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Cited by 271Neuroscience and Neuropharmacology ResearchMemory and Neural MechanismsNeurogenesis and neuroplasticity mechanisms

Perineuronal Nets Suppress Plasticity of Excitatory Synapses on CA2 Pyramidal Neurons

Open access
Carstens, Kelly E., Phillips, Mary L., Pozzo-Miller, Lucas, Weinberg, Richard J., Dudek, Serena M.·2016·The Journal of Neuroscience
DOI 10.1523/jneurosci.0245-16.2016PMC PMC4899529
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Abstract

UNLABELLED: Long-term potentiation of excitatory synapses on pyramidal neurons in the stratum radiatum rarely occurs in hippocampal area CA2. Here, we present evidence that perineuronal nets (PNNs), a specialized extracellular matrix typically localized around inhibitory neurons, also surround mouse CA2 pyramidal neurons and envelop their excitatory synapses. CA2 pyramidal neurons express mRNA transcripts for the major PNN component aggrecan, identifying these neurons as a novel source for PNNs in the hippocampus. We also found that disruption of PNNs allows synaptic potentiation of normally plasticity-resistant excitatory CA2 synapses; thus, PNNs play a role in restricting synaptic plasticity in area CA2. Finally, we found that postnatal development of PNNs on CA2 pyramidal neurons is modified by early-life enrichment, suggesting that the development of circuits containing CA2 excitatory synapses are sensitive to manipulations of the rearing environment. SIGNIFICANCE STATEMENT: Perineuronal nets (PNNs) are thought to play a major role in restricting synaptic plasticity during postnatal development, and are altered in several models of neurodevelopmental disorders, such as schizophrenia and Rett syndrome. Although PNNs have been predominantly studied in association with inhibitory neurons throughout the brain, we describe a dense expression of PNNs around excitatory pyramidal neurons in hippocampal area CA2. We also provide insight into a previously unrecognized role for PNNs in restricting plasticity at excitatory synapses and raise the possibility of an early critical period of hippocampal plasticity that may ultimately reveal a key mechanism underlying learning and memory impairments of PNN-associated neurodevelopmental disorders.

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Crossref · 10.1523/jneurosci.0245-16.2016

Cites

52 of 52 references verified0 citation errors · 0 not checkable

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Claims the paper makes

0 of 58 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Breaking down perineuronal nets permits potentiation at excitatory CA2 synapses that normally resist plasticity.

    “We also found that disruption of PNNs allows synaptic potentiation of normally plasticity-resistant excitatory CA2 synapses; thus, PNNs play a role in restricting synaptic plasticity in area CA2.”
    • Also stated in: § PNNs suppress synaptic plasticity in area CA2 · plain
      “However, a 2 h incubation with ChABC enabled LTP induction of excitatory synaptic responses in the CA2 SR (140 Ϯ 0.2% baseline, n ϭ 10), reaching levels comparable to that induced at CA1 synapses ( p ϭ 0.02, two-tailed unpaired t test compared with untreated slices).”
    Quote in the paperSubstantial claim
  • Findingown data

    CA2 pyramidal cells produce mRNA for aggrecan, a main perineuronal net component.

    “CA2 pyramidal neurons express mRNA transcripts for the major PNN component aggrecan, identifying these neurons as a novel source for PNNs in the hippocampus.”
    • Also stated in: § PNNs localize to excitatory synapses on CA2 pyramidal neurons · plain
      “We found that CA2 neurons identified by Purkinje cell protein 4 (PCP4 ) expression, but not CA1 and CA3 neurons, expressed aggrecan mRNA (Fig. 1c).”
    Quote in the paperSubstantial claim
  • Findingown data

    Early-life enrichment changes the postnatal development of perineuronal nets on CA2 pyramidal cells.

