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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 accessAbstract
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.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ 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 > PV Cell Development is Impaired in the Developing Auditory Cortex of Fmr1 KO Mice
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ 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 > PV Cell Development is Impaired in the Developing Auditory Cortex of Fmr1 KO Mice
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Abstract · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ 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 > PNN Formation is Selectively Impaired Around PV Interneurons in Fmr1 KO Auditory Cortex at P21
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ 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 > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Genetic Reduction of MMP-9 Restores Auditory Cortex Response Magnitudes in Fmr1 KO Neurons to WT Levels · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ 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 > Reduced PNN Formation Around GABAergic Interneurons in L4 Fmr1 KO Auditory Cortex at P21
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“PV cell density was lower in L4 Fmr1 KO auditory cortex compared to WT at all ages (genotype effect, P < 0.05; Fig. 1J).”
§ 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 > PNN Formation is Selectively Impaired Around PV Interneurons in Fmr1 KO Auditory Cortex at P21
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“However, at P21, Fmr1 KO mice showed increased response magnitude across the entire 200 ms recording window compared to WT, as seen previously in adults (Rotschafer and Razak 2013; Fmr1 KO vs. WT, P < 0.01; Fig. 5E).”
§ 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 > Response Magnitudes are Increased in Developing Auditory Cortex of Fmr1 KO Mice
What the sources say
- Not checked yetcites Rotschafer and Razak 2013
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although there was a delay in PNN development in Fmr1 KO auditory cortex, overall density of PNN-containing cells was not significantly different between genotypes.”
§ 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 > PV Cell Development is Impaired in the Developing Auditory Cortex of Fmr1 KO Mice
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found that at P21 PNN formation was selectively impaired around PV cells in Fmr1 KO auditory cortex compared to WT in both L2/3 (P < 0.01) and L4 (P < 0.0001; Fig. 1L).”
§ 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 > PNN Formation is Selectively Impaired Around PV Interneurons in Fmr1 KO Auditory Cortex at P21
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“First, we found that PV cell development and PNN formation around GABAergic interneurons were impaired in developing auditory cortex of Fmr1 KO mice.”
- Also stated in: § PNN Formation is Selectively Impaired Around PV Interneurons in Fmr1 KO Auditory Cortex at P21 · plain
“We found that at P21 PNN formation was selectively impaired around PV cells in Fmr1 KO auditory cortex compared to WT in both L2/3 (P < 0.01) and L4 (P < 0.0001; Fig. 1L).”
§ 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 > Abstract
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § PNN Formation is Selectively Impaired Around PV Interneurons in Fmr1 KO Auditory Cortex at P21 · plain
- It may state two separate claims as one. 43
- Probably not a substantial claim. 17
- The quote only partly states this claim. 1
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ 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 > MMP-9 Levels are Higher in the Developing Auditory Cortex of Fmr1 KO Mice
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ 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 > Response Magnitudes are Increased in Developing Auditory Cortex of Fmr1 KO Mice
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ 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 > Genetic Reduction of MMP-9 Restores Auditory Cortex Response Magnitudes in Fmr1 KO Neurons to WT Levels
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ 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 > MMP-9 Reduction Promotes PNN Formation Around PV Interneurons in Layer 4 of Fmr1 KO Auditory Cortex
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ 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 > MMP-9 Reduction Promotes PNN Formation Around PV Interneurons in Layer 4 of Fmr1 KO Auditory Cortex
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ 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 > PNN Formation is Selectively Impaired Around PV Interneurons in Fmr1 KO Auditory Cortex at P21
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ 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 > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.).”
§ 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 > Discussion
Strength:plain· not yet calibratedn = 4Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ 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 > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ 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 > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ 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 > Discussion
Strength:plain· not yet calibratedn = 3Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Spontaneous activity was also significantly higher in Fmr1 KO auditory cortex at P21 but not P14.”
§ 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 > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ 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 > Discussion
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ 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 > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ 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 > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ 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 > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Additionally, response magnitude increases in Fmr1 KO auditory cortex with age but not in WT (Fmr1 KO P14-> P21, P < 0.001).”
§ 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 > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ 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 > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ 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 > Discussion
What the sources say
- Not checked yetcites Rotschafer and Razak 2013
- Not checked yetcites Lovelace et al. 2016 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“MMP-9 deletion reverses several FXS phenotypes in Fmr1 KO mice (Sidhu et al. 2014), including impaired auditory response habituation (Lovelace et al. 2016).”
