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Cited by 204Neurogenesis and neuroplasticity mechanismsNeuroscience and Neuropharmacology ResearchProteoglycans and glycosaminoglycans research

Aggrecan Directs Extracellular Matrix-Mediated Neuronal Plasticity

Open access
Rowlands, Daire, Lensjø, Kristian K., Dinh, Tovy, Yang, Sujeong, Andrews, Melissa R., Hafting, Torkel, Fyhn, Marianne, Fawcett, James W. +1 more·2018·The Journal of Neuroscience
DOI 10.1523/jneurosci.1122-18.2018PMC PMC6596198
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Abstract

In the adult brain, the extracellular matrix (ECM) influences recovery after injury, susceptibility to mental disorders, and is in general a strong regulator of neuronal plasticity. The proteoglycan aggrecan is a core component of the condensed ECM structures termed perineuronal nets (PNNs), and the specific role of PNNs on neural plasticity remains elusive. Here, we genetically targeted the Acan gene encoding for aggrecan using a novel animal model. This allowed for conditional and targeted loss of aggrecan in vivo, which ablated the PNN structure and caused a shift in the population of parvalbumin-expressing inhibitory interneurons toward a high plasticity state. Selective deletion of the Acan gene in the visual cortex of male adult mice reinstated juvenile ocular dominance plasticity, which was mechanistically identical to critical period plasticity. Brain-wide targeting improved object recognition memory. SIGNIFICANCE STATEMENT The study provides the first direct evidence of aggrecan as the main functional constituent and orchestrator of perineuronal nets (PNNs), and that loss of PNNs by aggrecan removal induces a permanent state of critical period-like plasticity. Loss of aggrecan ablates the PNN structure, resulting in invoked juvenile plasticity in the visual cortex and enhanced object recognition memory.

Verified 2026-10-06 · 12 references not checked yet

AI snapshot

Written from the paper’s full text.

TL;DR

Using a conditional Acan knockout mouse, this study shows that aggrecan is required for perineuronal net (PNN) assembly and that removing it in adult visual cortex reinstates juvenile-like ocular dominance plasticity and improves object recognition memory. It identifies aggrecan as a main functional constituent and orchestrator of PNNs.

Key findings

  • Brain-wide conditional deletion of Acan (Acan-loxP +/+ CreNes) caused complete loss of WFA-labeled PNNs and prevented aggregation of other PNN components; heterozygous Acan-loxP +/-CreNes mice had anatomically normal PNNs but reduced WFA staining intensity (WFA ANOVA p=0.000244; Tukey heterozygous vs targeted p=0.0001934).
  • Both heterozygous and homozygous Acan knockout mice showed a shift toward lower parvalbumin (PV) expression in cortical PV+ interneurons compared with WT and Acan-loxP +/+ controls (>150 PV+ cells per group; ANOVA p<2e-16), suggesting a high-plasticity network state.
  • Local AAV9.Cre injection into adult V1 abolished aggrecan and WFA labeling by 8 weeks (WFA intensity lower in injected vs contralateral hemisphere, p=0.0006, paired t-test, n=6 mice). Four days of monocular deprivation produced a significant ocular dominance shift in AAV9.Cre-injected Acan-loxP +/+ mice (p=0.003, n=7), with increased ipsilateral responses (p=0.02) and reduced contralateral responses (p=0.009), while no effect was seen in non-injected Acan-loxP +/+ mice (p=0.21, n=4) or AAV9.Cre-injected Acan-loxP +/- mice (p=0.32, n=3).
  • In spontaneous object recognition, Acan-loxP +/+ CreNes mice retained memory at 24 hours, whereas WT, Acan-loxP +/+, and Acan-loxP +/-CreNes groups showed significant decline from 3-hour to 24-hour delays (WT p=0.02547; homozygous Acan-loxP +/+ p=0.001154; heterozygous Acan-loxP +/-CreNes p=0.01658; Acan-loxP +/+ CreNes p=0.3768).

