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Cited by 153Proteoglycans and glycosaminoglycans researchSchizophrenia research and treatmentNeuroscience and Neuropharmacology Research

Aggrecan and chondroitin-6-sulfate abnormalities in schizophrenia and bipolar disorder: a postmortem study on the amygdala

Open access
Pantazopoulos, H, Markota, M, Jaquet, F, Ghosh, D, Wallin, A, Santos, A, Caterson, B, Berretta, S·2015·Translational Psychiatry
DOI 10.1038/tp.2014.128PMC PMC4312825
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Abstract

Perineuronal nets (PNNs) are specialized extracellular matrix aggregates surrounding distinct neuronal populations and regulating synaptic functions and plasticity. Previous findings showed robust PNN decreases in amygdala, entorhinal cortex and prefrontal cortex of subjects with schizophrenia (SZ), but not bipolar disorder (BD). These studies were carried out using a chondroitin sulfate proteoglycan (CSPG) lectin marker. Here, we tested the hypothesis that the CSPG aggrecan, and 6-sulfated chondroitin sulfate (CS-6) chains highly represented in aggrecan, may contribute to these abnormalities. Antibodies against aggrecan and CS-6 (3B3 and CS56) were used in the amygdala of healthy control, SZ and BD subjects. In controls, aggrecan immunoreactivity (IR) was observed in PNNs and glial cells. Antibody 3B3, but not CS56, also labeled PNNs in the amygdala. In addition, dense clusters of CS56 and 3B3 IR encompassed CS56- and 3B3-IR glia, respectively. In SZ, numbers of aggrecan- and 3B3-IR PNNs were decreased, together with marked reductions of aggrecan-IR glial cells and CS-6 (3B3 and CS56)-IR 'clusters'. In BD, numbers of 3B3-IR PNNs and CS56-IR clusters were reduced. Our findings show disruption of multiple PNN populations in the amygdala of SZ and, more modestly, BD. Decreases of aggrecan-IR glia and CS-6-IR glial 'clusters', in sharp contrast to increases of CSPG/lectin-positive glia previously observed, indicate that CSPG abnormalities may affect distinct glial cell populations and suggest a potential mechanism for PNN decreases. Together, these abnormalities may contribute to a destabilization of synaptic connectivity and regulation of neuronal functions in the amygdala of subjects with major psychoses.

AI snapshot

Written from the paper’s full text.

TL;DR

Postmortem amygdala tissue from schizophrenia (SZ) and bipolar disorder (BD) subjects showed abnormalities in aggrecan and chondroitin-6-sulfate (CS-6) perineuronal nets (PNNs) and glial clusters. The findings suggest widespread CSPG pathology affecting distinct neuronal and glial populations, potentially destabilizing synaptic connectivity in major psychoses.

Key findings

  • In SZ, aggrecan-IR PNNs were decreased in the lateral nucleus (Tn, P<0.03, g=−0.95; Nd, P<0.04, g=−0.93), and aggrecan-IR glia were decreased in the lateral (P<0.01, g=−1.11), basal (P<0.01, g=−1.19), and accessory basal (P<0.005, g=−1.28) nuclei; aggrecan mRNA was increased in the lateral nucleus (P<0.03, g=0.90).
  • In SZ, 3B3-IR PNNs were decreased in lateral, basal, accessory basal, cortical, and medial nuclei (e.g., basal Tn, P<0.002, g=−2.12; cortical Tn, P<0.001, g=−1.88), 3B3-IR glial clusters were decreased in lateral, basal, accessory basal, cortical, central, and medial nuclei (e.g., lateral Tn, P<0.0003, g=−1.93), and CS56-IR glial clusters were decreased in lateral, basal, accessory basal, central, and medial nuclei (e.g., lateral Tn, P<0.0004, g=−2.09).
  • In BD, 3B3-IR PNNs were decreased in lateral, basal, accessory basal, and medial nuclei (e.g., lateral Tn, P<0.002, g=−2.14; medial Tn, P<0.007, g=−2.16), aggrecan-IR PNNs were decreased in lateral (Tn, P<0.04, g=−0.88) and accessory basal (Tn, P<0.04, g=−0.92; Nd, P<0.03, g=−1.37) nuclei, CS56-IR glial clusters were decreased in lateral, basal, accessory basal, and central nuclei (e.g., lateral Tn, P<0.002, g=−2.52), and 3B3-IR glial clusters were decreased only in the medial nucleus (Tn, P<0.03, g=−1.05).
  • In controls, aggrecan immunoreactivity was observed in PNNs and glial cells; 3B3, but not CS56, also labeled PNNs; dense CS56- and 3B3-IR glial clusters were present, and WFA did not label these clusters.

Methods

  • Postmortem human amygdala blocks from the Harvard Brain Tissue Resource Center: whole amygdala from normal controls (n=29), SZ (n=24), and BD (n=20) for histochemistry; subcohorts included aggrecan (control n=12, SZ n=12, BD n=13), CS56 (control n=13, SZ n=14, BD n=8), and 3B3 (control n=14, SZ n=13, BD n=8); additional tissue from 14 controls and 14 SZ subjects was used for quantitative PCR.
  • Immunocytochemistry used antibodies against aggrecan (cat-301), CS-6 (3B3 and CS56), GFAP, and WFA, with systematic random sampling and stereological counts of immunoreactive PNNs, glia, and glial clusters across amygdala nuclei; qRT-PCR measured ACAN transcript variants 1 and 2.
  • Group differences were assessed with ANCOVA stepwise linear regression, log-transformed values, Hedges’ g effect sizes, and separate comparisons of SZ and BD with normal controls, including covariates such as age, gender, postmortem interval, cause of death, medication exposure, and substance exposure.

Limitations

  • The paper states that cat-301 detects a distinct glycosylated form of aggrecan, so results may be specific to that form and may partly explain the aggrecan mRNA/protein discrepancy; WFA’s specific CSPG/sulfation targets are unknown, limiting cross-marker interpretation.
  • The paper states that SSRI records in BD subjects were insufficient to assess effects, and detected pharmacological effects were limited to SSRIs and lithium on a small number of outcome variables.
  • Evident from the text: this is a cross-sectional postmortem study, so it cannot establish causality or the developmental timing of abnormalities; marker subcohorts only partially overlap and some are small (e.g., BD n=8 for CS56 and 3B3), and several nuclei showed non-significant trends despite large effect sizes.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/tp.2014.128

Cites

103 of 103 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 98 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    CS56 did not label PNNs.

