Extracellular Matrix-Glial Abnormalities in the Amygdala and Entorhinal Cortex of Subjects Diagnosed With Schizophrenia
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CONTEXT: 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. HYPOTHESIS: 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. DESIGN: Postmortem case-control study. SETTING: The Translational Neuroscience Laboratory at McLean Hospital, Harvard Medical School. Specimens were obtained from the Harvard Brain Tissue Resource Center at McLean Hospital. PARTICIPANTS: 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). INTERVENTIONS: Quantitative, immunocytological, and histological postmortem investigations. MAIN OUTCOME MEASURES: 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. RESULTS: 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. CONCLUSIONS: 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.
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Oxidative stress may contribute to the slow emergence of psychoses by mistiming key windows of brain development.
“Given the pivotal role of PV cells and PNNs in regulating the onset and closure of brain plasticity (52,57), oxidative stress may contribute to the slow emergence of psychoses by mistiming key windows of brain development.”
From Perineuronal nets protect fast-spiking interneurons against oxidative stress (2013) · cites this paper as [52]
The Comments section (page unavailable) says PNN organization controls the closure of critical periods and suggests that disrupted PNN formation in schizophrenia may affect neural circuitry. The paper does not establish a role in the onset of those periods. The oxidative-stress proposal follows the citations in the citing sentence and is not attributed to this source. (LLM, conf=0.83)
Experimental — accuracy not yet measuredSpecific interactions with sugar residues in PNNs or sulfation patterns enable persistent uptake of Otx2, which promotes PNN formation, suggesting a positive feedback loop for PV-cell maintenance.
“Both specific interactions with sugar residues in the PNNs (52) or sulfation patterns (53) enable the persistent uptake of this factor, which in turn promotes PNN formation, suggesting a positive feedback loop for PV-cell maintenance.”
From Perineuronal nets protect fast-spiking interneurons against oxidative stress (2013) · cites this paper as [52]
The Methods section (page not specified) describes a lectin binding to a sugar residue in CSPGs, and the Abstract > Conclusions (page not specified) discusses PNNs around parvalbumin-positive neurons. Neither passage addresses Otx2 uptake or a feedback loop; searches for Otx2, sugar-residue interactions and sulfation patterns found no passage establishing that mechanism. (LLM, conf=0.75)
Experimental — accuracy not yet measuredAltered PNNs have been found in the human post mortem amygdala, entorhinal and prefrontal cortices of patients.
“Altered PNNs have been found in the human post mortem amygdala, entorhinal and prefrontal cortices of patients (65–67)”
From Prolonged Period of Cortical Plasticity upon Redox Dysregulation in Fast-Spiking Interneurons (2015) · cites this paper as [66]
In the amygdala and entorhinal cortex, WFA-positive PNN decreases in schizophrenia are accompanied by sharp, widespread increases of WFA-positive glial cells.
“In the amygdala and entorhinal cortex, WFA-positive PNN decreases were accompanied by sharp, widespread, increases of WFA-positive glial cells.3”
From Aggrecan and chondroitin-6-sulfate abnormalities in schizophrenia and bipolar disorder: a postmortem study on the amygdala (2015) · cites this paper as [3]
CSPGs are involved in the pathophysiology of schizophrenia.
“Emerging evidence from human postmortem, animal model and genetic studies points to their involvement in the pathophysiology of schizophrenia (SZ).1, 2, 3, 4, 5, 6, 7”
From Aggrecan and chondroitin-6-sulfate abnormalities in schizophrenia and bipolar disorder: a postmortem study on the amygdala (2015) · cites this paper as [3]
A large number of 3B3-IR PNNs were detected throughout the amygdala, outnumbering aggrecan-IR PNNs and WFA-positive PNNs, particularly within the basal nucleus, accessory basal nucleus, cortical nucleus and central/medial nuclei.
“A large number of 3B3-IR PNNs were detected throughout the amygdala, outnumbering by far aggrecan-IR PNNs (Supplementary Tables 4 and 5) as well as WFA-positive PNNs,3, 67 particularly within the BN, ABN, CO and CE/ME”
From Aggrecan and chondroitin-6-sulfate abnormalities in schizophrenia and bipolar disorder: a postmortem study on the amygdala (2015) · cites this paper as [3]
PNNs labeled with WFA are decreased in the amygdala, entorhinal cortex and prefrontal cortex, but not visual cortex, of subjects with schizophrenia.
