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

The DOI matches its Crossref record; 25 of the 37 references it cites were found in a registry or an index, and 12 are not checked yet; none of the 43 sources its claims cite is checked for support yet.

Aggrecan Directs Extracellular Matrix-Mediated Neuronal Plasticity

Open access

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.

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

Overview

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.

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Integrity signals

Registry

Crossref · 10.1523/jneurosci.1122-18.2018

Cites

25 of 37 references verified0 citation errors · 0 not checkable

Statistics

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Verification

Claims the paper makes

30 Own result · 28 Not checked yet · 21 Own interpretation · 5 Own method

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Show all 56 claims

  • It may state two separate claims as one. 15
  • Probably not a substantial claim. 14
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

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Metadata

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)
Venue
The Journal of Neuroscience
Published
2018-10-03
Volume
38
Issue
47
Pages
10102-10113
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
OpenAlex
W2894865807
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
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

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