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Cited by 165Genetics and Neurodevelopmental DisordersNeuroscience and Neuropharmacology ResearchAutism Spectrum Disorder Research

Genetic Reduction of Matrix Metalloproteinase-9 Promotes Formation of Perineuronal Nets Around Parvalbumin-Expressing Interneurons and Normalizes Auditory Cortex Responses in Developing Fmr1 Knock-Out Mice

Open access
Wen, Teresa H, Afroz, Sonia, Reinhard, Sarah M, Palacios, Arnold R, Tapia, Kendal, Binder, Devin K, Razak, Khaleel A, Ethell, Iryna M·2018·Cerebral Cortex
DOI 10.1093/cercor/bhx258PMC PMC6188540
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Abstract

Abnormal sensory responses associated with Fragile X Syndrome (FXS) and autism spectrum disorders include hypersensitivity and impaired habituation to repeated stimuli. Similar sensory deficits are also observed in adult Fmr1 knock-out (KO) mice and are reversed by genetic deletion of Matrix Metalloproteinase-9 (MMP-9) through yet unknown mechanisms. Here we present new evidence that impaired development of parvalbumin (PV)-expressing inhibitory interneurons may underlie hyper-responsiveness in auditory cortex of Fmr1 KO mice via MMP-9-dependent regulation of perineuronal nets (PNNs). First, we found that PV cell development and PNN formation around GABAergic interneurons were impaired in developing auditory cortex of Fmr1 KO mice. Second, MMP-9 levels were elevated in P12-P18 auditory cortex of Fmr1 KO mice and genetic reduction of MMP-9 to WT levels restored the formation of PNNs around PV cells. Third, in vivo single-unit recordings from auditory cortex neurons showed enhanced spontaneous and sound-driven responses in developing Fmr1 KO mice, which were normalized following genetic reduction of MMP-9. These findings indicate that elevated MMP-9 levels contribute to the development of sensory hypersensitivity by influencing formation of PNNs around PV interneurons suggesting MMP-9 as a new therapeutic target to reduce sensory deficits in FXS and potentially other autism spectrum disorders.

Verified 2026-10-06 · 16 references not checked yet

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Crossref · 10.1093/cercor/bhx258

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Claims the paper makes

0 of 39 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    A developmental increase in PV cell density occurs in both wild-type and Fmr1 knock-out auditory cortex at P21.

    “A significant developmental increase in PV cell density was observed in both WT and Fmr1 KO auditory cortex at P21 (Table 1; age effect, P < 0.01).”
    Quote in the paperNot a substantial claim
  • Findingown data

    PV cell density is lower in developing auditory cortex of Fmr1 knock-out mice compared to wild-type mice.

    “However, PV cell density was lower in the developing Fmr1 KO auditory cortex compared to WT (Table 1; genotype effect, P < 0.05).”
    • Also stated in: § Abstract · plain
      “First, we found that PV cell development and PNN formation around GABAergic interneurons were impaired in developing auditory cortex of Fmr1 KO mice.”
    Quote in the paperSubstantial claim
  • Findingown data

    A developmental increase in PV cell density is detected only in layer 4 but not layers 2/3 of wild-type auditory cortex.

    “However, a developmental increase in PV cell density was only detected in L4 but not L2/3 of WT auditory cortex (WT, P14 vs P21, P < 0.01; Fig. 1J).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Genetic reduction of MMP-9 restores auditory cortex response magnitudes in Fmr1 knock-out neurons to wild-type levels.

    “Third, in vivo single-unit recordings from auditory cortex neurons showed enhanced spontaneous and sound-driven responses in developing Fmr1 KO mice, which were normalized following genetic reduction of MMP-9.”
    • Also stated in: § Genetic Reduction of MMP-9 Restores Auditory Cortex Response Magnitudes in Fmr1 KO Neurons to WT Levels · plain
      “Responses were restored to WT levels with genetic reduction of MMP-9 levels in the Mmp9 +/-Fmr1 KO mice (Fig. 6B-D).”
    Quote in the paperSubstantial claim
  • Findingown data

    There are no genotype differences in the density of PNN-containing cells lacking GAD65/67 at P21.