“Specifically, PNNs labeled with a lectin CSPG marker, that is, Wisteria floribunda agglutinin (WFA), are decreased in the amygdala, entorhinal cortex and prefrontal cortex, but not visual cortex, of subjects with this disorder.3, 4”
From Aggrecan and chondroitin-6-sulfate abnormalities in schizophrenia and bipolar disorder: a postmortem study on the amygdala (2015) · cites this paper as [3]
PNN reductions affect neuronal populations larger than previously demonstrated, encompassing several amygdala nuclei.
“PNN reductions affect neuronal populations larger than previously demonstrated, encompassing several amygdala nuclei,3”
From Aggrecan and chondroitin-6-sulfate abnormalities in schizophrenia and bipolar disorder: a postmortem study on the amygdala (2015) · cites this paper as [3]
PNN decreases in BD were not detected using WFA.
“PNN decreases in this disorder were not detected using WFA.3”
From Aggrecan and chondroitin-6-sulfate abnormalities in schizophrenia and bipolar disorder: a postmortem study on the amygdala (2015) · cites this paper as [3]
In schizophrenia, robust decreases of aggrecan- and 3B3-IR PNNs, together with marked decreases of WFA-positive PNNs previously reported, strongly indicate a widespread PNN pathology.
“In subjects with SZ, robust decreases of aggrecan- and 3B3-IR PNNs, together with marked decreases of WFA-positive PNNs previously reported,3 strongly indicate a widespread PNN pathology.”
From Aggrecan and chondroitin-6-sulfate abnormalities in schizophrenia and bipolar disorder: a postmortem study on the amygdala (2015) · cites this paper as [3]
The results on aggrecan and CS-6, and previous findings using WFA, are consistent with regard to PNNs, but not with regard to glial cells.
“Our results on aggrecan and CS-6, and previous findings using WFA, are consistent with regard to PNNs, but not with regard to glial cells.3”
From Aggrecan and chondroitin-6-sulfate abnormalities in schizophrenia and bipolar disorder: a postmortem study on the amygdala (2015) · cites this paper as [3]
Abnormal glutamatergic transmission, polymorphisms of genes encoding for some PNN components, and altered CSPG expression in glial cells may, independently or in conjunction, cause defective PNN maturation.
“Abnormal glutamatergic transmission, polymorphisms of genes encoding for some of their components and altered CSPG expression in glial cells may, independently or in conjunction, cause defective PNN maturation.3, 5, 6, 7, 59”
From Aggrecan and chondroitin-6-sulfate abnormalities in schizophrenia and bipolar disorder: a postmortem study on the amygdala (2015) · cites this paper as [3]
In sharp contrast to increases of WFA-positive glial cells reported previously in schizophrenia, aggrecan-IR glia and CS-6-IR glial clusters were markedly decreased.
“In sharp contrast to increases of WFA-positive glial cells reported previously in SZ,3 aggrecan-IR glia and CS-6- (3B3 and CS56)-IR glial clusters were markedly decreased.”
From Aggrecan and chondroitin-6-sulfate abnormalities in schizophrenia and bipolar disorder: a postmortem study on the amygdala (2015) · cites this paper as [3]
The subject cohorts used for aggrecan and WFA overlapped to a great extent.
“Notably, the subject cohorts used for aggrecan (in this study) and for WFA,3 overlapped to a great extent.”
From Aggrecan and chondroitin-6-sulfate abnormalities in schizophrenia and bipolar disorder: a postmortem study on the amygdala (2015) · cites this paper as [3]
As virtually all WFA-positive glial cells were found to express GFAP, and numbers of GFAP-IR cells in the same SZ subjects were normal, the observed changes are interpreted as increased CSPG expression.
“As virtually all WFA-positive glial cells were found to express GFAP, and numbers of GFAP-IR cells in the same SZ subjects were normal, the observed changes are interpreted as increased CSPG expression.”
From Aggrecan and chondroitin-6-sulfate abnormalities in schizophrenia and bipolar disorder: a postmortem study on the amygdala (2015) · cites this paper as [3]
We have previously shown robust increases of WFA-positive glial cells in the amygdala of subjects with SZ, but not BD.
“We have previously shown robust increases of WFA-positive glial cells in the amygdala of subjects with SZ, but not BD.3”
From Aggrecan and chondroitin-6-sulfate abnormalities in schizophrenia and bipolar disorder: a postmortem study on the amygdala (2015) · cites this paper as [3]
Reports indicate that WFA-labeled perineuronal net density is much lower in schizophrenia entorhinal and prefrontal cortices.
“The density of PNNs labeled with Wisteria floribunda agglutinin (WFA), a lectin that binds to specific carbohydrate moieties on proteoglycans, has been reported to be markedly lower in the entorhinal and prefrontal cortices in schizophrenia (Mauney et al, 2013;Pantazopoulos et al, 2010Pantazopoulos et al, , 2015)).”