    “CS56 did not label PNNs.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Postmortem measurements of aggrecan and CS-6 immunoreactivity and mRNA in the amygdala reflect the antemortem state of these molecules in the donors.
  • Findingown data

    A small number of aggrecan-IR glia were scattered in all amygdala nuclei examined.

    “A small number of aggrecan-IR glia were scattered in all the amygdala nuclei examined.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Postmortem measurements of aggrecan and CS-6 immunoreactivity and mRNA in the amygdala reflect the antemortem state of these molecules in the donors.
  • Findingown data

    Several 3B3-IR PNNs were observed in close contact with 3B3-IR glial clusters.

    “Notably, several 3B3-IR PNNs were observed in close contact with 3B3-IR glial clusters”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Postmortem measurements of aggrecan and CS-6 immunoreactivity and mRNA in the amygdala reflect the antemortem state of these molecules in the donors.
    • Rests on an assumption: The number of CS-6-IR glial clusters is a valid proxy for the number of CS-6-IR glial cells in the amygdala.
  • Findingown data

    In controls, aggrecan immunoreactivity was observed in PNNs predominantly located within the lateral nucleus of the amygdala.

    “Aggrecan IR was observed in PNNs predominantly located within the LN.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Postmortem measurements of aggrecan and CS-6 immunoreactivity and mRNA in the amygdala reflect the antemortem state of these molecules in the donors.
  • Findingown data

    WFA labeling was not detected in the CS56- and 3B3-IR glial clusters.

    “WFA labeling was not detected in these clusters.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Postmortem measurements of aggrecan and CS-6 immunoreactivity and mRNA in the amygdala reflect the antemortem state of these molecules in the donors.
    • Rests on an assumption: The number of CS-6-IR glial clusters is a valid proxy for the number of CS-6-IR glial cells in the amygdala.
  • May combine two claims. 36
  • The quote only partly states this claim. 4
  • Classified as probably not a substantial claim. 32

  • May combine two claims.

    Findingown data

    Aggrecan-IR glia were not labeled by WFA and did not show GFAP immunoreactivity.

    “These cells were not labeled by WFA and did not show GFAP-IR”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Postmortem measurements of aggrecan and CS-6 immunoreactivity and mRNA in the amygdala reflect the antemortem state of these molecules in the donors.

  • May combine two claims.

    Findingown data

    In bipolar disorder, total number, but not numerical density, of aggrecan-IR PNNs was decreased in the lateral nucleus.

    “In subjects with BD, aggrecan-IR PNNs (Tn, but not Nd) were decreased in the LN (P<0.04, g=−0.88”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Postmortem measurements of aggrecan and CS-6 immunoreactivity and mRNA in the amygdala reflect the antemortem state of these molecules in the donors.

  • May combine two claims.

    Findingown data

    Within the lateral nucleus, approximately 54% of aggrecan-IR PNNs and over 80% of 3B3-IR PNNs are also labeled with WFA.

    “Within the LN, approximately half (54%) of the aggrecan-IR PNNs and over 80% of the 3B3-IR PNNs are also labeled with WFA”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Postmortem measurements of aggrecan and CS-6 immunoreactivity and mRNA in the amygdala reflect the antemortem state of these molecules in the donors.

  • May combine two claims.

    Findingown data

    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”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [3] Pantazopoulos H, Woo T-UW, Lim MP, Lange N, Berretta S . Extracellular matrix-glial abnormalities in the amygdala and entorhinal cortex of subjects diagnosed with schizophrenia. Arch Gen Psychiatry 2010; 67: 155–166. source

      Not checked in the free run.

    • cites [67] Pantazopoulos H, Murray EA, Berretta S . Total number, distribution, and phenotype of cells expressing chondroitin sulfate proteoglycans in the normal human amygdala. Brain Res 2008; 1207: 84–95. source

      Not checked in the free run.

    • Rests on an assumption: Postmortem measurements of aggrecan and CS-6 immunoreactivity and mRNA in the amygdala reflect the antemortem state of these molecules in the donors.

  • May combine two claims.

    Findingown data

    In subjects with BD, marked reductions of 3B3-IR PNNs in LN, BN, ABN, CO and ME were accompanied by more modest decreases of aggrecan-IR PNNs in LN and ABN.

    “In subjects with BD, marked reductions of 3B3-IR PNNs in LN, BN, ABN, CO and ME were accompanied by more modest decreases of aggrecan-IR PNNs in the LN and ABN.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    In schizophrenia, decreases in CS56-IR glial clusters in the cortical nucleus did not reach statistical significance.

    “Decreases in the CO did not reach statistical significance, although the effect size was relatively large (Tn, P<0.06, g=−0.98; Nd, P<0.06, g=−0.95”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Postmortem measurements of aggrecan and CS-6 immunoreactivity and mRNA in the amygdala reflect the antemortem state of these molecules in the donors.
    • Rests on an assumption: The number of CS-6-IR glial clusters is a valid proxy for the number of CS-6-IR glial cells in the amygdala.

  • May combine two claims.

    Findingown data

    3B3 and aggrecan only partially colocalize with WFA in PNNs, and virtually not at all in glia.

    “Our results show that 3B3 and aggrecan only partially colocalize with WFA in PNNs, and virtually not at all in glia (Supplementary Figures 1,2).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Postmortem measurements of aggrecan and CS-6 immunoreactivity and mRNA in the amygdala reflect the antemortem state of these molecules in the donors.

  • The quote only partly states this claim.

    Findingown data

    In schizophrenia, 3B3-IR glial clusters were decreased in the cortical nucleus.

    “CO (Tn, P<0.02, g=−1.12; Nd, P<0.04, g=−0.95)”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Postmortem measurements of aggrecan and CS-6 immunoreactivity and mRNA in the amygdala reflect the antemortem state of these molecules in the donors.
    • Rests on an assumption: The number of CS-6-IR glial clusters is a valid proxy for the number of CS-6-IR glial cells in the amygdala.

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based). The quote only partly states this claim.

    Findingown data

    In schizophrenia, CS56-IR glial clusters were significantly decreased in the medial nucleus.

    “and ME (Tn, P<0.04, g=−1.08; Nd, P<0.06, g=−0.98”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Postmortem measurements of aggrecan and CS-6 immunoreactivity and mRNA in the amygdala reflect the antemortem state of these molecules in the donors.
    • Rests on an assumption: The number of CS-6-IR glial clusters is a valid proxy for the number of CS-6-IR glial cells in the amygdala.