    “While PNN labeling was also detected around GAD65/67 negative cells (presumably excitatory neurons; arrowheads in Fig. 2C,D), there were no genotype differences in the density of PNN-containing cells lacking GAD65/67, indicating that impaired PNN formation was specific to GABAergic interneurons at P21.”
    Quote in the paperSubstantial claim
  • May combine two claims. 43
  • Classified as probably not a substantial claim. 17
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingown data

    In wild-type auditory cortex, MMP-9 levels decrease at P12 and remain low at P18.

    “In WT auditory cortex, MMP-9 levels decreased at P12 and remained low at P18 (Fig. 3A,B; effect of age P < 0.001), during the period of active PNN formation around PV cells and maturation of auditory cortex.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Fmr1 knock-out mice exhibit an age-related increase in spontaneous activity from P14 to P21 and more spontaneous activity at P21 compared to wild-type.

    “Fmr1 KO mice also exhibited age-related increase in spontaneous activity from P14 to P21 and more spontaneous activity in P21 Fmr1 KO auditory cortex compared to WT (Fmr1 KO mice P14-> P21 P < 0.01, Fmr1 KO vs. WT, P < 0.0001; Fig 5F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Spontaneous activity is significantly higher in Fmr1 knock-out mice compared to wild-type and is restored to wild-type levels with MMP-9 reduction.

    “The spontaneous activity was also significantly higher in the Fmr1 KO mice compared to WT (Fmr1 KO vs. WT, P < 0.0001; Fig. 6E) and was restored to WT levels with MMP-9 reduction (Fmr1 KO vs. Mmp9 +/-Fmr1 KO, P < 0.0001; Fig. 6E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The percentage of PV cells containing PNN is restored to wild-type levels in layer 4 of Mmp9 +/-Fmr1 knock-out auditory cortex at P21 and is significantly higher than in Fmr1 knock-out.

    “Moreover, the percentage of PV cells containing PNN was restored to WT levels in layer 4 of Mmp9 +/-Fmr1 KO auditory cortex at P21 and was significantly higher than in Fmr1 KO (P < 0.001; Fig. 4G).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    PNN density in layer 4 of Mmp9 +/-Fmr1 knock-out auditory cortex is significantly higher than in Fmr1 knock-out at P21, even exceeding wild-type levels.

    “PNN density was significantly higher in layer 4 of Mmp9 +/-Fmr1 KO auditory cortex than in Fmr1 KO at P21 (P < 0.0001; Fig. 4E), even exceeding WT levels (P < 0.01; Fig. 4E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    PNN density is lower in layer 4 Fmr1 knock-out auditory cortex compared to wild-type at P14 and does not reach wild-type levels until P30.

    “PNN density was lower in L4 Fmr1 KO auditory cortex compared to WT mice at P14 (P < 0.0001) and did not reach WT levels until P30 (Fig. 1K).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Perineuronal net cell density is reduced in Fmr1 knockout mice but is significantly higher in Mmp9 heterozygous Fmr1 knockout mice compared to knockout at P21.

    “PNN cell density was reduced in Fmr1 KO mice (*P < 0.05) but was significantly higher in Mmp9 +/-Fmr1 KO mice compared to KO (****P < 0.001).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    MMP-2 levels show developmental down-regulation from P3 to P18, but levels are similar between wild-type and Fmr1 knockout mice at all ages.

    “MMP-2 levels also showed a developmental down-regulation from P3 to P18 (Fig. 4C; P < 0.05) but levels were similar between WT and Fmr1 KO mice at all ages (Fig. 4C; P = n.s.).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Perineuronal net/parvalbumin cell density is reduced in Fmr1 knockout compared to wild-type cortex, but is significantly higher in Mmp9 heterozygous Fmr1 knockout compared to knockout at P21.

