Electron microscopy of oligodendroglia in severe mental illness
Introduction
The results of neuroimaging studies over the past decade have led to increased interest in brain pathology in schizophrenia and mood disorders. The prefrontal cortex and striatum are two areas of interest because disturbances in fronto-striatal connectivity have been proposed for these disorders 11, 61.
Neuroimaging and neuropathological studies have reported that schizophrenia and mood disorders may have some overlapping pathological features in the frontal lobe and striatum. Cortical gray matter volume deficits have been documented in both schizophrenia 9, 34, 36 and mood disorders [32]. Altered volume of basal ganglia structures has been reported in schizophrenia, bipolar disorder, and major depression, although medication effects may be a major confounding factor 4, 27, 52, 55. Positron emission tomography studies have revealed lower metabolic rate in the striatum [52] and in prefrontal cortex 10, 20, 62. Reduction in cerebral blood flow in the prefrontal cortex in schizophrenia 12, 62, 63 and in affective disorder 8, 25 have also been reported. Alterations in prefrontal neuronal density 5, 45, as well as alterations in density and size of glia 37, 39, 47, 46, have been reported in these disorders.
Our previous studies revealed ultrastructural alterations of astroglial cells in the caudate nucleus [59] and in myelinated fibers from the prefrontal cortex and caudate nucleus [58] in schizophrenia. These data are consistent with decreased prefrontal total white matter volume [9], lower diffusion anisotropy in white matter of the prefrontal cortex [10], and alteration of the corpus callosum in schizophrenia 7, 56.
Ultrastructural alterations of myelin sheath lamellae have been reported in the frontal cortex in schizophrenia in both biopsy [35] and autopsy material [58]. Our study demonstrated a loss of compactness of myelin sheath lamellae, abnormal inclusions between lamellae of myelin sheaths, and formation of concentric lamellar bodies (CLB) [58]. These findings may parallel the increased breakdown and decreased synthesis of membrane phospholipids in the frontal cortex in schizophrenia 15, 26, 53. The question arises, therefore, whether the changes of myelinated fibers are associated with alterations of oligodendroglial cells, the source of myelin sheaths.
Our preliminary electron microscopic study [38] demonstrated a significant increase in the number of concentric lamellar bodies (as an indicator of damage of myelin sheath lamellae) per unit tissue area in the head of the caudate nucleus in five cases of schizophrenia compared to five normal control cases. CLB were found engulfed by astrocytic processes in both neuropil and astrocyte end-feet in close apposition to capillaries. The changes were followed by ultrastructural alterations of oligodendroglial cells (a significant decrease in area of euchromatin in nuclei and a significant decrease in total area and the number of mitochondria in the cytoplasm of oligocytes). The data suggest that membrane pathology of myelinated fibers might be associated with damage of oligodendroglial cells in schizophrenia.
The aim of the present study was to test the hypothesis that brain pathology in schizophrenia is associated with pathology of oligodendroglial cells and myelinated fibers and to verify whether the pathology is region-specific and common in severe mental disorders. To this end, we performed: a qualitative study of oligodendroglial cells and myelinated fibers in the caudate nucleus and in the prefrontal cortex in postmortem brains from normal controls and from individuals with schizophrenia and bipolar disorder, and a morphometric study of oligodendroglial nuclei and organelles and of areal density of concentric lamellar bodies (as an indicator of damage of myelinated fibers) in tissue from normal controls and from individuals with schizophrenia.
Section snippets
Material and methods
Postmortem brain tissue was obtained from Moscow Psychiatric Hospitals nos. 1 and 15 and the Moscow Higher Medical School. The tissue was obtained within 6.5 hours of death from 16 subjects with schizophrenia, 6 subjects with bipolar disorder, and 16 normal controls. Consent for autopsy and research was obtained from family members. Two psychiatrists, working independently, diagnosed the cases using ICD-10 criteria for schizophrenia and bipolar disorder. Data on age at onset, duration of
Qualitative study of oligodendroglial cells in schizophrenia and bipolar disorder
Oligodendroglial cells in the control brains demonstrated well-preserved ultrastructure. These cells contained a round nucleus with electron-dense heterochromatin mostly in the periphery of the nucleus. Euchromatin was present as electron-lucent areas of the nucleus. The cytoplasm contained granular endoplasmic reticulum, free ribosomes, mitochondria, and poorly developed cisterns of Golgi apparatus (Fig. 1A). In contrast, oligodendroglial cells in the schizophrenia (SCH) and bipolar disorder
Discussion
The qualitative study demonstrated prominent ultrastructural alterations of oligodendroglial cells in SCH and BPD brains as compared to normal controls. Reactive, progressive, and regressive changes of oligodendroglial cells were revealed in both SCH and BPD. While reactive and progressive changes of oligodendroglia were also seen in control brains, the regressive changes of oligodendroglial cells that were common for SCH and BPD were rarely observed in control brains. Two types of regressive
Acknowledgements
We gratefully acknowledge a project award from the Theodore and Vada Stanley Foundation and the expert technical assistance of N. Matiatova and A. Teodorovich.
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