Methods

  • A conditional Acan-loxP mouse was generated from EUCOMM tm1a embryonic stem cells, converted to the tm1c allele, and crossed with Nestin-CRE for brain-wide deletion; local adult deletion used AAV9.hSyn.HI.eGFP-Cre injection into primary visual cortex.
  • Histology and biochemistry included WFA and aggrecan staining, immunohistochemistry for PNN components and PV, Western blotting, and qPCR; plasticity was assessed by optical imaging of intrinsic signals before and after 4-day monocular deprivation, and memory by spontaneous object recognition at 3-hour and 24-hour delays.
  • Experiments used male mice: histology at 3–4 months (n=3 per group), ocular dominance testing at 5–7 months (n=4, 3, and 7 across groups), and object recognition at ~3 months (>7 per group). Statistical analysis used R or GraphPad Prism with Shapiro-Wilk/F tests, Welch’s or paired t-tests, and ANOVA with Tukey post hoc tests.

Limitations

  • The paper does not include a dedicated limitations section; it states prior technical limitations such as off-target effects of chondroitinase ABC and embryonic lethality of Acan mutation, which motivated the new model.
  • Evident from the text: all reported experiments used male mice only, ocular dominance groups were small (n=3–7), and memory was assessed only with spontaneous object recognition.
  • Heterozygous Acan-loxP +/-CreNes mice showed reduced PNN intensity and altered PV expression but no detected behavioral alterations, indicating that some PNN/PV changes did not translate into the tested memory phenotype.

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

Integrity signals

Registry

Crossref · 10.1523/jneurosci.1122-18.2018

Cites

25 of 37 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 43 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Aggrecan protein is ablated in Acan-loxP +/+ CreNes mice as verified by immunohistochemistry and western blotting.

    “Ablation of aggrecan was verified by immunohistochemistry and western blotting (Fig. 1c, d)”
    Quote in the paperSubstantial claim
  • Findingown data

    The intensity of WFA staining is reduced in heterozygous Acan-loxP +/-CreNes mice compared to controls.

    “although the intensity of the WFA staining was reduced in the heterozygote (Fig. 2b-e).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The WFA histochemical signal specifically and quantitatively reflects the presence of PNNs.
  • Findingown data

    Brain-wide targeting of Acan in Acan-loxP +/+ CreNes mice causes complete loss of histochemical staining of PNNs in the cortex using WFA.

    “Targeting aggrecan in the brain of Acan-loxP +/+ CreNes mice was accompanied by complete loss of histochemical staining of PNNs in the cortex using the PNN marker Wisteria floribunda agglutinin (WFA) (Fig. 1b).”
    • Also stated in: § Abstract · plain
      “Loss of aggrecan ablates the PNN structure”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The WFA histochemical signal specifically and quantitatively reflects the presence of PNNs.
  • Findingown data

    Acan mRNA is reduced in the brain of Acan-loxP +/+ CreNes mice.

    “and reduced Acan mRNA in the brain (Fig. 1e).”
    Quote in the paperSubstantial claim
  • Findingown data

    Loss of aggrecan disrupts aggregation of the other PNN components in the visual cortex.

    “Again, loss of aggrecan disrupted aggregation of the other PNN components (Fig. 3e)”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The WFA histochemical signal specifically and quantitatively reflects the presence of PNNs.
  • May combine two claims. 15
  • Classified as probably not a substantial claim. 14

  • May combine two claims.

    Findingown data

    Non-targeted Acan-loxP +/+ mice with two intact alleles and targeted heterozygous Acan-loxP +/-CreNes mice with one intact allele both have anatomically normal PNNs.

    “In contrast, the non-targeted Acan-loxP +/+ mice with two intact alleles expressing Acan, and the targeted heterozygous Acan-loxP +/-CreNes mice having one intact allele, both had anatomically normal PNNs (Fig. 1b, f)”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The WFA histochemical signal specifically and quantitatively reflects the presence of PNNs.

  • May combine two claims.

    Findingown data

    Loss of aggrecan prevents aggregation of other PNN component ECM molecules into PNNs, effectively abolishing PNNs in the adult cortex.

    “The loss of aggrecan prevented aggregation of other PNN component ECM molecules into PNNs, effectively abolishing PNNs in the adult cortex (Fig. 1f, representative example from > 50 images per PNN component.Fig. 2a, overview of sampling).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The WFA histochemical signal specifically and quantitatively reflects the presence of PNNs.

  • May combine two claims.

    Findingown data

    Heterozygous Acan-loxP +/-CreNes mice have reduced perineuronal net intensity and altered parvalbumin expression.