    “PNN/PV cell density was reduced in Fmr1 KO compared to WT cortex (****P < 0.0001), but was significantly higher in Mmp9 +/-Fmr1 KO compared to KO (**P < 0.01).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Fmr1 knockout mice show a reduced percentage of parvalbumin cells with perineuronal nets, but this reduction is not seen after MMP-9 reduction in Mmp9 heterozygous Fmr1 knockout mice at P21.

    “Fmr1 KO mice showed reduced percentage of PV cells with PNNs but not after MMP-9 reduction in Mmp9 +/-Fmr1 KO mice (WT vs. Fmr1 KO, ****P < 0.0001; Mmp9 +/-Fmr1 KO vs. Fmr1 KO, ***P < 0.01).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There is a developmental increase in GAD-negative cells enwrapped with perineuronal nets from P21 to P30, with no genotype-specific differences.

    “There was a developmental increase in GAD-negative cells enwrapped with PNNs (P21 vs. P30; **P < 0.01), but there were no genotype-specific differences.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Spontaneous activity is significantly higher in Fmr1 knockout auditory cortex at P21 but not at P14.

    “Spontaneous activity was also significantly higher in Fmr1 KO auditory cortex at P21 but not P14.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In Fmr1 knockout auditory cortex, perineuronal nets are selectively lost around parvalbumin-positive GABAergic interneurons at P21, while PNN expression around parvalbumin-negative neurons does not differ at P21.

    “we observed a selective loss of PNNs around PV-positive GABAergic interneurons at P21, with no differences observed in PNN expression around PV-negative neurons at P21.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In Fmr1 knockout auditory cortex at P21, there is an increased number of spikes per stimulus in the ongoing response but not in the first 50 ms onset response compared to wild-type; this difference is not present at P14.

    “Analysis shows increased spikes/stimulus in the ongoing response (C) but not the first 50 ms onset response (B) in Fmr1 KO auditory cortex as compared to WT at P21 but not P14 (P21 WT vs. Fmr1 KO, **P < 0.01).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In wild-type mice, MMP-9 levels peak at P7 and decrease with age during auditory cortex development; in Fmr1 knockout mice, MMP-9 levels are elevated at all ages compared to wild-type.

    “Levels of MMP-9 peak at P7 and decrease with age during auditory cortex development in WT mice; however compared to WT levels MMP-9 levels are elevated in Fmr1 KO mice at all ages (P < 0.01).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Genetic reduction of MMP-9 in Fmr1 knockout mice rescues observed perineuronal net deficits and restores response magnitudes and spontaneous activity to wild-type levels.

    “Here we report that MMP-9 levels are also elevated during a developmental sensitive window in Fmr1 KO auditory cortex, whereas genetic reduction of MMP-9 in Fmr1 KO mice rescues observed PNN deficits and restores response magnitudes and spontaneous activity to WT levels.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Response magnitude increases in Fmr1 knockout auditory cortex with age from P14 to P21 but not in wild-type.

    “Additionally, response magnitude increases in Fmr1 KO auditory cortex with age but not in WT (Fmr1 KO P14-> P21, P < 0.001).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At P12, MMP-9 levels are significantly higher in Fmr1 knockout auditory cortex but not in MMP-9 heterozygous Fmr1 knockout auditory cortex compared to wild-type; MMP-9 levels are significantly lower in MMP-9 heterozygous Fmr1 knockout auditory cortex compared to Fmr1 knockout.

    “Levels of MMP-9 were significantly higher in Fmr1 KO (*P < 0.05) but not MMP-9 +/-Fmr1 KO auditory cortex as compared to WT, whereas MMP-9 levels were significantly lower in MMP-9 +/-Fmr1 KO auditory cortex as compared to Fmr1 KO (**P < 0.01).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Earlier work found hyperexcitable auditory cortex responses and poor habituation to repeated sounds in adult Fmr1 knock-out mice, pointing to an excitation/inhibition imbalance.

    “Our previous studies showed hyperexcitable auditory cortical responses (Rotschafer and Razak 2013) and impaired habituation to repeated sounds in adult Fmr1 KO mice (Lovelace et al. 2016), suggesting impaired E/I balance.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Rotschafer and Razak 2013

      Not checked in the free run.