  • The quote only partly states this claim.

    Findingown data

    In schizophrenia, 3B3-IR PNNs were decreased in the cortical nucleus.

    “CO (Tn, P<0.001, g=−1.88; Nd, P<0.003, g=−1.65)”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Postmortem measurements of aggrecan and CS-6 immunoreactivity and mRNA in the amygdala reflect the antemortem state of these molecules in the donors.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductreasoning

    Each six-well staining dish contained sections from schizophrenia, bipolar disorder and normal control subjects and was carried through each step for the same duration to avoid sequence effects.

    “Each six-well staining dish contained sections from SZ, BD and normal control subjects and was carried through each step for the same duration of time, so as to avoid sequence effects.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    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”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3] Pantazopoulos H, Woo T-UW, Lim MP, Lange N, Berretta S . Extracellular matrix-glial abnormalities in the amygdala and entorhinal cortex of subjects diagnosed with schizophrenia. Arch Gen Psychiatry 2010; 67: 155–166. source

      Not checked in the free run.

    • cites [4] Mauney SA, Athanas KM, Pantazopoulos H, Shaskan N, Passeri E, Berretta S et al. Developmental pattern of perineuronal nets in the human prefrontal cortex and their deficit in schizophrenia. Biol Psychiatry 2013; 74: 427–435. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Systematic random sampling criteria were used to distribute sections through the amygdala.

    “Using systematic random sampling criteria, sections through the amygdala were serially distributed in 26 compartments”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Sections were coded for quantitative analysis blinded to diagnosis.

    “All sections were mounted on gelatin-coated glass slides, coverslipped and coded for quantitative analysis blinded to diagnosis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Aggrecan is a major component of the brain ECM and of at least a subgroup of PNNs, and contains numerous CS chains with a predominant CS-6 representation.

    “Aggrecan is a major component of the brain ECM and of at least a subgroup of PNNs, and contains numerous CS chains with a predominant CS-6 representation.45, 46”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [45] Giamanco KA, Morawski M, Matthews RT . Perineuronal net formation and structure in aggrecan knockout mice. Neuroscience 2010; 170: 1314–1327. source

      Not checked in the free run.

    • cites [46] Giamanco KA, Matthews RT . Deconstructing the perineuronal net: cellular contributions and molecular composition of the neuronal extracellular matrix. Neuroscience 2012; 218: 367–384. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Aggrecan expression coincides with maturation of electrophysiological properties of neurons and formation of synapses during late stage developmental periods.

    “In parallel to PNN development, aggrecan expression coincides with the maturation of electrophysiological properties of neurons and the formation of synapses during late stage developmental periods.47, 48”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [47] Guimaraes A, Zaremba S, Hockfield S . Molecular and morphological changes in the cat lateral geniculate nucleus and visual cortex induced by visual deprivation are revealed by monoclonal antibodies Cat-304 and Cat-301. J Neurosci 1990; 10: 3014–3024. source

      Not checked in the free run.

    • cites [48] Kalb RG, Hockfield S . Molecular evidence for early activity-dependent development of hamster motor neurons. J Neurosci 1988; 8: 2350–2360. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    PNN formation is critically dependent on glial cells, which secrete and organize CSPGs and other ECM molecules.

    “This process is critically dependent on glial cells, which secrete and organize CSPGs and other ECM molecules.35, 36, 37”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [35] Faissner A, Pyka M, Geissler M, Sobik T, Frischknecht R, Gundelfinger ED et al. Contributions of astrocytes to synapse formation and maturation—potential functions of the perisynaptic extracellular matrix. Brain Res Rev 2010; 63: 26–38. source

      Not checked in the free run.

    • cites [36] Klausmeyer A, Conrad R, Faissner A, Wiese S . Influence of glial-derived matrix molecules, especially chondroitin sulfates, on neurite growth and survival of cultured mouse embryonic motoneurons. J Neurosci Res 2011; 89: 127–141. source

      Not checked in the free run.

    • cites [37] Wiese S, Karus M, Faissner A . Astrocytes as a source for extracellular matrix molecules and cytokines. Front Pharmacol 2012; 3: 120. source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Once formed, PNNs control neuronal access to growth and transcription factors, stabilize synaptic connectivity and compartmentalize the neuronal surface, regulating availability of glutamatergic receptors and neuronal firing properties.

    “Once formed, and throughout adulthood, PNNs control neuronal access to growth and transcription factors, stabilize synaptic connectivity and compartmentalize the neuronal surface, regulating the availability of glutamatergic receptors to postsynaptic specializations and, thus, neuronal firing properties.23, 25, 38”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [23] Frischknecht R, Gundelfinger ED . The brain's extracellular matrix and its role in synaptic plasticity. Adv Exp Med Biol 2012; 970: 153–171. source

      Not checked in the free run.

    • cites [25] Maeda N, Fukazawa N, Ishii M . Chondroitin sulfate proteoglycans in neural development and plasticity. Front Biosci 2010; 15: 626–644. source

      Not checked in the free run.

    • cites [38] Beurdeley M, Spatazza J, Lee HH, Sugiyama S, Bernard C, Di Nardo AA et al. Otx2 binding to perineuronal nets persistently regulates plasticity in the mature visual cortex. J Neurosci 2012; 32: 9429–9437. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Subjects with Braak stages III or higher were not included.

    “Subjects with Braak stages III or higher (modified Bielchowsky stain) were not included.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Localized PNN destruction reproduces functional abnormalities reminiscent of schizophrenia.

    “whereas localized PNN destruction reproduces functional abnormalities reminiscent of SZ.9”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Shah A, Lodge DJ . A loss of hippocampal perineuronal nets produces deficits in dopamine system function: relevance to the positive symptoms of schizophrenia. Transl Psychiatry 2013; 3: e215. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The cohort did not include subjects with evidence for gross and/or macroscopic brain changes, or clinical history consistent with cerebrovascular accident or other neurological disorders.

    “The cohort used for this study did not include subjects with evidence for gross and/or macroscopic brain changes, or clinical history consistent with cerebrovascular accident or other neurological disorders.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    GABAergic interneurons are one of the largest and most extensively investigated neuronal populations enveloped by PNNs.

    “Among several neuronal populations enveloped by PNNs, GABAergic interneurons are one of the largest and most extensively investigated.39, 40, 41”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [39] Bruckner G, Kacza J, Grosche J . Perineuronal nets characterized by vital labelling, confocal and electron microscopy in organotypic slice cultures of rat parietal cortex and hippocampus. J Mol Histol 2004; 35: 115–122. source

      Not checked in the free run.