§ 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 > Introduction
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Nevertheless, the precise boundary between primary auditory cortex (A1) and anterior auditory field (AAF) of the mouse auditory cortex cannot be clearly established.”
§ 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 > Immunohistochemistry and Image Analysis
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“converted to a TIFF file, encoded for blind analysis, and analyzed using Image J.”
§ 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 > Immunohistochemistry and Image Analysis
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ 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 > Immunohistochemistry and Image Analysis
What the sources say
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“Matrix Metalloproteinase-9 (MMP-9) is a secreted endopeptidase, which regulates PNN formation and organization by cleaving ECM components (Ethell and Ethell 2007).”
§ 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 > Introduction
What the sources say
- Not checked yetcites Ethell and Ethell 2007
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Abnormal sensory responses associated with Fragile X Syndrome (FXS) and autism spectrum disorders include hypersensitivity and impaired habituation to repeated stimuli.”
§ 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 > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ 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 > Response Magnitudes are Increased in Developing Auditory Cortex of Fmr1 KO Mice
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“These data are also consistent with altered PV cell function in other autism mouse models (Gogolla et al. 2009).”
§ 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 > Discussion
What the sources say
- Not checked yetcites Gogolla et al. 2009 source
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All images were acquired under identical conditions.”
§ 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 > Immunohistochemistry and Image Analysis
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ 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 > Abstract
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Normal development of fast-spiking parvalbumin (PV)-positive inhibitory interneurons is implicated in shaping”
§ 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 > Introduction
What the sources say
- Not checked yetcites Hensch 2005 source
- Not checked yetcites Jeevakumar and Kroener 2016
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ 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 > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“PNNs enwrap both inhibitory and excitatory neurons (Carulli et al. 2006)”
§ 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 > Discussion
What the sources say
- Not checked yetcites Carulli et al. 2006 source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Genotypes were confirmed by PCR analysis of genomic DNA isolated from mouse tails.”
§ 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 > Mice
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ 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 > In Vivo Extracellular Electrophysiology
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ 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 > Discussion
What the sources say
- Not checked yetcites Sugiyama et al. 2008 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ 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 > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“FMRP may regulate PV cell fate through translational control of transcription factors necessary for GABAergic neuron differentiation (reviewed in Sultan et al. 2013).”
§ 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 > Discussion
What the sources say
- Not checked yetcites Sultan et al. 2013 source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ 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 > Discussion
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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)”
§ 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 > Discussion
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ 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 > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ 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 > In Vivo Extracellular Electrophysiology
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ 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 > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ 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 > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ 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 > Discussion
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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.”
§ 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 > Discussion
What the sources say
- Not checked yetcites Reinhard et al. 2015 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ 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 > In Vivo Extracellular Electrophysiology
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ 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 > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ 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 > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ 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 > Discussion
What the sources say
- Not checked yetcites Liu et al. 2013
- Not checked yetcites Balmer 2016 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ 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 > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ 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 > Discussion
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ 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 > Mice
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one. The quote only partly states this claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Mmp9 +/-Fmr1 KO brain samples were collected and analyzed together with experimentally matched WT and KO groups.”
§ 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 > Discussion
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Toe pinch reflex was monitored to ensure sufficient anesthesia levels and maintained with supplemental doses of urethane and xylazine.”
§ 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 > In Vivo Extracellular Electrophysiology
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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)”
§ 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 > Discussion
What the sources say
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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.”
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?
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
MinorThe 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.
“P3, P7, P12, and P18 mice (n = 3-7 mice per group) were euthanized with isoflurane”
“(WT N: 6, 8, 4, and 4 mice.Fmr1 KO N: 6, 8, 4, and 4 mice).”
Reported slice counts exceed the stated per-brain yield
MinorThe 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.
“For each brain, an average of 5-6 slices containing auditory cortex were obtained.”
“Fmr1 KO N: P14 3/22; P21 6/45; P30 7/66; *P < 0.05; **P < 0.01; ****P < 0.0001”
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Metadata
- 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
- 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
- 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
- bronze
- doi.org
- 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.
A language model drew the claims from the paper on 2026-10-06, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-06 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
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.
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