    • cites Lovelace et al. 2016 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Removing MMP-9 reverses multiple FXS phenotypes in Fmr1 knock-out mice, among them poor habituation of auditory responses.

    “MMP-9 deletion reverses several FXS phenotypes in Fmr1 KO mice (Sidhu et al. 2014), including impaired auditory response habituation (Lovelace et al. 2016).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Sidhu et al. 2014 source

      Not checked in the free run.

    • cites Lovelace et al. 2016 source

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

    Study design and conductnone given

    The precise boundary between primary auditory cortex and anterior auditory field cannot be clearly established.

    “Nevertheless, the precise boundary between primary auditory cortex (A1) and anterior auditory field (AAF) of the mouse auditory cortex cannot be clearly established.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Images were encoded for blind analysis.

    “converted to a TIFF file, encoded for blind analysis, and analyzed using Image J.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Auditory cortex was identified using hippocampal landmarks, a method previously validated using tonotopic mapping and dye injection.

    “Auditory cortex was identified using hippocampal landmarks.This method has been previously validated using tonotopic mapping and dye injection (Martin del Campo et al. 2012) and comparison with the Paxinos mouse atlas and other publications on mouse auditory cortex (Anderson et al. 2009).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Martin del Campo et al. 2012 source

      Not checked in the free run.

    • cites Anderson et al. 2009 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MMP-9 is a secreted enzyme that cleaves extracellular matrix components and thereby controls perineuronal net formation and organization.

    “Matrix Metalloproteinase-9 (MMP-9) is a secreted endopeptidase, which regulates PNN formation and organization by cleaving ECM components (Ethell and Ethell 2007).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Ethell and Ethell 2007

      Not checked in the free run.

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

    Premisenone given

    Abnormal sensory responses in Fragile X Syndrome and autism spectrum disorders include hypersensitivity and impaired habituation to repeated stimuli.

    “Abnormal sensory responses associated with Fragile X Syndrome (FXS) and autism spectrum disorders include hypersensitivity and impaired habituation to repeated stimuli.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Auditory responses in Fmr1 knock-out cortex become abnormally large from P14 to P21, coinciding with the period when perineuronal nets mature around parvalbumin interneurons.

    “These data indicate that responses become abnormally high between P14 and P21 Fmr1 KO auditory cortex, a time window during which the PNNs mature around PV interneurons.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    These data are consistent with altered PV cell function in other autism mouse models.

    “These data are also consistent with altered PV cell function in other autism mouse models (Gogolla et al. 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Gogolla et al. 2009 source

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

    Study design and conductnone given

    All images were acquired under identical conditions.

    “All images were acquired under identical conditions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Similar sensory deficits are observed in adult Fmr1 knock-out mice and are reversed by genetic deletion of MMP-9.

    “Similar sensory deficits are also observed in adult Fmr1 knock-out (KO) mice and are reversed by genetic deletion of Matrix Metalloproteinase-9 (MMP-9) through yet unknown mechanisms.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Sidhu et al. 2014 source

      Not checked in the free run.

    • cites Lovelace et al. 2016 source

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  • May combine two claims.

    Premisecitation

    The typical maturation of fast-spiking parvalbumin-positive interneurons is thought to contribute to critical period plasticity, synaptic network stabilization, and network synchronization.

    “Normal development of fast-spiking parvalbumin (PV)-positive inhibitory interneurons is implicated in shaping”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Hensch 2005 source

      Not checked in the free run.

    • cites Jeevakumar and Kroener 2016

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  • May combine two claims.

    Interpretationreasoning

    Loss of perineuronal nets around parvalbumin cells may lead to impaired maturation, survival, and/or reduced excitability of parvalbumin neurons and an overall loss of inhibition in the network, resulting in fragile X syndrome-related sensory hypersensitivity.

