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.

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.

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.