    “Although heterozygous Acan-loxP +/-CreNes have reduced PNNs intensity and altered PV expression”
    • Also stated in: § REFERENCES: · plain
      “Both Acan-loxP +/-Cre and Acan-loxP +/+ Cre groups displayed a significant reduction in average mean intensity per PV+ cell compared to WT and Acan-loxP +/+ controls.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The shift in ocular dominance in AAV9.Cre injected Acan-loxP +/+ mice was driven both by a potentiation of ipsilateral responses and a reduction in contralateral responses.

    “Instead, the shift in OD was driven both by a potentiation of ipsilateral responses and a reduction in contralateral responses”
    • Also stated in: § REFERENCES: · plain
      “The MD in AAV9.Cre injected Acan-loxP +/+ caused both increased responses to ipsilateral stimulation (p=0.02,paired t-test, n=7 mice) and reduced responses to contralateral stimulation (p=0.009,paired-test, n=7 mice)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Four days of monocular deprivation did not affect ocular dominance in AAV9.Cre injected Acan-loxP +/- mice or non-injected Acan-loxP +/+ mice.

    “while no effect was observed in AAV9.Cre injected Acan-loxP +/-mice or non-injected Acan-loxP +/+ mice (Fig. 4c).”
    • Also stated in: § REFERENCES: · plain
      “Four days of MD did not affect ocular dominance in non-injected Acan-loxP +/+ mice (p=0.21,paired t-test, n=4 mice) or in heterozygous AAV9.Cre injected Acan-loxP +/-mice (p=0.32,paired t-test, n=3 mice).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Closure of critical periods and loss of juvenile plasticity coincide with maturation of inhibitory circuits and condensation of extracellular matrix around subtypes of neurons.

    “Closure of the CPs and concomitant loss of juvenile plasticity coincide with maturation of inhibitory circuits (Hensch, 2004) and condensation of extracellular matrix around subtypes of neurons.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hensch, 2004

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The identity of the CSPG responsible for the effects of PNN degradation on plasticity and memory has not been determined.

    “However, the identity of the CSPG responsible for these effects has not been determined.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Pizzorusso et al., 2002

      Not checked in the free run.

    • cites Carulli et al., 2010

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Enzymatic degradation of the chondroitin sulfate glycosaminoglycan (GAG) component or ablation of cartilage link protein 1 (Crtl1) restores juvenile plasticity in adult animals and affects memory and learning.

    “Remarkably, enzymatically degrading the CS glycosaminoglycan (GAG) component (Pizzorusso et al., 2002) or ablating the cross-linking cartilage link protein 1 (Crtl1) (Carulli et al., 2010) restores juvenile plasticity in the adult animal and affects memory and learning, as revealed by behavioral tasks such as fear memory extinction (Gogolla et al., 2009) and spontaneous object recognition (Romberg”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Pizzorusso et al., 2002

      Not checked in the free run.

    • cites Carulli et al., 2010

      Not checked in the free run.

    • cites Gogolla et al., 2009

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aggrecan is a major constituent of perineuronal nets (PNNs) and is encoded by the Acan gene.

    “The proteoglycan aggrecan is a core component of the condensed ECM structures termed perineuronal nets (PNNs)”
    • Also stated in: § INTRODUCTION · plain
      “Here we investigate the role of the CSPG aggrecan, a major constituent of PNNs, encoded by Acan (Matthews et al., 2002).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Matthews et al., 2002

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The extracellular matrix (ECM) is a strong regulator of neuronal plasticity and influences recovery after injury and susceptibility to mental disorders.

    “In the adult brain, the extracellular matrix (ECM) influences recovery after injury, susceptibility to mental disorders, and is in general a strong regulator of neuronal plasticity.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Pizzorusso et al., 2002

      Not checked in the free run.

    • cites Carulli et al., 2010

      Not checked in the free run.

    • cites Gogolla et al., 2009

      Not checked in the free run.

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

    Interpretationcitation

    Increased plasticity after perineuronal net removal could be a direct consequence of neuronal activity changes in parvalbumin-positive cells.

    “The increased plasticity after PNN removal could also be a direct consequence of neuronal activity changes in PV + cells.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The specific role of PNNs on neural plasticity remains elusive.

    “the specific role of PNNs on neural plasticity remains elusive.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Pizzorusso et al., 2002

      Not checked in the free run.

    • cites Carulli et al., 2010

      Not checked in the free run.

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

    Study design and conductreasoning

    The maze and all objects were wiped down with 70% EtOH between testing sessions to avoid olfactory bias.

