The DOI matches its Crossref record; 68 of the 84 references it cites were found in a registry or an index, and 16 are not checked yet; none of the 39 sources its claims cite is checked for support yet.
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.
Checked 2026-10-06 · 16 references not checked yet
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49 Own result · 24 Not checked yet · 13 Own interpretation · 10 Own method · 1 No basis given
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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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, 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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- 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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“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
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- 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
plain- Asserted: passes — The authors put it forward as true.
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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
“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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In 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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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 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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- 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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It 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
plainn = 4- Asserted: passes — The authors put it forward as true.
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It 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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plaindirect- Asserted: passes — The authors put it forward as true.
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It 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
plainn = 3- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It 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
plainn = 91- Asserted: passes — The authors put it forward as true.
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It 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
plain- Asserted: passes — The authors put it forward as true.
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It 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
plainn = 89- Asserted: passes — The authors put it forward as true.
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It 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
plaincorrelationaln = 4- Asserted: passes — The authors put it forward as true.
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It 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
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It 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
plaindirectn = 85- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plainn = 9- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It 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
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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- Based: passes — The paper gives a reason why it holds.
It 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
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably 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
plain- Asserted: passes — The authors put it forward as true.
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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
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
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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
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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
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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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
plain- Asserted: passes — The authors put it forward as true.
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
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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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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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
plain- Asserted: passes — The authors put it forward as true.
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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
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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
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably 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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It 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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably 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
plaindirect- Asserted: passes — The authors put it forward as true.
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It 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
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably 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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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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
plain- Asserted: passes — The authors put it forward as true.
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Probably 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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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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
“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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It 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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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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
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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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
plain- Asserted: passes — The authors put it forward as true.
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Probably 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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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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
“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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It 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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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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
“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
hedged- Asserted: passes — The authors put it forward as true.
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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
plain- Asserted: passes — The authors put it forward as true.
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Probably 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
plain- Asserted: passes — The authors put it forward as true.
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Probably 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
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably 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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably 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
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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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ 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 > Gelatin Zymography
“P3, P7, P12, and P18 mice (n = 3-7 mice per group) were euthanized with isoflurane”
§ 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
“(WT N: 6, 8, 4, and 4 mice.Fmr1 KO N: 6, 8, 4, and 4 mice).”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ 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
“For each brain, an average of 5-6 slices containing auditory cortex were obtained.”
§ 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
“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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Cited by
Sorted by citations
Perineuronal Nets: Plasticity, Protection, and Therapeutic Potential
Reichelt, A. C., Hare, D. J., Bussey, T. J., & Saksida, L. M. (2019) · Trends in Neurosciences · doi:10.1016/j.tins.2019.04.003 · Cited by 219
“Fmr1-null mice show decreased PNN development, reduced PV+ interneurons and increased MMP-9 expression [91].”
BackgroundCortical interneurons in autism
Contractor, A., Ethell, I. M., & Portera‐Cailliau, C. (2021) · Nature Neuroscience · doi:10.1038/s41593-021-00967-6 · Cited by 186
Self-citationTranslation-relevant EEG phenotypes in a mouse model of Fragile X Syndrome.
Lovelace, J. W., Ethell, I. M., Binder, D. K., & Razak, K. A. (2018) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.03.012 · Cited by 154
Self-citationThe Perineuronal ‘Safety’ Net? Perineuronal Net Abnormalities in Neurological Disorders
Wen, T. H., Binder, D. K., Ethell, I. M., & Razak, K. A. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00270 · Cited by 170
Self-citationWilliams, Z. J., He, J. L., Cascio, C. J., & Woynaroski, T. G. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2020.11.030 · Cited by 175
“, 2020; Rotschafer & Razak, 2013) can be attributed to an E/I imbalance in auditory cortex (Ethridge et al., 2017; Lovelace et al., 2020; Wen et al., 2018).”
BackgroundMicroglia as hackers of the matrix: sculpting synapses and the extracellular space
Crapser, J. D., Arreola, M. A., Tsourmas, K. I., & Green, K. N. (2021) · Cellular & Molecular Immunology · doi:10.1038/s41423-021-00751-3 · Cited by 178
“Minocycline-based inhibition of MMP9 [330] or Mmp9 deficiency [331] rescues the immature dendritic spine phenotype in fragile X mouse hippocampal neurons in vitro, and pharmacological blockade [257] or genetic reduction [256] of MMP-9 restores in vivo cortical PNN density in FXS mice, as discussed earlier.”