    “Finally, we found that postnatal development of PNNs on CA2 pyramidal neurons is modified by early-life enrichment, suggesting that the development of circuits containing CA2 excitatory synapses are sensitive to manipulations of the rearing environment.”
    • Also stated in: § PNN development is regulated by experience · plain
      “We found that WFA staining intensity in the CA2 SP was significantly greater in EE-exposed animals than those reared in standard housing at PN 21 and PN 45 ( p ϭ 0.047 and p ϭ 0.001 respec-tively; two-way ANOVA, Bonferroni's post hoc test for pairwise comparison), but not at PN 14, the earliest age tested (Fig. 3b; p Ͼ 0.05).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: WFA staining intensity reliably measures the amount or development of perineuronal nets in CA2.
  • Findingown data

    Perineuronal net staining was sparse in the neighboring CA1 stratum pyramidale and stratum radiatum.

    “In contrast, staining for PNNs in the neighboring CA1 SP and SR layers was sparse (Fig. 2c).”
    Quote in the paperNot a substantial claim
  • Findingown data

    CA2 neuron input resistance fell significantly after 0.05 U/ml ChABC (n=11 per group, p<0.0043).

    “CA2 neuron input resistance was significantly decreased after 0.05 U/ml ChABC treatment (n ϭ 11 per group, *p Ͻ 0.0043, two-tailed unpaired t test).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 27
  • The quote only partly states this claim. 2
  • Classified as probably not a substantial claim. 24

  • May combine two claims.

    Findingown data

    Perineuronal nets, an extracellular matrix type usually found around inhibitory cells, also encircle CA2 pyramidal neurons in mouse and cover their excitatory synapses.

    “Here, we present evidence that perineuronal nets (PNNs), a specialized extracellular matrix typically localized around inhibitory neurons, also surround mouse CA2 pyramidal neurons and envelop their excitatory synapses.”
    • Also stated in: § PNNs localize to excitatory synapses on CA2 pyramidal neurons · plain
      “Three different PNN markers, WFA, the chondroitin sulfate proteoglycans aggrecan and neurocan, labeled select inhibitory interneurons throughout the hippocampus (Fig. 1a), but also intensely labeled EGFP-expressing CA2 pyramidal neurons (Fig. 1b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    WFA, aggrecan, and neurocan labeled some inhibitory interneurons across the hippocampus and also strongly labeled EGFP-expressing CA2 pyramidal neurons.

    “Three different PNN markers, WFA, the chondroitin sulfate proteoglycans aggrecan and neurocan, labeled select inhibitory interneurons throughout the hippocampus (Fig. 1a), but also intensely labeled EGFP-expressing CA2 pyramidal neurons (Fig. 1b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    A 2 h ChABC incubation allowed LTP of CA2 stratum radiatum excitatory synaptic responses (140 ± 0.2% baseline, n=10), comparable to CA1, with p=0.02 versus untreated slices.

    “However, a 2 h incubation with ChABC enabled LTP induction of excitatory synaptic responses in the CA2 SR (140 Ϯ 0.2% baseline, n ϭ 10), reaching levels comparable to that induced at CA1 synapses ( p ϭ 0.02, two-tailed unpaired t test compared with untreated slices).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    No significant ChABC effects were found for resting membrane potential, membrane capacitance, or decay time.

    “Significant effects were not detected in other properties, including resting membrane potential, membrane capacitance, and decay time.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    ChABC also enabled LTP when GABA_A receptors were blocked by bicuculline, with a significant difference from untreated slices at 10 min (p=0.022, n=8 and 4).

    “Similar results were obtained when experiments on ChABC-treated or control-treated slices were performed in the presence of the GABA A -receptor blocker bicuculline (significant difference between ChABC-treated and untreated slices, p ϭ 0.022 at 10 min, two-tailed unpaired t test compared with untreated slices, n ϭ 8 and 4 respectively).”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingcitation

    With the LTP pairing protocol, CA2 neuron synaptic responses did not potentiate (92.0 ± 0.1% baseline, n=10), while CA1 responses showed typical LTP (140 ± 0.1%, n=12).