    “The maze and all objects were wiped down with 70% EtOH in between each testing session in order to avoid any olfactory bias that could have been introduced during the previous testing session.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Parvalbumin (PV) expression on GABAergic interneurons is influenced by PNNs in the hippocampus.

    “Recently, parvalbumin (PV) expression on GABAergic interneurons has been shown to be influenced by PNNs in the hippocampus (Yamada et al., 2015)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Yamada et al., 2015

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The three globular domains G1, G2 and G3 interact with several matrix molecules aiding cross-linking, which could explain the failure of other components to aggregate in the absence of aggrecan.

    “The three globular domains; G1, G2 and G3 interact with several matrix molecules aiding cross-linking, which could explain the failure of other components to aggregate in its absence.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Perineuronal net structure is based on tight cross-linking of matrix proteins, chondroitin sulfate and hyaluronic acid polysaccharides forming a condensed compact matrix, and on negatively charged sulfation patterns allowing specific interactions with positively charged domains in PNN interacting proteins.

  • May combine two claims.

    Premisecitation

    ChABC-treated and Crtl1 knockout animals show enhanced memory retention at three and 24 hour delays.

    “Animals were tested after three and 24 hour delays, at which times ChABC-treated and Crtl1 knockout animals show enhanced memory retention (Romberg et al., 2013).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Romberg et al., 2013

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The timeframe of the ocular dominance shift after monocular deprivation in Acan knockout is faster than in critical-period aged mice but in line with previous work on adult mice with induced plasticity.

    “The timeframe of this shift is faster than what has been observed in CP aged mice (Sato and Stryker, 2008), but is in line with previous work on adult mice with induced plasticity (Fu et al., 2015).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Sato and Stryker, 2008

      Not checked in the free run.

    • cites Fu et al., 2015

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Several interventions affecting perineuronal nets have effects on learning and memory.

    “Several interventions affecting PNNs have effects on learning and memory (Gogolla et al., 2009;Carulli et al., 2010;Romberg et al., 2013).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Gogolla et al., 2009

      Not checked in the free run.

    • cites Carulli et al., 2010

      Not checked in the free run.

    • cites Romberg et al., 2013

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).

    Premisecitation

    The level of parvalbumin in parvalbumin-positive interneurons determines whether the network is in a state of high or low plasticity.

    “Others have suggested that the level of PV in PV+ interneurons determine if the network is in a state of high or low plasticity (Donato et al., 2013)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Donato et al., 2013

      Not checked in the free run.

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

    Study design and conductreasoning

    The presentation of the object pairs and their appearance in either the left or right sample arm were counterbalanced to avoid unforeseen bias.

    “The presentation of the object pairs and their appearance in either the left or right sample arm were counterbalanced so that a particular object in a set or a particular side might be novel for one animal and not for another to avoid unforeseen bias.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The differentiation state and activity of PV+ interneurons relate to learning and memory formation.

    “and the differentiation state and activity of PV+ interneurons relate to learning and memory formation (Donato et al., 2013).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Donato et al., 2013

      Not checked in the free run.

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

    Study design and conductnone given

    To reduce variance in antibody binding, all groups used for quantification were histologically stained in batches using the same conditions and antibody solutions.

    “To reduce variance in antibody binding all groups used for quantification were histologically stained in batches using the same conditions and antibody solutions.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The ratio of 4- and 6-sulfated chondroitin sulfate influences neuronal plasticity.

    “Indeed, the ratio of 4-and 6-sulfated CS influences neuronal plasticity (Miyata et al., 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Miyata et al., 2012

      Not checked in the free run.

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

    Study design and conductnone given

    The tracer injections were intentionally targeted to a more medial part of V1 to prevent leakage into the neighboring V2L region.

    “The tracer injections were intentionally targeted to a more medial part of V1 to prevent leakage into the neighboring V2L region.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    A shift in the distribution of WFA histochemical labeling intensity correlates with the degree of neuronal plasticity in learning and memory.

    “A shift in the distribution of WFA histochemical labeling intensity has been suggested to correlate with the degree of neuronal plasticity in learning and memory (Balmer et al., 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Balmer et al., 2009

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Aggrecan plays a key role for perineuronal net structure, possibly through the large number of glycan chains it carries, but clearly by affecting formation.

    “Our data suggest that aggrecan plays a key role for the PNN structure, possibly through the large number of glycan chains that it carries, but clearly by affecting formation.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Perineuronal net structure is based on tight cross-linking of matrix proteins, chondroitin sulfate and hyaluronic acid polysaccharides forming a condensed compact matrix, and on negatively charged sulfation patterns allowing specific interactions with positively charged domains in PNN interacting proteins.