    “Thus the loss of PNN around PV cells may lead to impaired maturation, survival and/or reduced excitability of PV neurons and overall loss of inhibition in the network leading to FXSrelated sensory hypersensitivity.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Perineuronal nets surround both inhibitory and excitatory neurons.

    “PNNs enwrap both inhibitory and excitatory neurons (Carulli et al. 2006)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Carulli et al. 2006 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Genotypes were confirmed by PCR analysis of genomic DNA isolated from mouse tails.

    “Genotypes were confirmed by PCR analysis of genomic DNA isolated from mouse tails.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    The distribution of neuron depths did not differ between wild-type and Fmr1 knock-out at P14, and wild-type, Fmr1 knock-out, and Mmp9 +/-Fmr1 knock-out mice at P21.

    “the distribution of neuron depths did not differ between WT and KO at P14, and WT, KO, and Mmp9 +/-Fmr1 KO mice at P21 (P = n.s.; Chisquare: Depth × Genotype).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Perineuronal nets regulate parvalbumin cell maturation through internalization of the homeoprotein Otx2, which is required for transcription, normal parvalbumin development, and critical period plasticity in the developing visual cortex.

    “PNNs also regulate PV cell maturation via internalization of homeoprotein Otx2, which is needed for transcription, normal PV development and critical period plasticity in developing visual cortex (Sugiyama et al. 2008).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Sugiyama et al. 2008 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Elevated MMP-9 levels in Fmr1 knockout auditory cortex are most likely responsible for the developmental delay in perineuronal net formation around parvalbumin cells and are at least partially responsible for auditory processing deficits.

    “Elevated MMP-9 levels in Fmr1 KO auditory cortex are most likely responsible for the developmental delay in PNN formation around PV cells during auditory cortex development and is at least partially responsible for auditory processing deficits.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    FMRP may regulate parvalbumin cell fate through translational control of transcription factors necessary for GABAergic neuron differentiation.

    “FMRP may regulate PV cell fate through translational control of transcription factors necessary for GABAergic neuron differentiation (reviewed in Sultan et al. 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sultan et al. 2013 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Perineuronal nets regulate the survival and excitability of parvalbumin interneurons and the stabilization of sensory circuits.

    “PNNs regulate survival (Morawski et al. 2004(Morawski et al. , 2015;;Cabungcal et al. 2013) and excitability of PV interneurons (Dityatev et al. 2007;Carulli et al. 2010;Balmer 2016), and stabilization of sensory circuits (Pizzorusso et al. 2002;McRae et al. 2007).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Morawski et al. 2004 source

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    • cites Dityatev et al. 2007 source

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    • cites Pizzorusso et al. 2002 source

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

    Premisecitation

    Genetic deletion of MMP-9 rescues several other fragile X syndrome phenotypes, including improper dendritic spine maturation, enhanced mGluR5-dependent long-term depression, abnormal social behavior, and macroorchidism.

    “Genetic deletion of MMP-9 rescues several other FXS phenotypes, including improper dendritic spine maturation, enhanced mGluR5-dependent-LTD, abnormal social behavior and macroorchidism (Sidhu et al. 2014)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Sidhu et al. 2014 source

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    • cites Gkogkas et al. 2014 source

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  • May combine two claims.

    Interpretationown data

    Auditory hypersensitivity develops between P14 and P21 in Fmr1 knockout mice, coinciding with a critical window for excitation/inhibition balance maturation and perineuronal net formation in the auditory cortex.

    “Auditory hypersensitivity developed between P14 and P21, which coincides with a critical window for E/I balance maturation and PNN formation in the auditory cortex.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    The frequency response of the sound delivery system was flat within ±4 dB between 5 and 40 kHz.

    “The frequency response of the sound delivery system, assessed with a 1 inch Bruel and Kjaer microphone and measuring amplifier, was flat within ± 4 dB between 5 and 40 kHz.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Delayed perineuronal net formation may contribute to enhanced excitability in P21 Fmr1 knockout mice, but it does not explain the impaired parvalbumin cell development that occurs at P14.