BackgroundInfluentialVitamin D in Synaptic Plasticity, Cognitive Function, and Neuropsychiatric Illness
Mayne, P., & Burne, T. H. J. (2019) · Trends in Neurosciences · doi:10.1016/j.tins.2019.01.003 · Cited by 166
“, chondroitinase or hyaluronase) that degrade PNNs experimentally? 2 and MMP-24, have been shown to have direct CSPG-degrading properties in the brain [122,123] and more PNNs are expressed in juvenile MMP-9-null mice [124].”
BackgroundPerineuronal nets in brain physiology and disease
Testa, D., Prochiantz, A., & Nardo, A. A. D. (2018) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2018.09.011 · Cited by 153
Sensory Processing Phenotypes in Fragile X Syndrome
Rais, M., Binder, D. K., Razak, K. A., & Ethell, I. M. (2018) · ASN NEURO · doi:10.1177/1759091418801092 · Cited by 143
“…2013; Juczewski et al., 2016) m m Enhanced long-term depression and deficient cortical long-term potentiation (Li et al., 2002; Zhao et al., 2005; Wilson & Cox, 2007; Ng et al., 2013; Jackson, 2017) m m r, z Enhanced MMP-9 activity (Bilousova et al., 2009; Gkogkas et al., 2014; Sidhu et al.,…”
BackgroundSelf-citationAuditory EEG Biomarkers in Fragile X Syndrome: Clinical Relevance
Ethridge, L. E., Stefano, L. A. D., Schmitt, L., Woodruff, N., Brown, K. L., Tran, M., Wang, J., Pedapati, E. V., Erickson, C. A., & Sweeney, J. A. (2019) · Frontiers in Integrative Neuroscience · doi:10.3389/fnint.2019.00060 · Cited by 114
Tewari, B. P., Chaunsali, L., Prim, C. E., & Sontheimer, H. W. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.1022754 · Cited by 115
Wilkinson, C. L., & Nelson, C. A. (2021) · Molecular Autism · doi:10.1186/s13229-021-00425-x · Cited by 101
Krishnaswamy, V. R., Benbenishty, A., Blinder, P., & Sagi, I. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03182-6 · Cited by 96
Bozzelli, P. L., Alaiyed, S., Kim, E., Villapol, S., & Conant, K. E. (2018) · Neural Plasticity · doi:10.1155/2018/5735789 · Cited by 93
“This is supported by recent work showing that PNN is more abundantly expressed in juvenile MMP-9-null mice [49].”
BackgroundMultielectrode array analysis of EEG biomarkers in a mouse model of Fragile X Syndrome
Jonak, C. R., Lovelace, J. W., Ethell, I. M., Razak, K. A., & Binder, D. K. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104794 · Cited by 87
Self-citationAlaiyed, S., McCann, M., Mahajan, G., Rajkowska, G., Stockmeier, C. A., Kellar, K. J., Wu, J. Y., & Conant, K. (2020) · The Journal of Neuroscience · doi:10.1523/jneurosci.2387-19.2020 · Cited by 84
Developmental studies in fragile X syndrome
Razak, K. A., Dominick, K. C., & Erickson, C. A. (2020) · Journal of Neurodevelopmental Disorders · doi:10.1186/s11689-020-09310-9 · Cited by 87
Self-citationLovelace, J. W., Rais, M., Palacios, A. R., Shuai, X. S., Bishay, S., Popa, O., Pirbhoy, P. S., Binder, D. K., Nelson, D. L., Ethell, I. M., et al. (2019) · Cerebral Cortex · doi:10.1093/cercor/bhz141 · Cited by 82
Self-citationDevelopmental Changes in EEG Phenotypes in a Mouse Model of Fragile X Syndrome
Wen, T. H., Lovelace, J. W., Ethell, I. M., Binder, D. K., & Razak, K. A. (2018) · Neuroscience · doi:10.1016/j.neuroscience.2018.11.047 · Cited by 81
“We chose to study the FVB background here because previous studies have examined the development of parvalbumin expression, perineuronal nets and singleunit responses in this strain (Rotschafer and Razak, 2013; Wen et al., 2017).”