    • cites [40] Celio MR . Perineuronal nets of extracellular matrix around parvalbumin-containing neurons of the hippocampus. Hippocampus 1993; 3 (Spec No): 55–60. source

      Not checked in the free run.

    • cites [41] Pantazopoulos H, Lange N, Hassinger L, Berretta S . Subpopulations of neurons expressing parvalbumin in the human amygdala. J Comp Neurol 2006; 496: 706–722. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    CSPG-enriched PNNs form in an activity-dependent manner during late postnatal development, completing neuronal maturation.

    “CSPG-enriched PNNs form in an activity-dependent manner during late postnatal development, completing neuronal maturation.32, 33, 34”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [32] McRae PA, Rocco MM, Kelly G, Brumberg JC, Matthews RT . Sensory deprivation alters aggrecan and perineuronal net expression in the mouse barrel cortex. J Neurosci 2007; 27: 5405–5413. source

      Not checked in the free run.

    • cites [33] Gati G, Morawski M, Lendvai D, Matthews RT, Jager C, Zachar G et al. Chondroitin sulphate proteoglycan-based perineuronal net establishment is largely activity-independent in chick visual system. J Chem Neuroanat 2010; 40: 243–247. source

      Not checked in the free run.

    • cites [34] Ye Q, Miao QL . Experience-dependent development of perineuronal nets and chondroitin sulfate proteoglycan receptors in mouse visual cortex. Matrix Biol 2013; 32: 352–363. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    CS-4 and CS-6 are the two most common sulfation patterns in the brain.

    “Chondroitin-4-sulfation (CS-4) and chondroitin-6 sulfation (CS-6) are the two most common sulfation patterns in the brain, with several variations depending on the position of the sulfation on the CS chains43, 44”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [43] Miyata S, Komatsu Y, Yoshimura Y, Taya C, Kitagawa H . Persistent cortical plasticity by upregulation of chondroitin 6-sulfation. Nat Neurosci 2012; 15: 414–422, S1-2. source

      Not checked in the free run.

    • cites [44] Caterson B, Griffin J, Mahmoodian F, Sorrell JM . Monoclonal antibodies against chondroitin sulphate isomers: their use as probes for investigating proteoglycan metabolism. Biochem Soc Trans 1990; 18: 820–823. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Omission of the first (cat-301, 3B3 or CS56) or secondary antibodies did not result in detectable signal.

    “Omission of the first (cat-301, 3B3 or CS56) or secondary antibodies did not result in detectable signal.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Numbers of CS chains and their patterns of sulfation fundamentally affect their functions, such as their ability to interact with growth factors and cytokines.

    “Numbers of CS chains and their patterns of sulfation fundamentally affect their functions, such as their ability to interact with other molecules including growth factors and cytokines.43”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [43] Miyata S, Komatsu Y, Yoshimura Y, Taya C, Kitagawa H . Persistent cortical plasticity by upregulation of chondroitin 6-sulfation. Nat Neurosci 2012; 15: 414–422, S1-2. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Diagnoses of schizophrenia and bipolar disorder were made by two psychiatrists on the basis of retrospective review of medical records and extensive questionnaires concerning social and medical history provided by family members.

    “Diagnoses of SZ and BD were made by two psychiatrists on the basis of retrospective review of medical records and extensive questionnaires concerning social and medical history provided by the family members.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Models of oxidative stress relevant to schizophrenia show reductions of PNNs.

    “Models of oxidative stress relevant to this disorder show reductions of PNNs,8”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Cabungcal JH, Steullet P, Morishita H, Kraftsik R, Cuenod M, Hensch TK et al. Perineuronal nets protect fast-spiking interneurons against oxidative stress. Proc Natl Acad Sci USA 2013; 110: 9130–9135. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Sections from all brains included in the study were processed simultaneously within the same session to avoid procedural differences.

    “Sections from all the brains included in the study were processed simultaneously within the same session to avoid procedural differences.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    CSPGs are composed of specific core proteins to which chondroitin sulfate chains are attached.

    “CSPGs are composed of specific core proteins to which chondroitin sulfate (CS) chains are attached42”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Maeda N . Structural variation of chondroitin sulfate and its roles in the central nervous system. Cent Nerv Syst Agents Med Chem 2010; 10: 22–31. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Polymorphisms of genes encoding for several CSPGs have been associated with schizophrenia.

    “Finally, polymorphisms of genes encoding for several CSPGs have been associated with SZ.5, 6, 7”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [5] Buxbaum JD, Georgieva L, Young JJ, Plescia C, Kajiwara Y, Jiang Y et al. Molecular dissection of NRG1-ERBB4 signaling implicates PTPRZ1 as a potential schizophrenia susceptibility gene. Mol Psychiatry 2008; 13: 162–172. source

      Not checked in the free run.

    • cites [6] Muhleisen TW, Mattheisen M, Strohmaier J, Degenhardt F, Priebe L, Schultz CC et al. Association between schizophrenia and common variation in neurocan (NCAN), a genetic risk factor for bipolar disorder. Schizophr Res 2012; 138: 69–73. source

      Not checked in the free run.

    • cites [7] So HC, Fong PY, Chen RY, Hui TC, Ng MY, Cherny SS et al. Identification of neuroglycan C and interacting partners as potential susceptibility genes for schizophrenia in a Southern Chinese population. Am J Med Genet B Neuropsychiatr Genet 2010; 153B: 103–113. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PNNs are formed during late postnatal development, a time period coinciding with the typical onset of psychoses.

    “PNNs are formed during late postnatal development,4, 26 a time period coinciding with the typical onset of psychoses.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [4] Mauney SA, Athanas KM, Pantazopoulos H, Shaskan N, Passeri E, Berretta S et al. Developmental pattern of perineuronal nets in the human prefrontal cortex and their deficit in schizophrenia. Biol Psychiatry 2013; 74: 427–435. source

      Not checked in the free run.

    • cites [26] Wang D, Fawcett J . The perineuronal net and the control of CNS plasticity. Cell Tissue Res 2012; 349: 147–160. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [3] Pantazopoulos H, Woo T-UW, Lim MP, Lange N, Berretta S . Extracellular matrix-glial abnormalities in the amygdala and entorhinal cortex of subjects diagnosed with schizophrenia. Arch Gen Psychiatry 2010; 67: 155–166. source

      Not checked in the free run.