    “While delayed PNN formation may contribute to enhanced excitability in P21 Fmr1 KO mice, this does not explain impaired PV cell development that occurs during early PNN formation at P14.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Fmr1 knockout neurons exhibit increased response magnitudes and spontaneous activity and parvalbumin/perineuronal net deficits during a developmental window that coincides with the maturation of cortical inhibition.

    “Fmr1 KO neurons exhibit increased response magnitudes and spontaneous activity and PV/PNN deficits during this developmental window that coincides with the maturation of cortical inhibition.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    MMP-9 levels are elevated in fragile X syndrome human brains and in the hippocampus of Fmr1 knockout mice.

    “MMP-9 levels are elevated in FXS human brains and the hippocampus of Fmr1 KO mice (Dziembowska et al., 2013;Sidhu et al. 2014;Gkogkas et al. 2014).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Dziembowska et al., 2013 source

      Not checked in the free run.

    • cites Sidhu et al. 2014 source

      Not checked in the free run.

    • cites Gkogkas et al. 2014 source

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  • May combine two claims.

    Interpretationown data

    A significant reduction in parvalbumin expression and parvalbumin/perineuronal net colocalization in MMP-9 knockout mice is consistent with the role of MMP-9 in neurodevelopment, suggesting that too much or too little MMP-9 would affect parvalbumin cell development.

    “In addition, we found a significant reduction in PV expression and PV/PNN colocalization in MMP-9 -/mice (not shown), which is consistent with MMP-9 role in neurodevelopment (reviewed in Reinhard et al. 2015), suggesting that too much or too little MMP-9 would affect PV cell development.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Reinhard et al. 2015 source

      Not checked in the free run.

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

    Study design and conductown data

    Mice used for recordings were age-matched male wild-type, Fmr1 knock-out, and Mmp9 +/-Fmr1 knock-out.

    “Here age-matched (P13-16 and P19-23) male WT, Fmr1 KO, Mmp9 +/-Fmr1 mice were anesthetized with a combination of 1 g/kg urethane and 20 mg/kg xylazine.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The abnormally high MMP-9 levels, altered parvalbumin/perineuronal net development, and increased responses observed in Fmr1 knockout auditory cortex occur during a critical window of auditory cortex development in mice.

    “The abnormally high MMP-9 levels, altered PV/PNN development and increased responses that we observed in Fmr1 KO auditory cortex occur during a critical window of auditory cortex development in mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Developmental delay in perineuronal net formation in Fmr1 knockout auditory cortex may be attributed to elevated MMP-9 levels, because genetic reduction of MMP-9 reverses abnormal perineuronal net formation around parvalbumin cells and restores auditory response magnitude at P21.

    “Another major finding presented here is that developmental delay in PNN formation in Fmr1 KO auditory cortex may be attributed to elevated MMP-9 levels, as genetic reduction in MMP-9 levels was able to reverse abnormal PNN formation around PV cells and to restore auditory response magnitude at P21.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Chondroitinase ABC, which cleaves perineuronal net proteoglycans, reduces GABA A inhibitory postsynaptic currents and reduces the excitability of parvalbumin fast-spiking cortical interneurons.

    “Chondroitinase ABC, an enzyme that cleaves PNN proteoglycans, reduces GABA A inhibitory postsynaptic currents (Liu et al. 2013) and reduces excitability of PV fast-spiking cortical interneurons (Balmer 2016).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Liu et al. 2013

      Not checked in the free run.

    • cites Balmer 2016 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Increased single neuron hyperexcitability in Fmr1 knockout auditory cortex may arise from delayed maturation of parvalbumin neurons, which can occur with disruption of perineuronal nets.

    “Taken together, these data indicate that increased single neuron hyperexcitability in Fmr1 KO auditory cortex may arise from delayed maturation of PV neurons, which can occur with disruption of PNNs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Hypersensitive neural circuits are not present around the time of hearing onset in Fmr1 knockout mice, but develop between P14 and P21, suggesting a window for potential treatment of sensory hypersensitivity.