InfluentialSelf-citationCircadian Rhythms of Perineuronal Net Composition
Pantazopoulos, H., Gisabella, B., Rexrode, L., Benefield, D., Yıldız, E., Seltzer, P., Valeri, J., Chelini, G., Reich, A., Ardelt, M., et al. (2020) · eNeuro · doi:10.1523/eneuro.0034-19.2020 · Cited by 77
“10 components mediated by matrix proteases (Pantazopoulos and Berretta, 2016; Lasek et al., 2018; Wen et al., 2018).”
BackgroundKourdougli, N., Suresh, A., Liu, B., Juárez, P., Lin, A., Chung, D. T., Sams, A. G., Gandal, M. J., Martínez‐Cerdeño, V., Buonomano, D. V., et al. (2023) · Neuron · doi:10.1016/j.neuron.2023.06.009 · Cited by 73
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Perineuronal net degradation rescues CA2 plasticity in a mouse model of Rett syndrome
Carstens, K. E., Lustberg, D. J., Shaughnessy, E. K., McCann, K. E., Alexander, G. M., & Dudek, S. M. (2021) · Journal of Clinical Investigation · doi:10.1172/jci137221 · Cited by 57
Gonzalez, D., Tomasek, M. P., Hays, S. A., Sridhar, V., Ammanuel, S. G., Chang, C.-W., Pawlowski, K. S., Huber, K. M., & Gibson, J. R. (2019) · Journal of Neuroscience · doi:10.1523/jneurosci.0886-19.2019 · Cited by 64
“…responses in sensory cortical areas, it is unknown whether the enhancement is due to cortical or subcortical Fmr1 deletion (Zhang et al., 2014a; Lovelace et al., 2016; Wen et al., 2018), and some studies do not observe enhanced cortical sensory responses (Goel et al., 2018; Antoine et al., 2019).”
BackgroundPirbhoy, P. S., Rais, M., Lovelace, J. W., Woodard, W., Razak, K. A., Binder, D. K., & Ethell, I. M. (2020) · Journal of Neurochemistry · doi:10.1111/jnc.15037 · Cited by 62
“A third group that did not undergo EEG surgery or recording received a single treatment of SB-3CT (25 mg/kg) or vehicle injections at P21–22 (Figure 7a).”
BackgroundMethodInfluentialSelf-citationThe Role of Extracellular Matrix in Human Neurodegenerative Diseases
Pintér, P., & Alpár, A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231911085 · Cited by 68
Mechanisms underlying auditory processing deficits in Fragile X syndrome
McCullagh, E. A., Rotschafer, S. E., Auerbach, B. D., Klug, A., Kaczmarek, L. K., Cramer, K. S., Kulesza, R. J., Razak, K. A., Lovelace, J. W., Lu, Y., et al. (2020) · The FASEB Journal · doi:10.1096/fj.201902435r · Cited by 66
Self-citationRupert, D. D., & Shea, S. D. (2022) · Frontiers in Neural Circuits · doi:10.3389/fncir.2022.886629 · Cited by 58
Molecular profiling of the hippocampus of children with autism spectrum disorder
Rexrode, L., Hartley, J., Showmaker, K. C., Challagundla, L., Vandewege, M. W., Martin, B. E., Blair, E., Bollavarapu, R., Antonyraj, R. B., Hilton, K., et al. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02441-8 · Cited by 73
“…(black lines). association studies (GWAS) implicate several ECM genes in ASD, including genes encoding for endogenous proteases such as ADAMTS3, ADAMTS5, ADAMTS14 [32 – 35], that genetic factors in ECMs may contribute to the broad ECM gene expression changes we observed in children with ASD.”
Hyperexcitability and homeostasis in fragile X Syndrome.
Liu, X., Kumar, V., Tsai, N.-P., & Auerbach, B. D. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.805929 · Cited by 53
“Thus, it is possible that the abnormal development of PNNs and PV cells observed in the cortex of FMR1 KO animals (Selby et al., 2007; Wen et al., 2018) may underly delayed or impaired critical period plasticity seen at excitatory synapses in these animals (Harlow et al.”
BackgroundInfluentialNeural Correlates of Auditory Hypersensitivity in Fragile X Syndrome
Razak, K. A., Binder, D. K., & Ethell, I. M. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.720752 · Cited by 55
“Lovelace et al. (55) compared EEG recordings between adultWT and Fmr1KOmice on FVB background and showed elevated baseline gamma power, reduced phase locking at gamma band frequencies with the chirp stimuli, enhanced non-phase gamma band power during the chirp trials and enhanced N1 ERP amplitude.”