    • cites [5] Buxbaum JD, Georgieva L, Young JJ, Plescia C, Kajiwara Y, Jiang Y et al. Molecular dissection of NRG1-ERBB4 signaling implicates PTPRZ1 as a potential schizophrenia susceptibility gene. Mol Psychiatry 2008; 13: 162–172. source

      Not checked in the free run.

    • cites [59] Dityatev A, Bruckner G, Dityateva G, Grosche J, Kleene R, Schachner M . Activity-dependent formation and functions of chondroitin sulfate-rich extracellular matrix of perineuronal nets. Dev Neurobiol 2007; 67: 570–588. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Together, our findings show PNN loss/disruption in the amygdala of subjects with SZ and, perhaps to a lesser extent, BD.

    “Together, our findings show PNN loss/disruption in the amygdala of subjects with SZ and, perhaps to a lesser extent, BD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    WFA may not detect CS-6 sulfation patterns, at least not those recognized by 3B3 and CS56, and may label only some forms of aggrecan.

    “Together, these findings indicate that WFA may not detect CS-6 sulfation patterns, at least not those recognized by 3B3 and CS56, and may label only some forms of aggrecan (see below).45”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [45] Giamanco KA, Morawski M, Matthews RT . Perineuronal net formation and structure in aggrecan knockout mice. Neuroscience 2010; 170: 1314–1327. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Taken together, the results indicate that PNN abnormalities in the amygdala of subjects with schizophrenia are widespread, involving the lateral, basal, accessory basal, cortical and medial nuclei, and thus a range of neuronal populations broader than previously thought.

    “Taken together, these results indicate that PNN abnormalities in the amygdala of subjects with SZ are widespread, involving the LN as well as the BN, ABN, CO and ME, and thus a range of neuronal populations broader than previously thought.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Postmortem measurements of aggrecan and CS-6 immunoreactivity and mRNA in the amygdala reflect the antemortem state of these molecules in the donors.
    • Rests on an assumption: The sample of donors is representative of the broader populations of individuals with schizophrenia and bipolar disorder.

  • May combine two claims.

    Interpretationreasoning

    CS-6 expression in PNNs in BD subjects may be decreased in the otherwise normal WFA-positive PNNs, or may reflect loss of a subset of PNNs not detectable with WFA.

    “Thus, CS-6 expression in PNNs in BD subjects may be decreased in the otherwise normal WFA-positive PNNs, or may reflect loss of a subset of PNNs not detectable with WFA.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    PNN maturation during late postnatal development contributes to the closure of critical periods of development, stabilizing successful synaptic connectivity and instating a restricted mode of synaptic plasticity characteristic of adulthood.

    “PNN maturation during late postnatal development contributes to the closure of critical periods of development, stabilizing successful synaptic connectivity and instating a restricted mode of synaptic plasticity characteristic of adulthood.4, 23, 82, 83, 84”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [4] Mauney SA, Athanas KM, Pantazopoulos H, Shaskan N, Passeri E, Berretta S et al. Developmental pattern of perineuronal nets in the human prefrontal cortex and their deficit in schizophrenia. Biol Psychiatry 2013; 74: 427–435. source

      Not checked in the free run.

    • cites [23] Frischknecht R, Gundelfinger ED . The brain's extracellular matrix and its role in synaptic plasticity. Adv Exp Med Biol 2012; 970: 153–171. source

      Not checked in the free run.

    • cites [82] Gogolla N, Caroni P, Luthi A, Herry C . Perineuronal nets protect fear memories from erasure. Science 2009; 325: 1258–1261. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In the lateral nucleus, where these three markers at least in part colocalize in PNNs, the findings suggest that PNNs may be lost or at least lack several key elements.

    “In the LN, where these three markers, at least in part, colocalize in PNNs, our findings suggest that PNNs may be lost or at least lack several key elements.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Postmortem measurements of aggrecan and CS-6 immunoreactivity and mRNA in the amygdala reflect the antemortem state of these molecules in the donors.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Lithium treatment was shown in rodents to facilitate enzymatic CSPG digestion.

    “lithium treatment was shown in rodents to facilitate enzymatic CSPG digestion.71, 72”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [71] Yick LW, So KF, Cheung PT, Wu WT . Lithium chloride reinforces the regeneration-promoting effect of chondroitinase ABC on rubrospinal neurons after spinal cord injury. J Neurotrauma 2004; 21: 932–943. source

      Not checked in the free run.

    • cites [72] Frederick JP, Tafari AT, Wu SM, Megosh LC, Chiou ST, Irving RP et al. A role for a lithium-inhibited Golgi nucleotidase in skeletal development and sulfation. Proc Natl Acad Sci USA 2008; 105: 11605–11612. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Pantazopoulos H, Woo T-UW, Lim MP, Lange N, Berretta S . Extracellular matrix-glial abnormalities in the amygdala and entorhinal cortex of subjects diagnosed with schizophrenia. Arch Gen Psychiatry 2010; 67: 155–166. source

      Not checked in the free run.

    • Rests on an assumption: Postmortem measurements of aggrecan and CS-6 immunoreactivity and mRNA in the amygdala reflect the antemortem state of these molecules in the donors.

  • May combine two claims.

    Interpretationcitation

    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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Pantazopoulos H, Woo T-UW, Lim MP, Lange N, Berretta S . Extracellular matrix-glial abnormalities in the amygdala and entorhinal cortex of subjects diagnosed with schizophrenia. Arch Gen Psychiatry 2010; 67: 155–166. source

      Not checked in the free run.

    • Rests on an assumption: Postmortem measurements of aggrecan and CS-6 immunoreactivity and mRNA in the amygdala reflect the antemortem state of these molecules in the donors.
    • Rests on an assumption: The number of CS-6-IR glial clusters is a valid proxy for the number of CS-6-IR glial cells in the amygdala.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationown data

    In other amygdala nuclei tested, where the large majority of PNNs detected were labeled with 3B3, but not aggrecan or WFA, a similar conclusion may be premature.

    “In the other amygdala nuclei tested, where the large majority of PNNs detected were labeled with 3B3, but not aggrecan or WFA, a similar conclusion may be premature.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    No data are available regarding which CSPGs and sulfation patterns WFA detects.

    “no data are available regarding which CSPGs and sulfation patterns WFA detects.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The cat-301 antibody labels a distinct glycosylated form of the aggrecan core protein, whereas other glycosylated forms may be only partially recognized.