    “Therefore, hypersensitive neural circuits are not present around the time of hearing onset in the Fmr1 KO mice, but develop between P14 and P21 suggesting a window for potential treatment of sensory hypersensitivity.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims. The quote only partly states this claim.

    Study design and conductnone given

    All procedures were approved by the Institutional Animal Care and Use Committee at the University of California, Riverside and carried out in accordance with NIH Guide for the Care and Use of Laboratory Animals.

    “All procedures were approved by the Institutional Animal Care and Use Committee at the University of California, Riverside and carried out in accordance with NIH”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Mmp9 heterozygous Fmr1 knockout brain samples were collected and analyzed together with experimentally matched wild-type and knockout groups.

    “Mmp9 +/-Fmr1 KO brain samples were collected and analyzed together with experimentally matched WT and KO groups.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Toe pinch reflex was monitored to ensure sufficient anesthesia levels.

    “Toe pinch reflex was monitored to ensure sufficient anesthesia levels and maintained with supplemental doses of urethane and xylazine.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The role of extracellular matrix in cortical plasticity has been previously reported.

    “The role of ECM in cortical plasticity has been previously reported (Pizzorusso et al. 2002;Nagy et al. 2006;McRae et al. 2007;Rivera et al. 2010)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Pizzorusso et al. 2002 source

      Not checked in the free run.

    • cites Nagy et al. 2006 source

      Not checked in the free run.

    • cites McRae et al. 2007 source

      Not checked in the free run.

55 of 55

  • The paper relies on this without support.

    MMP-9 protein levels measured by gelatin zymography reflect MMP-9 enzymatic activity in vivo.

    “Levels of MMP-2 and MMP-9 proteins were quantified by densitometry using Image J.”

  • The paper relies on this without support.

    Genetic reduction of MMP-9 in Mmp9+/- Fmr1 knock-out mice does not cause compensatory changes that independently affect PNN formation or auditory responses.

    “The FVB.Cg-Mmp-9 tm1Tvu /J mice were backcrossed, in-house, with Fmr1 KO mice to generate Mmp9 +/-Fmr1 KO mice, which had only 1 allele of the Mmp9 gene and reduced expression of MMP-9.”

  • The paper relies on this without support.

    The restoration of auditory responses by MMP-9 reduction is mediated by changes in PNN formation around PV cells rather than by a direct effect of MMP-9 on neuronal excitability.

    “These data implicate MMP-9 in the development of auditory cortex hyperexcitability in Fmr1 KO mice via the regulation of PNN formation around PV interneurons and provide further support for targeting MMP-9 in treatment of FXS.”

  • The paper relies on this without support.

    Findings in mouse auditory cortex are relevant to human FXS sensory deficits.

    “These findings indicate that elevated MMP-9 levels contribute to the development of sensory hypersensitivity by influencing formation of PNNs around PV interneurons suggesting MMP-9 as a new therapeutic target to reduce sensory deficits in FXS and potentially other autism spectrum disorders.”

  • The authors state this as an assumption.

    In wild-type animals, FMRP translationally suppresses MMP-9 production.

    “In WT animals, there is normal production of FMRP, which translationally suppresses MMP-9 production, resulting in normal development and maturation of PV interneurons (white) and PNNs (black) and normal neural excitability.”

  • The authors state this as an assumption.

    In Fmr1 knockout mice, loss of FMRP leads to upregulated production of MMP-9.

    “Fmr1 KO results in loss of FMRP and upregulated production of MMP-9.”
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?

  • The role of PNNs in neural and network excitability is only beginning to be understood.

    “However, the role of PNNs in neural and network excitability is only beginning to be understood (Balmer, 2016; Murase et al., 2017; Wen et al., 2017).”

    From The Perineuronal ‘Safety’ Net? Perineuronal Net Abnormalities in Neurological Disorders (2018) · cites this paper as Wen et al., 2017

  • Aggrecan-rich PNNs may be unstable in the presence of MMP-9, leading to abnormal development and neural excitability.