    “As reported previously for untreated slices, synaptic responses recorded from CA2 neurons were not potentiated following an LTP”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Zhao et al., 2007

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    At PN21 and PN45, WFA staining intensity in CA2 stratum pyramidale was significantly higher in enriched-housing animals than in standard-housing animals, but not at PN14.

    “We found that WFA staining intensity in the CA2 SP was significantly greater in EE-exposed animals than those reared in standard housing at PN 21 and PN 45 ( p ϭ 0.047 and p ϭ 0.001 respec-tively; two-way ANOVA, Bonferroni's post hoc test for pairwise comparison), but not at PN 14, the earliest age tested (Fig. 3b; p Ͼ 0.05).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: WFA staining intensity reliably measures the amount or development of perineuronal nets in CA2.

  • May combine two claims.

    Findingown data

    Normalized WFA fluorescence in CA2 SP was significantly higher in EE mice than controls at PN 21 and PN 45, but not at PN 14.

    “Normalized WFA fluorescence intensity was significantly greater in CA2 SP of EE mice compared with control at PN 21 (N ϭ 8 and 7 for control and EE respectively) and PN 45 (N ϭ 6 and 9 for control and EE respectively; Bonferroni's post hoc test for pairwise comparison after two-way ANOVA,*p Ͻ 0.05, ***p ϭ 0.0008).No significant difference was observed at PN 14”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    PNNs increase during postnatal development and with experience.

    “PNNs increase during postnatal development and are increased with experience.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Electron microscopy reveals WFA staining on dendritic spines of CA2 pyramidal cells in the SR and on CA2 somata in the SP, with little labeling in CA1 SP and SR.

    “Electron micrographs showing WFA staining along dendritic spines of CA2 pyramidal neurons in the SR (top, red arrowheads), and area CA2 somata in the SP (bottom), and sparse labeling of WFA in area CA1 SP and SR (bottom; scale bar, 2 m).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Anti-aggrecan, WFA, and neurocan label EGFP-expressing CA2 pyramidal neurons and their proximal neurites.

    “Anti-aggrecan (top), WFA (middle), and neurocan (bottom), indicated in green, label EGFP-expressing CA2 pyramidal neurons and their proximal neurites in red”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    In mice, perineuronal nets begin near postnatal day 14, rise gradually to adult levels, and often coincide with the end of critical periods for synaptic plasticity.

    “PNNs first appear in the brain around postnatal day (PN) 14 in the mouse, and gradually increase until they are fully expressed in adulthood, often tracking the end of critical windows of synaptic plasticity (Hensch, 2004;Horii-Hayashi et al., 2015).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Hensch, 2004

      Not checked in the free run.

    • cites Horii-Hayashi et al., 2015

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pizzorusso et al. linked the presence or absence of visual cortex perineuronal nets with closure and reopening of ocular dominance plasticity, supporting a role for these nets in limiting experience-dependent plasticity.

    “presence and absence of PNNs in the visual cortex and the closure and reopening of ocular dominance plasticity, strongly supporting a role for PNNs in limiting experience-dependent plasticity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Pizzorusso et al. (2002)

      Not checked in the free run.

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

    Premisecitation

    Dark rearing, which lowers activity, delays and weakens perineuronal net development around visual cortex inhibitory neurons.

    “Similarly, decreasing activity via dark rearing delays and attenuates PNN development around inhibitory neurons in the visual cortex (Pizzorusso et al., 2002).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Pizzorusso et al., 2002

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CA2 neurons receive excitatory input from dentate gyrus, entorhinal cortex, and CA3; the CA3-to-CA2 synapses in stratum radiatum strongly resist plasticity.

    “CA2 neurons receive excitatory synapses from the dentate gyrus, entorhinal cortex, and area CA3, and it is these synapses from CA3 in CA2 stratum radiatum (SR) that are highly resistant to plasticity (Zhao et al., 2007;Chevaleyre and Siegelbaum, 2010;Kohara et al., 2014).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Zhao et al., 2007

      Not checked in the free run.

