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Extracellular matrix-glial abnormalities in the amygdala and entorhinal cortex of subjects diagnosed with schizophrenia.

ABSTRACT: Chondroitin sulfate proteoglycans (CSPGs), a main component of the brain extracellular matrix, regulate developmental and adult neural functions that are highly relevant to the pathogenesis of schizophrenia. Such functions, together with marked expression of CSPGs in astrocytes within the normal human amygdala and evidence of a disruption of astrocytic functions in this disease, point to involvement of CSPG-glial interactions in schizophrenia.Chondroitin sulfate proteoglycan-related abnormalities involve glial cells and extracellular matrix pericellular aggregates (perineuronal nets) in the amygdala and entorhinal cortex of subjects with schizophrenia.Postmortem case-control study.The Translational Neuroscience Laboratory at McLean Hospital, Harvard Medical School. Specimens were obtained from the Harvard Brain Tissue Resource Center at McLean Hospital.Two separate cohorts of healthy control (n = 15; n = 10) and schizophrenic (n = 11; n = 10) subjects and a cohort of subjects with bipolar disorder (n = 11).Quantitative, immunocytological, and histological postmortem investigations.Numerical densities of CSPG-positive glial cells and perineuronal nets, glial fibrillary acidic protein-positive astrocytes, and total numbers of parvalbumin-positive neurons in the deep amygdala nuclei and entorhinal cortex.In schizophrenia, massive increases in CSPG-positive glial cells were detected in the deep amygdala nuclei (419%-1162%) and entorhinal cortex (layer II; 480%-1560%). Perineuronal nets were reduced in the lateral nucleus of the amygdala and lateral entorhinal cortex (layer II). Numerical densities of glial fibrillary acidic protein-positive glial cells and total numbers of parvalbumin-positive neurons were unaltered. Changes in CSPG-positive elements were negligible in subjects with bipolar disorder.Marked changes in functionally relevant molecules in schizophrenia point to a pivotal role for extracellular matrix-glial interactions in the pathogenesis of this disease. Disruption of these interactions, unsuspected thus far, may represent a unifying factor contributing to disturbances of neuronal migration, synaptic connectivity, and GABAergic, glutamatergic, and dopaminergic neurotransmission in schizophrenia. The lack of CSPG abnormalities in bipolar disorder points to a distinctive aspect of the pathophysiology of schizophrenia in key medial temporal lobe regions.

SUBMITTER: Pantazopoulos H

PROVIDER: S-EPMC4208310 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Extracellular matrix-glial abnormalities in the amygdala and entorhinal cortex of subjects diagnosed with schizophrenia.

Pantazopoulos Harry H Woo Tsung-Ung W TU Lim Maribel P MP Lange Nicholas N Berretta Sabina S

Archives of general psychiatry 20100201 2

<h4>Context</h4>Chondroitin sulfate proteoglycans (CSPGs), a main component of the brain extracellular matrix, regulate developmental and adult neural functions that are highly relevant to the pathogenesis of schizophrenia. Such functions, together with marked expression of CSPGs in astrocytes within the normal human amygdala and evidence of a disruption of astrocytic functions in this disease, point to involvement of CSPG-glial interactions in schizophrenia.<h4>Hypothesis</h4>Chondroitin sulfat ...[more]

PMID: 20124115

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Project description:Emerging evidence points to proteoglycan abnormalities in the pathophysiology of schizophrenia (SZ). In particular, markedly abnormal expression of chondroitin sulfate proteoglycans (CSPGs), key components of the extracellular matrix, was observed in the medial temporal lobe. CSPG functions, including regulation of neuronal differentiation and migration, are highly relevant to the pathophysiology of SZ. CSPGs may exert similar functions in the olfactory epithelium (OE), a continuously regenerating neural tissue that shows cell and molecular abnormalities in SZ. We tested the hypothesis that CSPG expression in OE may be altered in SZ. CSPG-positive cells in postmortem OE from non-psychiatric control (n=9) and SZ (n=10) subjects were counted using computer-assisted light microscopy. 'Cytoplasmic' CSPG (c-CSPG) labeling was detected in sustentacular cells and some olfactory receptor neurons (c-CSPG+ORNs), while 'pericellular' CSPG (p-CSPG) labeling was found in basal cells and some ORNs (p-CSPG+ORNs). Dual labeling for CSPG and markers for mature and immature ORNs suggests that c-CSPG+ORNs correspond to mature ORNs, and p-CSPG+ORNs to immature ORNs. Previous studies in the same cohort demonstrated that densities of mature ORNs were unaltered (Arnold et al., 2001). In the present study, numerical densities of c-CSPG+ORNs were significantly decreased in SZ (p<0.025; 99.32% decrease), suggesting a reduction of CSPG expression in mature ORNs. Previous studies showed a striking increase in the ratios of immature neurons with respect to basal cells. In this study, we find that the ratio of p-CSPG+ORNs/CSPG+basal cells was significantly increased (p=0.03) in SZ, while numerical density changes of p-CSPG+ORNs (110.71% increase) or CSPG+basal cells (53.71% decrease), did not reach statistical significance. Together, these results indicate that CSPG abnormalities are present in the OE of SZ and specifically point to a reduction of CSPG expression in mature ORNs in SZ. Given the role CSPGs play in OE cell differentiation and axon guidance, we suggest that altered CSPG expression may contribute to ORN lineage dysregulation, and olfactory identification abnormalities, observed in SZ.

Project description:As more biomarkers for Alzheimer's disease and age-related brain conditions become available, more sophisticated analytic approaches are needed to take full advantage of the information they convey. Most work has been done using categorical approaches but the joint relationships of tau PET, amyloid PET and cortical thickness in their continuous distributions to cognition have been under-explored. We evaluated non-demented subjects over age 50 years in the Mayo Clinic Study of Aging, 2037 of whom had undergone 3 T MRI scan, 985 amyloid PET scan with 11C-Pittsburgh compound B (PIB) and MRI, and 577 PIB-PET, 18F-AV1451 flortaucipir PET and MRI. Participants received a nine-test cognitive battery. Three test scores (logical memory delayed recall, visual reproduction delayed recall and auditory verbal learning test delayed recall) were used to generate a memory composite z-score. We used Gradient Boosting Machine models to analyse the relationship between regional cortical thickness, flortaucipir PET signal, PIB-PET signal and memory z-scores. Age, education, sex and number of test exposures were included in the model as covariates. In this population-based study of non-demented subjects, most of the associations between biomarkers and memory z-scores accrued after 70 years of age. Entorhinal cortex exhibited the strongest associations between biomarkers and memory z-scores. Other temporal regions showed similar but attenuated associations, and non-temporal regions had negligible associations between memory z-scores and biomarkers. Entorhinal flortaucipir PET signal, PIB-PET signal and entorhinal cortical thickness were independently and additively associated with declining memory z-scores. In contrast to global PIB-PET signal where only very high amyloid-? levels were associated low memory z-scores, entorhinal flortaucipir PET signal just above background levels was associated with low memory z-scores. The lowest memory z-scores occurred with the confluence of elevated entorhinal flortaucipir PET signal and lower entorhinal cortical thickness.

Dataset Information

Extracellular matrix-glial abnormalities in the amygdala and entorhinal cortex of subjects diagnosed with schizophrenia.

Publications

Extracellular matrix-glial abnormalities in the amygdala and entorhinal cortex of subjects diagnosed with schizophrenia.

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