  • May combine two claims.

    Premisecitation

    Longer lasting sensory deprivation has been shown to induce some ocular dominance plasticity also in adult mice, but the mechanism differs from juvenile plasticity.

    “Longer lasting sensory deprivation has been shown to induce some OD plasticity also in adult mice, but the mechanism differs from juvenile plasticity (Sawtell et al., 2003;Ranson et al., 2012).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Sawtell et al., 2003

      Not checked in the free run.

    • cites Ranson et al., 2012

      Not checked in the free run.

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

    Premisecitation

    Aggrecan and perineuronal nets have been implied in various psychiatric disorders and in the progression of neurodegenerative diseases.

    “Recently, aggrecan and PNNs have been implied in various psychiatric disorders (Pantazopoulos et al., 2015), and in the progression of neurodegenerative diseases (Suttkus et al., 2016).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Pantazopoulos et al., 2015

      Not checked in the free run.

    • cites Suttkus et al., 2016

      Not checked in the free run.

28 of 28

  • The paper relies on this without support.

    The WFA histochemical signal specifically and quantitatively reflects the presence of PNNs.

    “using the PNN marker Wisteria floribunda agglutinin (WFA)”
    “PNNs detected by WFA were absent in the brain.”

  • The paper relies on this without support.

    The mouse visual cortex is a valid model for studying critical period plasticity.

    “Selective deletion of the Acan gene in the visual cortex of male adult mice reinstated juvenile ocular dominance plasticity”

  • The paper relies on this without support.

    The role of aggrecan, the backbone of perineuronal nets, in plasticity regulation remains to be investigated, and a full picture of plasticity regulation is lacking.

    “Although several PNN CSPGs have been linked to plasticity regulation, the role of aggrecan, the backbone of PNN remains to be investigated, and a full picture of plasticity regulation is lacking.”

  • The paper relies on this without support.

    Aggrecan-containing perineuronal nets play an essential role in regulation of brain plasticity.

    “It has been suggested that aggrecan-containing PNNs play an essential role in regulation of brain plasticity.”

  • The paper relies on this without support.

    Condensation of perineuronal nets in sensory cortices correlates with closure of periods of heightened neuronal plasticity in sensory systems.

    “Condensation of PNNs in sensory cortices correlates with closure of periods of heightened neuronal plasticity in sensory systems.”

  • The paper relies on this without support.

    Monocular deprivation in adults normally affects only responses to ipsilateral eye stimulation.

    “While monocular deprivation in adults normally effects only responses to ipsilateral eye stimulation”

  • The paper relies on this without support.

    Decreased parvalbumin expression and synapses are associated with hippocampal learning, while fear conditioning leads to a high-parvalbumin state.

    “Decreased PV expression and synapses are associated with hippocampal learning, while fear conditioning leads to a high-PV state.”

  • The paper relies on this without support.

    Parvalbumin-positive neuron-controlled shifts in network state are an integrated mechanism of learning and memory acquisition.

    “PV+ neuron-controlled shifts in network state are suggested as an integrated mechanism of learning and memory acquisition.”

  • The paper relies on this without support.

    ChABC treatment to degrade perineuronal nets shifted the network to a low-parvalbumin state, indicating that the glycans on CSPGs are a key component in controlling parvalbumin interneuron influence on network state.

    “ChABC treatment to degrade PNNs shifted the network to a low-PV state, indicating that the glycans on CSPGs are a key component in controlling PV interneuron influence on network state.”

  • The paper relies on this without support.

    Mounting evidence from other brain structures supports a broader role for perineuronal nets where they affect behavior, memory and learning processes.

    “Mounting evidence from other brain structures supports a broader role for PNNs where they affect behavior, memory and learning processes.”

  • The paper relies on this without support.

    Perineuronal net structure is based on tight cross-linking of matrix proteins, chondroitin sulfate and hyaluronic acid polysaccharides forming a condensed compact matrix, and on negatively charged sulfation patterns allowing specific interactions with positively charged domains in PNN interacting proteins.

    “These mechanisms are based on the distinctive PNN structure; the tight cross-linking structures of matrix proteins, CS and hyaluronic acid polysaccharides forming a condensed compact matrix surrounding the cell soma and proximal dendrites, and the ability of the negatively charged sulfation patterns of the CS to allow specific interactions with positively charged domains in PNN interacting”
11 of 11

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?