    • cites Chevaleyre and Siegelbaum, 2010

      Not checked in the free run.

    • cites Kohara et al., 2014

      Not checked in the free run.

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

    Premisecitation

    Normal early experience is needed for perineuronal net expression to begin in motor, visual, and somatosensory regions, while comparable manipulations later in life have no effect.

    “Interestingly, the onset of PNN expression requires normal early experience in several brain regions, including motor, visual, and somatosensory systems, and similar manipulations performed in adulthood were without effect (Kalb and Hockfield, 1988;Guimara ˜es et al., 1990;Kind et al., 1995;Lander et al., 1997;McRae et al., 2007).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Kalb and Hockfield, 1988

      Not checked in the free run.

    • cites Guimara ˜es et al., 1990

      Not checked in the free run.

    • cites Kind et al., 1995

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Treating cultured inhibitory neurons with chondroitinase to degrade perineuronal nets raises interneuron excitability without changing the number or distribution of perisomatic GABAergic terminals.

    “Degradation of PNNs around inhibitory neurons in culture (mainly PV-positive interneurons) with the bacterial enzyme chondroitinase (ChABC) increases interneuron excitability without affecting the number or distribution of perisomatic GABAergic presynaptic terminals (Dityatev et al., 2007), suggesting that PNNs function to regulate inhibitory neuron activity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Dityatev et al., 2007

      Not checked in the free run.

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

    Premisecitation

    Area CA2 lies between CA3 and CA1 and is molecularly distinct from its neighboring hippocampal areas.

    “Hippocampal area CA2, positioned between areas CA3 and CA1, has recently been appreciated as an important module of the hippocampus that is molecularly distinct from its neighboring areas (Caruana et al., 2012;Dudek et al., 2016).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Caruana et al., 2012

      Not checked in the free run.

    • cites Dudek et al., 2016

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Perineuronal nets are believed to restrain plasticity.

    “Although components of the extracellular matrix (ECM) have been implicated in promoting synaptic plasticity, perineuronal nets (PNNs), a specialized form of ECM typically found around inhibitory neurons, are thought to inhibit plasticity (Dityatev et al., 2010).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Dityatev et al., 2010

      Not checked in the free run.

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

    Study design and conductown data

    The animal procedures received approval from the relevant institutional animal care and use committees and followed NIH care and use guidelines.

    “All procedures were approved by National Institute of Environmental Health Sciences, University of Alabama at Birmingham, and University of North Carolina Animal Care and Use Committees and were in accordance with the National Institutes of Health guidelines for care and use of animals.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Interpretationown data

    The findings indicate that perineuronal nets, or another chondroitinase-sensitive extracellular matrix component, limit plasticity at the normally resistant CA2 stratum radiatum synapses.

    “ECM, restrict plasticity at the normally plasticity-resistant synapses in CA2 SR.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The LTP facilitation seen after ChABC in CA2 comes from perineuronal net breakdown, not from other chondroitinase-sensitive extracellular matrix components.

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

    Premisecitation

    Adult mice given enrichment had lower PNN density around cerebellar neurons.

    “adult mice exposed to enrichment had reduced PNN density around cerebellar neurons (Foscarin et al., 2011)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Foscarin et al., 2011

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PNN proteoglycans carry a strong negative charge and may buffer and limit the diffusion of cations such as calcium.

    “PNN proteoglycans are highly negatively charged and may function to buffer and restrict diffusion of cations like calcium (Bru ¨ckner et al., 1993).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Bru ¨ckner et al., 1993

      Not checked in the free run.

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

    Premisecitation

    Other studies have found that adult enrichment reduces PNNs in several brain regions.

    “other studies have reported a decrease in PNNs after exposure to enrichment in adulthood in several brain regions”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Sale et al., 2007

      Not checked in the free run.