    “This antibody labels a distinct glycosylated form of the aggrecan core protein, whereas other glycosylated forms may be only partially recognized.56, 75”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [56] Matthews RT, Kelly GM, Zerillo CA, Gray G, Tiemeyer M, Hockfield S . Aggrecan glycoforms contribute to the molecular heterogeneity of perineuronal nets. J Neurosci 2002; 22: 7536–7547. source

      Not checked in the free run.

    • cites [75] Fryer HJ, Kelly GM, Molinaro L, Hockfield S . The high molecular weight Cat-301 chondroitin sulfate proteoglycan from brain is related to the large aggregating proteoglycan from cartilage, aggrecan. J Biol Chem 1992; 267: 9874–9883. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The specific binding site for WFA is known.

    “Although the specific binding site for WFA is known,58”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Kurokawa T, Tsuda M, Sugino Y . Purification and characterization of a lectin from Wistaria floribunda seeds. J Biol Chem 1976; 251: 5686–5693. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    PNN reductions suggest altered neuronal maturation and firing properties and instability of neuronal synaptic connectivity.

    “and suggest altered neuronal maturation and firing properties and instability of neuronal synaptic connectivity.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Reports that aggrecan knockout results in loss of WFA-positive PNNs support the possibility that PNNs may be lost or lack key elements.

    “Reports that aggrecan knockout results in loss of WFA-positive PNNs45, 46 support this possibility.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [45] Giamanco KA, Morawski M, Matthews RT . Perineuronal net formation and structure in aggrecan knockout mice. Neuroscience 2010; 170: 1314–1327. source

      Not checked in the free run.

    • cites [46] Giamanco KA, Matthews RT . Deconstructing the perineuronal net: cellular contributions and molecular composition of the neuronal extracellular matrix. Neuroscience 2012; 218: 367–384. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    PNN maturation occurs in an experience-dependent manner, requiring neuronal activation through glutamatergic excitation, availability of key PNN components, expression on neurons of ECM surface receptors, and transcription factors inducing neuronal maturation.

    “Their maturation occurs in an experience-dependent manner, requiring (i) neuronal activation through glutamatergic excitation,78 (ii) availability of key PNN components, such as specific CSPGs, link proteins and tenascin R, (iii) expression on neurons of ECM surface receptors79, 80 and (iv) transcription factors inducing neuronal maturation.25, 38”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [78] Dityatev A, Brückner G, Dityateva G, Grosche J, Kleene R, Schachner M . Activity-dependent formation and functions of chondroitin sulfate-rich extracellular matrix of perineuronal nets. Dev Neurobiol 2007; 67: 570–588. source

      Not checked in the free run.

    • cites [79] Carulli D, Rhodes KE, Fawcett JW . Upregulation of aggrecan, link protein 1, and hyaluronan synthases during formation of perineuronal nets in the rat cerebellum. J Comp Neurol 2007; 501: 83–94. source

      Not checked in the free run.

    • cites [25] Maeda N, Fukazawa N, Ishii M . Chondroitin sulfate proteoglycans in neural development and plasticity. Front Biosci 2010; 15: 626–644. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The detected effects of SSRIs and lithium are consistent with a corrective mechanism, showing positive correlations with CSPG-IR PNNs and glia in the face of significant decreases of these elements in diagnosis groups.

    “These effects are consistent with a corrective mechanism, showing positive correlations with CSPG-IR PNNs and glia in the face of significant decreases of these elements in diagnosis groups.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Glial/CSPG cluster abnormalities may represent a contributing factor to dysregulated glutamatergic transmission, and more broadly to neuron/glia interactions, in major psychoses.

    “Glial/CSPG cluster abnormalities may thus represent a contributing factor to dysregulated glutamatergic transmission, and more broadly to neuron/glia interactions, in major psychoses.15, 22, 105, 106”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [15] Coyle JT . The glutamatergic dysfunction hypothesis for schizophrenia. Harv Rev Psychiatry 1996; 3: 241–253. source

      Not checked in the free run.

    • cites [22] Halassa MM, Fellin T, Haydon PG . The tripartite synapse: roles for gliotransmission in health and disease. Trends Mol Med 2007; 13: 54–63. source

      Not checked in the free run.

    • cites [105] Goudriaan A, de Leeuw C, Ripke S, Hultman CM, Sklar P, Sullivan PF et al. Specific glial functions contribute to schizophrenia susceptibility. Schizophr Bull 2013; 40: 925–935. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    These findings indicate that CSPG abnormalities are widespread within the amygdala, and affect distinct neuronal and glial cell populations.

    “These findings indicate that CSPG abnormalities are widespread within the amygdala, and affect distinct neuronal and glial cell populations.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The role of CSPGs in PNN functions depends, at least in part, on their sulfation pattern; for instance CS-6 and CS-4 impact voltage-dependent calcium channels in distinct ways.

    “Relevant to the present results, the role of CSPGs in these functions depends, at least in part, on their sulfation pattern; for instance CS-6 and CS-4 impact voltage-dependent calcium channels in distinct ways.89”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89] Vigetti D, Andrini O, Clerici M, Negrini D, Passi A, Moriondo A . Chondroitin sulfates act as extracellular gating modifiers on voltage-dependent ion channels. Cell Physiol Biochem 2008; 22: 137–146. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These clusters were shown in rodents to surround a small number of neurons and regulate glutamatergic transmission.

    “These clusters were shown in rodents to surround a small number of neurons and regulate glutamatergic transmission.70, 100, 101”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [70] Hayashi N, Tatsumi K, Okuda H, Yoshikawa M, Ishizaka S, Miyata S et al. DACS, novel matrix structure composed of chondroitin sulfate proteoglycan in the brain. Biochem Biophys Res Commun 2007; 364: 410–415. source

      Not checked in the free run.

    • cites [100] Horii-Hayashi N, Tatsumi K, Matsusue Y, Okuda H, Okuda A, Hayashi M et al. Chondroitin sulfate demarcates astrocytic territories in the mammalian cerebral cortex. Neurosci Lett 2010; 483: 67–72. source

      Not checked in the free run.

    • cites [101] Okuda H, Tatsumi K, Morita S, Shibukawa Y, Korekane H, Horii-Hayashi N et al. Chondroitin sulfate proteoglycan tenascin-R regulates glutamate uptake by adult brain astrocytes. J Biol Chem 2014; 289: 2620–2631. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Our findings suggest that PNN abnormalities may impact on emotion processing and plasticity in major psychoses, potentially contributing to a disruption of fear learning reported in subjects with SZ.