From Reduced Labeling of Parvalbumin Neurons and Perineuronal Nets in the Dorsolateral Prefrontal Cortex of Subjects with Schizophrenia (2016) · cites this paper as Pantazopoulos et al, 2010
Within each brain structure examined, WFA-labeled PNN reductions in schizophrenia were selective for distinct subregions: the lateral nucleus of the amygdala, superficial layers of the entorhinal cortex, and layers III and V of the prefrontal cortex.
“Within each brain structure examined, WFA-labeled PNN reductions were selective for distinct subregions, i.e. the lateral nucleus of the amygdala, superficial layers of the entorhinal cortex and layers III and V of the prefrontal cortex.”
From Losing the sugar coating: Potential impact of perineuronal net abnormalities on interneurons in schizophrenia (2015) · cites this paper as Pantazopoulos et al., 2010
Human postmortem studies show involvement of PNNs in schizophrenia.
“Emerging evidence from human postmortem studies highlights the involvement of PNNs in schizophrenia (SZ) (Mauney et al., 2013; Pantazopolous et al., 2014; Pantazopoulos et al., 2010).”
From Losing the sugar coating: Potential impact of perineuronal net abnormalities on interneurons in schizophrenia (2015) · cites this paper as Pantazopoulos et al., 2010
Our group has shown marked decreases of PNNs in several brain regions of subjects diagnosed with schizophrenia.
“Our group has shown marked decreases of PNNs in several brain regions of subjects diagnosed with SZ (Mauney et al., 2013; Pantazopolous et al., 2014; Pantazopoulos et al., 2010).”
From Losing the sugar coating: Potential impact of perineuronal net abnormalities on interneurons in schizophrenia (2015) · cites this paper as Pantazopoulos et al., 2010
Perineuronal nets are markedly altered in people with schizophrenia.
“Perineuronal nets (PNNs) were shown to be markedly altered in subjects with schizophrenia.”
From Losing the sugar coating: Potential impact of perineuronal net abnormalities on interneurons in schizophrenia (2015) · cites this paper as Pantazopoulos et al., 2010
PNN decreases have been detected in the amygdala, entorhinal cortex, and prefrontal cortex of subjects with schizophrenia.
“In particular, decreases of PNNs have been detected in the amygdala, entorhinal cortex and prefrontal cortex.”
From Losing the sugar coating: Potential impact of perineuronal net abnormalities on interneurons in schizophrenia (2015) · cites this paper as Pantazopoulos et al., 2010
The distribution of WFA-labeled PNN reductions in schizophrenia matches the normal distribution of WFA-labeled PNNs and GABAergic interneurons expressing parvalbumin.
“The distribution of these changes matches closely not only the normal distribution of WFA-labeled PNNs, but also that of GABAergic interneurons expressing PVB (Pantazopoulos et al., 2010).”
From Losing the sugar coating: Potential impact of perineuronal net abnormalities on interneurons in schizophrenia (2015) · cites this paper as Pantazopoulos et al., 2010
PNN abnormalities in schizophrenia are large in magnitude, robust to confounding factors, and shared by several brain regions involved in schizophrenia.
“These abnormalities are large in magnitude, robust to confounding factors and shared by several brain regions involved in SZ (Mauney et al., 2013; Pantazopolous et al., 2014; Pantazopoulos et al., 2010).”
From Losing the sugar coating: Potential impact of perineuronal net abnormalities on interneurons in schizophrenia (2015) · cites this paper as Pantazopoulos et al., 2010
Numbers of parvalbumin-expressing neurons were normal in the amygdala and entorhinal cortex, and densities of WFA-labeled PNNs were unchanged in the central nucleus of the amygdala and visual cortex of subjects with schizophrenia.
“Notably, numbers of these neurons were normal in the amygdala and entorhinal cortex, and densities of WFA-labeled PNNs were unchanged in the central nucleus of the amygdala and visual cortex of subjects with SZ (Mauney et al., 2013; Pantazopoulos et al., 2010)(Fig. 3, unpublished data).”
From Losing the sugar coating: Potential impact of perineuronal net abnormalities on interneurons in schizophrenia (2015) · cites this paper as Pantazopoulos et al., 2010
A similar disruption of inhibitory activity may occur in subjects with schizophrenia in brain regions affected by PNN abnormalities, such as the amygdala, entorhinal cortex, and prefrontal cortex.