    • cites Foscarin et al., 2011

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    AVPR1b and Oxtr couple to Gq-type G-proteins and can therefore participate in controlling calcium levels in CA2 spines.

    “Both receptors are known to be coupled to the”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    These results agree with an earlier report that ChABC did not affect basal synaptic transmission or paired-pulse facilitation in CA1.

    “These findings are consistent with a previous report showing that ChABC treatment had no effect on basal synaptic transmission and pairedpulse facilitation in area CA1.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bukalo et al., 2001

      Not checked in the free run.

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

    Premisecitation

    Amblyopic rats given enrichment as adults had fewer PNNs in visual cortex.

    “amblyopic rats exposed to EE in adulthood had reduced PNNs in the visual cortex (Sale et al., 2007)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sale et al., 2007

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Degrading perineuronal nets can reopen periods of heightened plasticity in multiple brain areas.

    “PNN degradation can reopen critical windows of plasticity in a number of brain regions”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Pizzorusso et al., 2002

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    • cites Gogolla et al., 2009

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    • cites Romberg et al., 2013

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  • Classified as probably not a substantial claim.

    Premisecitation

    CA2 neurons are known to be highly resistant to cell death caused by seizures and ischemia.

    “neurons in area CA2 have long been noted as being remarkably resistant to cell death from both seizure and ischemic insult (Sloviter et al., 1991)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Sloviter et al., 1991

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

    Premisecitation

    RGS14 has been linked to a signaling cascade that suppresses LTP in area CA2.

    “which has been implicated in the signaling pathway suppressing LTP in area CA2 (Lee et al., 2010)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lee et al., 2010

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

    Study design and conductnone given

    Fluorescence quantification was repeated and analyzed with the experimenter unaware of condition.

    “For each experiment, fluorescence quantification was repeated and analyzed with the experimenter blinded to condition.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Cells entered analysis only when series and input resistance varied by less than 25%.

    “Series and input resistances were monitored by measuring the response to a 10 mV step at each sweep and cells were included for analysis if Ͻ25% change in series and input resistance was detected.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In area CA1, unlike area CA2, perineuronal net degradation weakened LTP.

    “However, in contrast to our work in area CA2, PNN degradation resulted in an attenuation of LTP in area CA1 (Bukalo et al., 2001).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Bukalo et al., 2001

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  • May combine two claims.

    Interpretationcitation

    CA2 synapses possess the machinery needed for LTP, but postsynaptic calcium is limiting.

    “indicating that CA2 synapses have the cellular machinery for LTP, but that calcium is limited in the postsynaptic neurons (Simons et al., 2009)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Simons et al., 2009

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  • May combine two claims.

    Premisecitation

    External calcium at 4 mM does not suffice to induce LTP in area CA2, whereas 10 mM does.

    “Raising external calcium levels to 4 mM is insufficient to induce LTP in area CA2, but the very high concentration of 10 mM allows for the induction of LTP”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Simons et al., 2009

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

    Premisecitation

    PNNs have been associated with neuroprotective roles.

    “PNNs have also been linked to neuroprotective functions (Morawski et al., 2004;Cabungcal et al., 2013)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Morawski et al., 2004

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    • cites Cabungcal et al., 2013

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

    Premisecitation

    CA2 neurons contain elevated amounts of RGS14.

    “CA2 neurons express high levels of the protein regulator of G-protein signaling 14 (RGS 14 )”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lee et al., 2010

      Not checked in the free run.

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

    Premisecitation

    Perineuronal net degradation causes a small impairment of LTP in area CA1.

    “PNN degradation modestly disrupts LTP in area CA1 (Bukalo et al., 2001)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bukalo et al., 2001

      Not checked in the free run.

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

    Study design and conductown data

    The enrichment study was repeated in a separate cohort, and data were combined after normalizing each mean gray value to the PN45 enriched value.

