP and VP were lower after 28 weeks with olanzapine (-13%, p<0.01) as compared to the patients before treatment but the mean platelet area was not changed. Vv of granules was reduced in VP after 8 and 28 weeks of olanzapine (-13%, p<0,05). Vv of vacuoles was increased in GP in 28 weeks with olanzapine vs. 8 weeks with olanzapine (+16%, p<0.01) and in VP in 28 weeks of treatment vs.patients before treatment (+13%, p<0.01). In patients before treatment, Vv of vacuoles in VP was significantly higher in nonresponders as compared to the responders (+11%, p<0.05) and significantly correlated with PS content (r=0.26, p=0.04). The association between the number and Vv of vacuoles in VP before treatment and time point for positive treatment effect was found for the first time. CONCLUSION: Ultrastructural changes in Vv of vacuoles in platelets of schizophrenia patients treated with olanzapine are associated with serotonin metabolism and therapeutic efficacy.

[Reactivity of perineuronal astrocytes in the prefrontal cortex in schizophrenia: an ultrastructural morphometric study].

OBJECTIVE: Previously the ultrastructural alterations of astrocytes have been reported in schizophrenia. Reduced dendritic arborization of the neurons in layer 5 of the prefrontal cortex has been found in schizophrenia. Authors hypothesized that the abnormalities in perineuronal astrocytes (PA) might contribute to these neuronal changes. It was aimed to study the ultrastructure of PA in the prefrontal cortex in schizophrenia. MATERIAL AND METHODS: Postmortem electron microscopic morphometric study of PA was performed in layer 5, area 10 of the prefrontal cortex in 39 cases of schizophrenia and 37 controls. RESULTS: No significant group differences were found in areas of cell, nucleus, cytoplasm, volume fraction (Vv) of lipofuscin granules and areal density of PA. However, in the subgroup of women with schizophrenia, the areal density of PA was significantly lower and the area of PA was significantly higher as compared to the subgroup of healthy women (-52%, p<0,01; +32%, p<0.05 respectively) and to the subgroup of men with schizophrenia (-56%, p<0,01; +23%, p<0,05 respectively). The area of PA nucleus was negatively correlated with the duration of disease (r= -0.37, p=0.02) and positively with the age of disease onset (ADO) (r=0,47, p<0,01). Areas of PA and of PA nucleus were significantly lower in early ADO (<21 y.o.) as compared to the adult ADO (>21 y.o.) (-24%, p<0.05). Vv of lypofuscin granules was correlated with the age in control group (r=0.52, p=0.001), but not in schizophrenia group (r=0.13, p=0.4). CONCLUSION: Significant differences in PA reactivity in the prefrontal cortex in the schizophrenia are associated with gender and age at onset of the disease.

[Morphochemical characteristics of hippocampal neuron's response to the hypofunction of the dopaminergic system].

Differences in the response of August rats' hippocampal field СА1 and СА3 neurons to the chronic haloperidol administration (a model of parkinsonism) were revealed by interferometric methods. Based on the morphochemical parameters (nuclear and cytoplasmic area, protein content and concentration), the changes of field СА1 neurons can be regarded as functionally active (all parameters are significantly higher than in controls), and those of field СА3 neurons - as initial stages of degeneration (the significant decrease of neuron sizes). The differences in the response found in this study can be associated with the functional characteristics of СА1 and СА3 fields.

[Abnormal patterns of cortical synaptic connectivity in schizophrenia].

Electron microscopic morphometric study of postmortem prefrontal cortex (area 10) and visual cortex (area 17) was performed to estimate the numeric density (Nv) of synapses in layers I and II, neurons in layer II and the number of synapses per neuron in layer II in 20 cases of chronic schizophrenia and 16 healthy controls using stereological physical dissector method. In the prefrontal cortex the Nv of axospinous synapses was significantly lower in layer I (-20%, p < 0.05) in schizophrenia group and in the subgroup with predominantly positive symptoms as compared to controls (p < 0.05). On the contrary, a significantly higher Nv of synapses (+24%, p < 0.05) and the number of synapses per neuron were found in layer II (+42%, p < 0.05) in schizophrenia group and in the subgroups of cases with predominantly negative symptoms and a continuous course of schizophrenia (p < 0.001) as compared to the control group. The subgroup of cases with predominantly negative symptoms displayed a significantly lower number of neurons in layer II of the prefrontal cortex compared to controls (p < 0.05) and the subgroup of cases with predominantly positive symptoms (p < 0.01). In the visual cortex the number of axodendritic synapses per neuron in layer II was significantly higher in schizophrenia, but the other parameters did not differ from those in the control group. These prominent abnormalities of synaptic connectivity might be the structural basis for altered cognitive functions associated with changes in intracortical, cortico-cortical, and cortico-subcortical pathways, and could contribute to the formation of positive and negative symptoms and altered neuronal plasticity in patients with schizophrenia.