“We suggest that a similar disruption of inhibitory activity may occur in subjects with SZ in brain regions affected by PNN abnormalities, such as the amygdala, entorhinal cortex and prefrontal cortex (Mauney et al., 2013; Pantazopolous et al., 2014; Pantazopoulos et al., 2010).”
From Losing the sugar coating: Potential impact of perineuronal net abnormalities on interneurons in schizophrenia (2015) · cites this paper as Pantazopoulos et al., 2010
In subjects with schizophrenia, decreases of PNNs in multiple brain regions were robust to confounding variables, including exposure to pharmacological agents, and did not correlate with age at onset of the disease or duration of illness.
“In subjects with SZ, decreases of PNNs in multiple brain regions were robust to confounding variables, including exposure to pharmacological agents, and did not correlate with age at onset of the disease or duration of illness (Mauney et al., 2013; Pantazopolous et al., 2014; Pantazopoulos et al., 2010).”
From Losing the sugar coating: Potential impact of perineuronal net abnormalities on interneurons in schizophrenia (2015) · cites this paper as Pantazopoulos et al., 2010
Human PNNs occur in the entorhinal cortex, amygdala, hippocampus, visual and prefrontal cortices, and motor and somatosensory cortex.
“in humans, PNNs have also been found to be present in a variety of brain regions, including entorhinal cortex (Pantazopoulos et al., 2010), amygdala (Pantazopoulos et al., 2008; Pantazopoulos et al., 2010), hippocampus (Lendvai et al., 2013), motor and somatosensory cortex (Hausen et al., 1996), visual cortex (Mauney et al., 2013; Murakami et al., 1994; Seeger et al., 1996) and prefrontal cortex (”
From Perineuronal nets and schizophrenia: The importance of neuronal coatings (2014) · cites this paper as Pantazopoulos et al., 2010
PNNs may be involved in the pathophysiology of schizophrenia.
“Recent evidence suggests that PNNs may also be involved in the pathophysiology of schizophrenia.”
From Perineuronal nets and schizophrenia: The importance of neuronal coatings (2014) · cites this paper as Pantazopoulos et al., 2010
The perineuronal net surrounding many parvalbumin interneurons is reduced in the dorsolateral prefrontal cortex, entorhinal cortex, and amygdala of schizophrenia patients.
“Moreover, the extracellular matrix (perineuronal net: PNN) that surrounds many PVI is reduced in DLPFC (Mauney et al., 2013), entorhinal cortex, and amygdala of schizophrenia patients (Pantazopoulos et al., 2010).”
From Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: A “central hub” in schizophrenia pathophysiology? (2016) · cites this paper as Pantazopoulos et al., 2010
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“In particular, CSPG-enriched perineuronal nets were decreased in several brain regions, often in associationwithmarked increased of CSPG-positive glial cells (Pantazopoulos et al., 2010; Enwright et al., 2012; Mauney et al., 2013).”
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- Authors
- Pantazopoulos, H., Woo, T.-U. W., Lim, M. P., Lange, N., & Berretta, S.
- Affiliations
- Harvard University (US)
- Northeastern University (US)
- Venue
- Archives of General Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2010-02-01
- Volume
- 67
- Issue
- 2
- Pages
- 155
- ISSN
- 0003-990X (ISSN-L)
- PMC
- PMC4208310
- OpenAlex
- W2094785210
- Cited by
- 296
- References
- 63
- Citations by year
- 2026: 9 · 2025: 16 · 2024: 22 · 2023: 17 · 2022: 19 · 2021: 32 · 2020: 20 · 2019: 23 · 2018: 25 · 2017: 20 · 2016: 19 · 2015: 15 · 2014: 22 · 2013: 14 · 2012: 13
- FWCI
- 8.07
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Archives of General Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (MH083222, R01MH066280, R01MH086522, R21MH083222, MH 066280, R01MH076060, MH 066955, R01MH066955)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- schizophrenia, chondroitin sulfate proteoglycans, extracellular matrix, astrocytes, perineuronal nets, amygdala, entorhinal cortex, glial fibrillary acidic protein, parvalbumin neurons, bipolar disorder, postmortem brain, schizophrenia pathogenesis, GABAergic neurotransmission, glutamatergic neurotransmission, dopamine signaling
- MeSH terms
- Adolescent, Adult, Amygdala, Astrocytes, Bipolar Disorder, Child, Extracellular Matrix, Female, Humans, Immunohistochemistry, Middle Aged, Neuroglia, Chondroitin Sulfate Proteoglycans, Schizophrenia, Temporal Lobe, Case-Control Studies, Age of Onset, Entorhinal Cortex, Young Adult, In Vitro Techniques
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