    “As aggrecan has been previously identified as an MMP-9 target (Mercuri et al., 2000; Madsen et al., 2010; Rankin-Gee et al., 2015), aggrecan-rich PNNs may be unstable in the presence of MMP-9, leading to abnormal development and neural excitability (Murase et al., 2017; Wen et al., 2017).”

    From The Perineuronal ‘Safety’ Net? Perineuronal Net Abnormalities in Neurological Disorders (2018) · cites this paper as Wen et al., 2017

  • Peak MMP-9 expression is observed during postnatal development and is reduced during adulthood.

    “Peak MMP-9 expression is observed during postnatal development and is reduced during adulthood (Bednarek et al., 2009; Reinhard et al., 2015; Wen et al., 2017).”

    From The Perineuronal ‘Safety’ Net? Perineuronal Net Abnormalities in Neurological Disorders (2018) · cites this paper as Wen et al., 2017

  • We found delayed PNN development in the developing auditory cortex of Fmr1 KO mice.

    “We found delayed PNN development and increased MMP-9 activity levels in the developing auditory cortex of Fmr1 KO mice (Wen et al., 2017), which may lead to impaired PV cell development and reduced inhibition.”

    From The Perineuronal ‘Safety’ Net? Perineuronal Net Abnormalities in Neurological Disorders (2018) · cites this paper as Wen et al., 2017

  • We found increased MMP-9 activity levels in the developing auditory cortex of Fmr1 KO mice.

    “We found delayed PNN development and increased MMP-9 activity levels in the developing auditory cortex of Fmr1 KO mice (Wen et al., 2017), which may lead to impaired PV cell development and reduced inhibition.”

    From The Perineuronal ‘Safety’ Net? Perineuronal Net Abnormalities in Neurological Disorders (2018) · cites this paper as Wen et al., 2017

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.

  • P7 zymography sample size exceeds the stated range

    Minor

    The methods give 3-7 mice per group for the developmental zymography experiment, but the Figure 3 caption reports eight WT and eight Fmr1 KO mice at P7.

  • Reported slice counts exceed the stated per-brain yield

    Minor

    The methods state that an average of 5-6 auditory-cortex slices was obtained per brain. Figure 1 reports 66 slices from seven Fmr1 KO animals at P30-more than nine slices per animal.

2 of 2

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Authors
Wen, T. H., Afroz, S., Reinhard, S. M., Palacios, A. R., Tapia, K., Binder, D. K., Razak, K. A., & Ethell, I. M.
Affiliations
University of California, Riverside (US)
Corresponding author
  • Razak, Khaleel A
  • Ethell, Iryna M
ORCID
Venue
Cerebral Cortex
Publisher
Oxford University Press (OUP)
Published
2017-10-13
Volume
28
Issue
11
Pages
3951-3964
ISSN
  • 1047-3211 (ISSN-L)
  • 1460-2199
DOI
10.1093/cercor/bhx258
PMC
PMC6188540
OpenAlex
W2763626521
Semantic Scholar
83b8ef7c7618272f1557fd06aa2421fbc73c141a
Cited by
165
References
84
Citations by year
2026: 13 · 2025: 20 · 2024: 23 · 2023: 15 · 2022: 18 · 2021: 27 · 2020: 24 · 2019: 17 · 2018: 8
FWCI
8.87
Type
journal article
Language
en
Open access
Licence
academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations
  • Cerebral Cortex (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institutes of Health (NIH) (1U54 HD082008-01)
  • US Army Medical Research (W81XWH-15-1-0436)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
Keywords
fragile X syndrome, Fmr1 knockout mice, MMP-9, perineuronal nets, parvalbumin interneurons, auditory cortex, sensory hypersensitivity, autism spectrum disorder, inhibitory interneurons, auditory habituation, therapeutic target
MeSH terms
Animals, Auditory Cortex, Disease Models, Animal, Fragile X Syndrome, Interneurons, Male, Nerve Net, Parvalbumins, Mice, Knockout, Matrix Metalloproteinase 9, Fragile X Messenger Ribonucleoprotein 1, GABAergic Neurons

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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