    “This study was repeated in a separate cohort of animals and the data combined by normalizing each mean gray value-the value for the PN 45 enriched cohort-for each study.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationcitation

    Regulation of PNNs in area CA2 during development may be a therapeutic target for developmental disorders such as schizophrenia and Rett syndrome.

    “Developmental regulation of PNNs in area CA2 may therefore represent a therapeutic target for PNNassociated developmental disorders, such as schizophrenia and Rett syndrome”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Belichenko et al., 1997

      Not checked in the free run.

    • cites Mauney et al., 2013

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  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    The developmental time course of PNNs in CA2 pyramidal neurons matches that of PNNs in brain regions known for critical periods.

    “Considering that the development of PNNs in hippocampal area CA2 pyramidal neurons parallels the expression timeline of PNNs located in brain regions noted for their critical periods for plasticity”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Recent work links area CA2 to social aggression and social recognition memory.

    “recent reports implicate area CA2 in social aggression and social recognition memory (Hitti and Siegelbaum, 2014;Pagani et al., 2015;Smith et al., 2016)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Hitti and Siegelbaum, 2014

      Not checked in the free run.

    • cites Pagani et al., 2015

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    • cites Smith et al., 2016

      Not checked in the free run.

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

    Premisecitation

    Early postnatal enrichment restores PNN development in dark-reared animals and advances critical period maturation.

    “early postnatal enrichment was found to rescue PNN development in dark-reared animals and promote critical period maturation (Bartoletti et al., 2004)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bartoletti et al., 2004

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The data suggest a possible early critical period for synaptic plasticity in area CA2.

    “our data raise the intriguing possibility of an early critical period for synaptic plasticity in area CA2”
    Quote in the paperSubstantial claim
44 of 44

  • The paper relies on this without support.

    The LTP facilitation seen after ChABC in CA2 comes from perineuronal net breakdown, not from other chondroitinase-sensitive extracellular matrix components.

    “We also found that disruption of PNNs allows synaptic potentiation of normally plasticity-resistant excitatory CA2 synapses; thus, PNNs play a role in restricting synaptic plasticity in area CA2.”

  • The paper relies on this without support.

    WFA staining intensity reliably measures the amount or development of perineuronal nets in CA2.

    “WFA staining intensity was quantified using measures of pixel luminescence value on ImageJ software (National Institutes of Health) using a region of interest (ROI) contoured around either CA2 pyramidal neurons in stratum pyramidale (SP) or CA2 apical dendrites using GFP fluorescence in a dorsal hippocampal section.”

  • The paper relies on this without support.

    Aggrecan mRNA in CA2 pyramidal cells means those cells synthesize aggrecan protein.

    “Localization of aggrecan mRNA in the pyramidal cell layer of area CA2 indicates that CA2 pyramidal neurons synthesize at least one major component of the PNN matrix, identifying such neurons as a novel source of PNNs in the hippocampus.”

  • The paper relies on this without support.

    Perineuronal nets are mainly found on inhibitory neurons in the neocortex.

    “Because PNNs are predominantly associated with inhibitory neurons in the neocortex”

  • The paper relies on this without support.

    ChABC's effect on synaptic plasticity is caused by PNN degradation rather than by other actions of the enzyme.

    “Plasticity of EPSC amplitudes is enhanced in CA2 neurons treated with the PNN-degrading enzyme ChABC, compared with untreated controls.”

  • The paper relies on this without support.

    The markers WFA, aggrecan, and neurocan specifically label perineuronal nets.

    “PNN markers surround CA2 pyramidal neurons and dendrites.”
6 of 6

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?

  • All social memory associated regions are highly populated with PNN-surrounded PV neurons.

    “All the social memory associated regions are highly populated with PNN-surrounded PV neurons [46, 66, 130, 131].”