    “Our findings suggest that PNN abnormalities may impact on emotion processing and plasticity in major psychoses, potentially contributing to a disruption of fear learning reported in subjects with SZ.94”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [94] Holt DJ, Coombs G, Zeidan MA, Goff DC, Milad MR . Failure of neural responses to safety cues in schizophrenia. Arch Gen Psychiatry 2012; 69: 893–903. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In adulthood, mature PNNs regulate synaptic functions representing the fourth element of the 'tetrapartite' synapse.

    “In adulthood, mature PNNs regulate synaptic functions representing the fourth element of what has been termed the ‘tetrapartite' synapse.85, 86”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [85] Dall'Oglio A, Xavier LL, Hilbig A, Ferme D, Moreira JE, Achaval M et al. Cellular components of the human medial amygdaloid nucleus. J Comp Neurol 2013; 521: 589–611. source

      Not checked in the free run.

    • cites [86] Dityatev A, Rusakov DA . Molecular signals of plasticity at the tetrapartite synapse. Curr Opin Neurobiol 2011; 21: 353–359. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Pantazopoulos H, Woo T-UW, Lim MP, Lange N, Berretta S . Extracellular matrix-glial abnormalities in the amygdala and entorhinal cortex of subjects diagnosed with schizophrenia. Arch Gen Psychiatry 2010; 67: 155–166. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    These functions underlie the role of the adult ECM in neuronal excitability, receptor desensitization, long-term potentiation and long-term depression.

    “Overall, these functions underlie the role of the adult ECM to neuronal excitability, receptor desensitization, long-term potentiation and long-term depression.59, 87, 88, 90, 91, 92, 93”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [59] Dityatev A, Bruckner G, Dityateva G, Grosche J, Kleene R, Schachner M . Activity-dependent formation and functions of chondroitin sulfate-rich extracellular matrix of perineuronal nets. Dev Neurobiol 2007; 67: 570–588. source

      Not checked in the free run.

    • cites [87] Frischknecht R, Heine M, Perrais D, Seidenbecher CI, Choquet D, Gundelfinger ED . Brain extracellular matrix affects AMPA receptor lateral mobility and short-term synaptic plasticity. Nat Neurosci 2009; 12: 897–904. source

      Not checked in the free run.

    • cites [90] Kochlamazashvili G, Henneberger C, Bukalo O, Dvoretskova E, Senkov O, Lievens PM et al. The extracellular matrix molecule hyaluronic acid regulates hippocampal synaptic plasticity by modulating postsynaptic L-type Ca(2+) channels. Neuron 2010; 67: 116–128. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Decreases of glial cells expressing CS-6 in both SZ and BD indicate that CS-6 sulfation on these cells may differentially contribute to the changes in PNNs observed in these disorders, and may impact glutamate reuptake and neurite outgrowth.

    “Decreases of glial cells expressing CS-6 in both SZ and BD indicate that CS-6 sulfation on these cells may differentially contribute to the changes in PNNs observed in these disorders, and may impact glutamate reuptake and neurite outgrowth.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    In SZ, reductions of aggrecan and 3B3-IR PNNs in LN, together with previously reported decreases of WFA-positive PNNs in the same nucleus, suggest PNN loss.

    “In SZ, reductions of aggrecan and 3B3-IR PNNs in LN, together with previously reported decreases of WFA-positive PNNs in the same nucleus, suggest PNN loss.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    In the LN, these changes may directly affect fear conditioning, whereas changes in the BN may impact on hippocampal context learning, and involvement of the CE, ME and ABN suggests direct effects on the bed nucleus of the stria terminalis, speculatively impacting on sustained fear mechanisms.

    “In the LN, these changes may directly affect fear conditioning, whereas changes in the BN may impact on hippocampal context learning, and involvement of the CE, ME and ABN suggests direct effects on the bed nucleus of the stria terminalis, speculatively impacting on sustained fear mechanisms.95, 96, 97, 98”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [95] Shin JW, Geerling JC, Loewy AD . Inputs to the ventrolateral bed nucleus of the stria terminalis. J Comp Neurol 2008; 511: 628–657. source

      Not checked in the free run.

    • cites [96] Walker DL, Davis M . Role of the extended amygdala in short-duration versus sustained fear: a tribute to Dr. Lennart Heimer. Brain Struct Funct 2008; 213: 29–42. source

      Not checked in the free run.

    • cites [97] Maren S, Phan KL, Liberzon I . The contextual brain: implications for fear conditioning, extinction and psychopathology. Nat Rev Neurosci 2013; 14: 417–428. source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Astrocytes form microdomains modulating glutamatergic synapses and extrasynaptic glutamate receptors, and CSPGs control lateral diffusion of cell surface receptors, extrasynaptic diffusion of negatively charged transmitters such as glutamate, and expression of glial transmitter transporters.

    “This possibility is in line with growing evidence indicating that astrocytes form microdomains modulating glutamatergic synapses and extrasynaptic glutamate receptors, and that CSPGs (cell surface bound and as part of ECM) control (i) lateral diffusion of cell surface receptors, (ii) the extrasynaptic diffusion of negatively charged transmitters such as glutamate and (iii) the expression of glial”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [23] Frischknecht R, Gundelfinger ED . The brain's extracellular matrix and its role in synaptic plasticity. Adv Exp Med Biol 2012; 970: 153–171. source

      Not checked in the free run.

    • cites [87] Frischknecht R, Heine M, Perrais D, Seidenbecher CI, Choquet D, Gundelfinger ED . Brain extracellular matrix affects AMPA receptor lateral mobility and short-term synaptic plasticity. Nat Neurosci 2009; 12: 897–904. source

      Not checked in the free run.

    • cites [102] Bridges R, Lutgen V, Lobner D, Baker DA . Thinking outside the cleft to understand synaptic activity: contribution of the cystine-glutamate antiporter (System xc-) to normal and pathological glutamatergic signaling. Pharmacol Rev 2012; 64: 780–802. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PNNs control the lateral mobility of cell surface molecules including glutamatergic receptors, modulate L-type voltage-dependent calcium channels and voltage-gated potassium channels, and affect the local concentration of calcium ions.

    “PNNs control the lateral mobility of cell surface molecules including glutamatergic receptors, thus regulating their availability on the postsynaptic membrane specialization, modulate L-type voltage-dependent calcium channels and voltage-gated potassium channels and affect the local concentration of calcium ions.30, 31, 87, 88”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [30] Dityatev A, Schachner M . The extracellular matrix and synapses. Cell Tissue Res 2006; 326: 647–654. source

      Not checked in the free run.

