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Recent investigations of postmortem brain from schizophrenic patients have revealed reduced numbers of neurons in several different corticolimbic brain regions. In the prefrontal and anterior cingulate cortices, more specific decreases in the numbers of interneurons, but not pyramidal cells, have been reported to occur preferentially in layer II. Based on this latter finding, a loss of inhibitory basket cells leading to a compensatory upregulation of the GABAA receptor has been hypothesized to occur in schizophrenic patients and to be a contributory factor in the pathophysiology of this disorder. We now report the results of a high-resolution quantitation of GABAA receptor binding in anterior cingulate cortex of postmortem specimens from normal and schizophrenic cases. The results indicate a preferential increase in bicuculline-sensitive 3H-muscimol binding on neuronal cell bodies of layers II and III, but not layers V and VI, of the schizophrenic cases. There was no difference in the size of neurons in any of the layers examined when the control and schizophrenic groups were compared. The neuropil of layer I also showed significantly greater GABAA binding in schizophrenics. The differences seen in the schizophrenic group did not appear to be the result of exposure to antipsychotic medication because one patient who was medication naive and a second who had received minimal exposure to antipsychotic drugs also showed elevated GABAA receptor binding. Since information processing depends on corticocortical integration in outer layers I-III, a disturbance of inhibitory activity in these superficial layers of limbic cortex may contribute to the defective associative function seen in schizophrenia.

The relative distribution and cellular localization of the dopamine D1 and D2 receptor subtypes were assessed in frozen sections of rat medial prefrontal cortex (mPFC). The D1 and D2 receptor binding sites were labeled with the selective high-affinity antagonists SCH 23390 and N-(p-aminophenethyl)-spiperone (NAPS), respectively, coupled to either Bodipy or Texas red fluorophores. Under the incubation conditions employed, kinetic, competition, and selectivity studies showed that these modified ligands retained pharmacological selectivity. Optimal binding fluorescence was at 100 nM of each ligand, and fluorescence increased linearly from 1 to 15 min of incubation at 2 degrees C. NAPS-Texas red binding fluorescence was inhibited with 10 nM quinpirole (D2 agonist), but not 10 nM SKF 38393 (D1 agonist), while SCH 23390-Texas red binding was inhibited with SKF 38393, but not quinpirole. The localization of dopamine receptor binding was assessed in montages constructed from low-magnification photomicrographs through the depth of the cortex, or in corresponding high-magnification photomicrographs. Cells showing D1- or D2-like receptor binding fluorescence were present in layers II-VI, with the highest density observed in layers V and VI. The addition of mianserin (100 nM, 5-HT2 antagonist) to incubated sections slightly reduced the numbers of labeled cells in each cortical layer, but retained the preferential localization to the deeper layers. Two separate observations supported the idea that the fluorescently coupled ligands were localized to neuronal cell bodies. First, receptor labeling with the fluorescently coupled ligands co-localized almost exclusively to cells in the cortical mantle showing neuron-specific enolase immunoreactivity. Second, a comparison of the cell size distribution taken from adjacent Nissl-stained sections with the size of cells showing D1- or D2-like receptor binding fluorescence revealed complete overlapping of fluorescence with neuronal cell bodies. In mPFC layer VI, the size of cells showing D1-like receptor binding fluorescence was 77.8 +/- 5.1 microns2, similar to non-pyramidal neurons, while that for D2-like receptor binding fluorescence was 108.2 +/- 4.5 microns2, consistent with both large interneurons and small pyramidal cells. Only a small percentage of cells showing D1- or D2-like receptor binding overlapped in size with glia, but this occurred almost exclusively within the white matter region below the cortical mantle. These findings are consistent with the hypothesis that the D1 and D2 receptor subtypes are found on different populations of neurons, although some overlap probably occurs.(ABSTRACT TRUNCATED AT 400 WORDS)

An electron microscopic analysis has been carried out to compare the neuroglial cells and pericytes within the primary visual cortex, area 17, of young (5-6 years) and old (25-35 years) rhesus monkeys. All of the neuroglial cell types accumulate inclusions within their cytoplasm as they age, and the inclusions within the astrocytes and oligodendrocytes are essentially characteristic of those cell types. The astrocytes probably acquire their inclusions by phagocytosis, and it is suggested that the inclusions in the oligodendrocytes are caused by an age-related degeneration of the myelin sheaths they produce. The inclusions within the microglia are very heterogeneous. They are more massive than in the other neuroglial cells, so that their inclusions may almost fill the microglia. Pericytes also accumulate inclusions with age and there is evidence to suggest that they empty the contents of their inclusions vacuoles directly into the capillaries. On the basis of counts of the numbers of profiles of neuroglial cells displaying nuclei in thin sections, the only cells to increase in number with age are the microglia. They show an increase of about 44% when the cortices of young and old monkeys are compared.

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