    From The extracellular matrix and perineuronal nets in memory (2022) · cites this paper as [66]

    The Discussion identifies hippocampal CA2 as implicated in social recognition memory, and the section on PNN localization reports that PNN markers label select inhibitory interneurons in the hippocampus. But the paper does not show that all social-memory-associated regions are highly populated with PNN-surrounded PV neurons; its principal finding is dense PNN labeling around excitatory CA2 pyramidal neurons. No page numbers are available in our copy. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • In the CA2, PNN depletion enables LTP.

    “For example, in the CA2, an area associated with social memory and which usually does not exhibit LTP, PNN depletion enables LTP [66].”

    From The extracellular matrix and perineuronal nets in memory (2022) · cites this paper as [66]

  • PNNs predominantly enwrap PV inhibitory neurons in most brain areas, but they surround excitatory neurons in the CA2.

    “While PNNs predominantly enwrap PV inhibitory neurons in most brain areas, they surround excitatory neurons in the CA2 [66, 71].”

    From The extracellular matrix and perineuronal nets in memory (2022) · cites this paper as [66]

  • In CA2, PNNs suppress LTP in excitatory synapses on pyramidal neurons.

    “PNNs are usually associated with restriction of synaptic plasticity on inhibitory PV neurons, but in CA2, the PNNs also suppress LTP in excitatory synapses on pyramidal neurons [66].”

    From The extracellular matrix and perineuronal nets in memory (2022) · cites this paper as [66]

  • PNNs usually restrict synaptic plasticity on inhibitory PV neurons.

    “PNNs are usually associated with restriction of synaptic plasticity on inhibitory PV neurons, but in CA2, the PNNs also suppress LTP in excitatory synapses on pyramidal neurons [66].”

    From The extracellular matrix and perineuronal nets in memory (2022) · cites this paper as [66]

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.

  • The condition effect has inconsistent ANOVA degrees of freedom

    Minor

    The two Figure 3 analyses use the same two housing conditions and age groups, but panel b reports 2 numerator degrees of freedom for condition while panel c reports 1. A two-level condition factor has 1 numerator degree of freedom.

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Authors
Carstens, K. E., Phillips, M. L., Pozzo-Miller, L., Weinberg, R. J., & Dudek, S. M.
Affiliations
  • University of North Carolina at Chapel Hill (US)
  • Civitan International (US)
  • National Institutes of Health (US)
ORCID
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2016-06-08
Volume
36
Issue
23
Pages
6312-6320
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.0245-16.2016
PMC
PMC4899529
OpenAlex
W2410908538
Semantic Scholar
e25a3569c55d49e43bcaa10c5b535c9d4b82ebca
Cited by
271
References
52
Citations by year
2026: 23 · 2025: 39 · 2024: 40 · 2023: 25 · 2022: 21 · 2021: 23 · 2020: 27 · 2019: 23 · 2018: 21 · 2017: 22 · 2016: 6
FWCI
13.46
Type
journal article
Language
en
Open access
Locations
  • Journal of Neuroscience (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
  • UNC Libraries
Funders
  • National Institutes of Health
  • National Institute of Neurological Disorders and Stroke (R01NS039444, R01NS065027)
  • National Institute of Environmental Health Sciences (ES100221, Z01ES100221)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
perineuronal nets, excitatory synapses, synaptic plasticity, hippocampal CA2, pyramidal neurons, aggrecan, extracellular matrix, long-term potentiation, postnatal development, rearing conditions, neurodevelopmental disorders, schizophrenia, Rett syndrome, learning and memory
MeSH terms
Animals, Animals, Newborn, Extracellular Matrix, Female, Glutamate Decarboxylase, Male, Membrane Proteins, Mice, Inbred C57BL, Mice, Transgenic, Nerve Net, Nerve Tissue Proteins, Extracellular Matrix Proteins, Pyramidal Cells, Gene Expression Regulation, Developmental, Excitatory Amino Acid Agents, Excitatory Postsynaptic Potentials, Satellite Cells, Perineuronal, Green Fluorescent Proteins, Mice, CA2 Region, Hippocampal

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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