    • cites [31] Dityatev A, Schachner M, Sonderegger P . The dual role of the extracellular matrix in synaptic plasticity and homeostasis. Nat Rev Neurosci 2010; 11: 735–746. source

      Not checked in the free run.

    • cites [87] Frischknecht R, Heine M, Perrais D, Seidenbecher CI, Choquet D, Gundelfinger ED . Brain extracellular matrix affects AMPA receptor lateral mobility and short-term synaptic plasticity. Nat Neurosci 2009; 12: 897–904. source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Pantazopoulos H, Woo T-UW, Lim MP, Lange N, Berretta S . Extracellular matrix-glial abnormalities in the amygdala and entorhinal cortex of subjects diagnosed with schizophrenia. Arch Gen Psychiatry 2010; 67: 155–166. source

      Not checked in the free run.

64 of 64

  • The paper relies on this without support.

    Postmortem measurements of aggrecan and CS-6 immunoreactivity and mRNA in the amygdala reflect the antemortem state of these molecules in the donors.

    “Tissue blocks containing the whole amygdala from a cohort of normal control donors (n=29), and donors with SZ (n=24) or BD (n=20) and were used for histochemical and immunocytochemical investigations”

  • The paper relies on this without support.

    The number of CS-6-IR glial clusters is a valid proxy for the number of CS-6-IR glial cells in the amygdala.

    “Quantitative analysis for normal and comparison studies (below) focused on the number of glial clusters because under light microscopy the intensity of the diffuse immunolabeling did not allow clear identification of individual CS-6-IR glial cells”

  • The paper relies on this without support.

    The diagnostic classification of subjects as schizophrenia, bipolar disorder, or control is accurate.

    “Diagnoses of SZ and BD were made by two psychiatrists on the basis of retrospective review of medical records and extensive questionnaires concerning social and medical history provided by the family members.”

  • The paper relies on this without support.

    The sample of donors is representative of the broader populations of individuals with schizophrenia and bipolar disorder.

    “Tissue blocks containing the whole amygdala from a cohort of normal control donors (n=29), and donors with SZ (n=24) or BD (n=20) and were used for histochemical and immunocytochemical investigations”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Disruption of PNNs has been particularly well documented in schizophrenia, with marked decreases of CSPG-labeled PNNs in the amygdala, entorhinal cortex and PFC.

    “Disruption of PNNs has been particularly well documented in schizophrenia, with marked decreases of CSPG--labeled PNNs in the amygdala, entorhinal cortex and PFC (Pantazopoulos et al., 2010a;Mauney et al., 2013;Pantazopoulos et al., 2015).”

    From Casting a Wide Net: Role of Perineuronal Nets in Neural Plasticity (2016) · cites this paper as Pantazopoulos et al., 2015

  • CSPGs in PNNs are labelled by WFA differently from CS-56, possibly because of differences in CSPG sidechain sulphation or epitope availability.

    “CSPGs contained in PNNs are labelled by the plant lectin WFA in a manner distinct from CS-56 (Hayashi et al. , 2007; Pantazopoulos et al. , 2015; Yutsudo and Kitagawa, 2015), potentially due to differences in CSPG sidechain sulphation status (Sorg et al. , 2016) or epitope availability.”

    From Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntington's disease (2020) · cites this paper as Pantazopoulos et al. , 2015

  • 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, 2015

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • BD discussion includes a 3B3-IR PNN decrease in the CO that results do not report

    Minor

    The discussion lists the CO among nuclei with decreased 3B3-IR PNNs in bipolar disorder, but the results list decreases only in the LN, BN, AB and ME.

  • Pharmacological effects described as limited to SSRIs and lithium despite a reported VPA effect

    Minor

    The technical discussion says detected pharmacological effects were limited to SSRIs and lithium, whereas the results report an effect of VPA used to adjust the 3B3-IR PNN analyses.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 3

  1. Amaral DG, Price JL, Pitkanen A, Carmichael ST . Anatomical organization of the primate amygdaloid complex. In: Aggleton JP (ed). The Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction. Wiley-Liss: New York, NY, USA, 1992.
  2. Baldessarini RJ, Tarazi FI . Pharmacotherapy of psychosis and mania. In: Brunton LL, Lazo JS, Parker KL (eds). Goodman and Gilman's The Pharmacological Basis of Therapeutics, 11th edn. McGraw-Hill Press: New York, NY, USA, 1995; 461–500.
  3. Dityatev A, Brückner G, Dityateva G, Grosche J, Kleene R, Schachner M . Activity-dependent formation and functions of chondroitin sulfate-rich extracellular matrix of perineuronal nets. Dev Neurobiol 2007; 67: 570–588. · DOI · Paper page

Cited by

Sorted by citations

Authors
Pantazopoulos, H., Markota, M., Jaquet, F., Ghosh, D., Wallin, A., Santos, A., Caterson, B., & Berretta, S.
Affiliations
  • Harvard University (US)
  • McLean Hospital (US)
  • Cardiff University (GB)
Corresponding author
Berretta, S
ORCID
Venue
Translational Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2015-01-20
Volume
5
Issue
1
Pages
e496-e496
ISSN
2158-3188 (ISSN-L)
DOI
10.1038/tp.2014.128
PMC
PMC4312825
OpenAlex
W2112406695
Cited by
153
References
103
Citations by year
2026: 11 · 2025: 13 · 2024: 15 · 2023: 14 · 2022: 13 · 2021: 16 · 2020: 19 · 2019: 10 · 2018: 17 · 2017: 9 · 2016: 11 · 2015: 5
FWCI
7.45
Type
journal article
Language
en
Open access
Licence
Locations
  • Translational Psychiatry (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
Funders
  • Versus Arthritis (19858)
  • National Institutes of Health
  • National Institute of Mental Health (R01MH091348, R01MH086522, R21MH083222)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
aggrecan, chondroitin-6-sulfate, perineuronal nets, amygdala, schizophrenia, bipolar disorder, proteoglycans, extracellular matrix, glial cells, synaptic connectivity, major psychoses
MeSH terms
Adult, Aged, Aged, 80 and over, Amygdala, Bipolar Disorder, Chondroitin Sulfates, Female, Humans, Immunohistochemistry, Male, Middle Aged, Neuroglia, Schizophrenia, Case-Control Studies, Aggrecans

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

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