  • Digestion of CSPGs in the primary visual cortex in rats or deletion of aggrecan in mice decreases inhibitory activity, causing the network to revert to an immature juvenile state and an increased level of activity-dependent plasticity.

    “In line with this, digestion of CSPGs in the primary visual cortex in rats or deletion of aggrecan in mice decreases inhibitory activity, causing the network to revert to an immature juvenile state and an increased level of activity-dependent plasticity [47, 69].”

    From The extracellular matrix and perineuronal nets in memory (2022) · cites this paper as [69]

    The Results and Discussion report that aggrecan deletion in adult mice restores juvenile-like ocular-dominance plasticity in visual cortex. The Discussion also reports a similar effect after enzymatic PNN degradation in adult rats, but says reduced PV-neuron activity was found in previous work and only proposes it as a possible cause of the increased plasticity. It does not establish that aggrecan deletion itself decreases inhibitory activity or that this decrease causes the plasticity. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Disaggregation of PNNs by genetic deletion of aggrecan shifts the population of PV inhibitory interneurons toward a juvenile-like plasticity state, accompanied by increased performance in the SOR memory task.

    “Similarly, disaggregation of PNNs by genetic deletion of aggrecan shifts the population of PV inhibitory interneurons toward a juvenile-like plasticity state, accompanied by increased performance in the SOR memory task [69].”

    From The extracellular matrix and perineuronal nets in memory (2022) · cites this paper as [69]

  • Enhanced plasticity and learning is observed following experimental perineuronal net ablation.

    “enhanced plasticity and learning is observed following experimental PNN ablation [23, 24]”

    From Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain (2020) · cites this paper as [24]

  • Aggrecan staining at 12 months confirmed morphological abnormalities and loss of 5xFAD subiculum and cortical PNNs.

    “Finally, disease-related effects on PNNs were validated at 12mo by staining for aggrecan, a core PNN CSPG [24], which confirmed the morphological abnormalities as well as the loss of 5xFAD subiculum and cortical PNNs at this timepoint (p<0.001, p<0.05; Fig. S2D-F).”

    From Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain (2020) · cites this paper as [24]

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.

  • Object-recognition group sizes contradict "more than seven per group"

    Minor

    The Results state that each group had more than seven animals, but the reported group sizes include two groups of seven.

  • The Cre-carrying viral vector is given two different names

    Minor

    The methods identify the purchased vector with an eGFP-Cre insert, whereas the Results give its name without "-Cre" while still describing it as carrying Cre recombinase.

2 of 2

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Authors
Rowlands, D., Lensjø, K. K., Dinh, T., Yang, S., Andrews, M. R., Hafting, T., Fyhn, M., Fawcett, J. W., & Dick, G.
Affiliations
  • University of Oslo (NO)
  • University of Cambridge (GB)
  • University of Southampton (GB)
  • Czech Academy of Sciences (CZ)
ORCID
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2018-10-03
Volume
38
Issue
47
Pages
10102-10113
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.1122-18.2018
PMC
PMC6596198
OpenAlex
W2894865807
Semantic Scholar
9d76c8f2d73c04f3367a993907c15081487d05ea
Cited by
204
References
37
Citations by year
2026: 20 · 2025: 40 · 2024: 30 · 2023: 23 · 2022: 33 · 2021: 17 · 2020: 26 · 2019: 14 · 2018: 1
FWCI
5.33
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • ePrints Soton (University of Southampton) (submittedVersion)
Funders
  • Christopher and Dana Reeve Foundation
  • Universitetet i Oslo
  • Norges Forskningsråd (231248)
  • Medical Research Council (MR/R004544/1, MR/R004463/1)
  • Biotechnology and Biological Sciences Research Council (BB/N008189/1)
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
Keywords
aggrecan, perineuronal nets, extracellular matrix, neuroplasticity, parvalbumin interneurons, ocular dominance plasticity, critical period plasticity, visual cortex, object recognition memory, conditional gene deletion, proteoglycans
MeSH terms
Animals, Cell Line, Extracellular Matrix, Mice, Inbred C57BL, Mice, Transgenic, Nerve Net, Neuronal Plasticity, Photic Stimulation, Visual Cortex, Mice, Knockout, Mice, 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.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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