BackgroundMethodResultInfluentialSelf-citationAlaiyed, S., Bozzelli, P. L., Caccavano, A., Wu, J. Y., & Conant, K. E. (2019) · Journal of Neurochemistry · doi:10.1111/jnc.14671 · Cited by 52
Interneuron Dysfunction and Inhibitory Deficits in Autism and Fragile X Syndrome
Nomura, T. (2021) · Cells · doi:10.3390/cells10102610 · Cited by 51
“Similar findings were reported in the developing auditory cortex, and perineuronal net (PNN) formation, which is the extracellular matrix associated with PV interneurons, is also impaired in the same mouse line [79].”
ResultPerineuronal Nets: Subtle Structures with Large Implications
Carceller, H., Gramuntell, Y., Klimczak, P., & Nácher, J. (2022) · The Neuroscientist · doi:10.1177/10738584221106346 · Cited by 54
Resolving the Synaptic versus Developmental Dichotomy of Autism Risk Genes
Heavner, W. E., & Smith, S. E. P. (2020) · Trends in Neurosciences · doi:10.1016/j.tins.2020.01.009 · Cited by 50
“Chronic treatment with an NMDAR antagonist between P7 and P21 prevents both NMDAR hypofunction and social behavior deficits in adults, demonstrating that pre-weaning NMDAR tone can induce long-term changes in adult function [54].”
InfluentialExtracellular Metalloproteinases in the Plasticity of Excitatory and Inhibitory Synapses
Wiera, G., & Mozrzymas, J. W. (2021) · Cells · doi:10.3390/cells10082055 · Cited by 36
“Significantly, while Fmr1 genetic knockout mice, a model of fragile X syndrome, are characterized by elevated MMP9 activity and loss of perineuronal nets around parvalbumin-expressing interneurons in the auditory cortex of juvenile mice, the MMP9 deficiency restored the proper PNN formation [69].”
BackgroundSantos‐Silva, T., Colodete, D. A. E., Lisboa, J. R., Freitas, I. D. S., Lopes, C. F. B., Hadera, V., Lima, T. S. A., Souza, A. J., & Gomes, F. V. (2024) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/bcpt.13994 · Cited by 39
“66 These studies suggest a role for MMP-9 in PNNs degradation during neurodevelopment, supporting the functional integrity of PV interneurons.”
BackgroundCheung, S. W., Bhavnani, E., Simmons, D. G., Bellingham, M. C., & Noakes, P. G. (2024) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12982 · Cited by 36
“MMP-9 expression is not increased in α -MNs of SOD1 G93A mice PNNs are degraded by endopeptidases such as MMP-9 [25, 26].”
BackgroundMinocycline Treatment Reverses Sound Evoked EEG Abnormalities in a Mouse Model of Fragile X Syndrome
Lovelace, J. W., Ethell, I. M., Binder, D. K., & Razak, K. A. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00771 · Cited by 39
Self-citationFrom molecules to behavior: Implications for perineuronal net remodeling in learning and memory
Sanchez, B., Kraszewski, P., Lee, S., & Cope, E. C. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.16036 · Cited by 41
A conceptualized model linking matrix metalloproteinase-9 to schizophrenia pathogenesis
Bitanihirwe, B. K. Y., & Woo, T.-U. W. (2020) · Schizophrenia Research · doi:10.1016/j.schres.2019.12.015 · Cited by 35
Reinhard, S. M., Rais, M., Afroz, S., Hanania, Y., Pendi, K., Espinoza, K., Rosenthal, R., Binder, D. K., Ethell, I. M., & Razak, K. A. (2019) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2019.107042 · Cited by 37
Self-citationSanz‐Morello, B., Pfisterer, U., Hansen, N. W., Demharter, S., Thakur, A., Fujii, K., Левицкий, С. А., Montalant, A., Korshunova, I., Mammen, P. P. A., et al. (2020) · The EMBO Journal · doi:10.15252/embj.2020105759 · Cited by 33
Circuit-level theories for sensory dysfunction in autism: convergence across mouse models
Monday, H. R., Wang, H. C., & Feldman, D. E. (2023) · Frontiers in Neurology · doi:10.3389/fneur.2023.1254297 · Cited by 31
“Delayed PV maturation also occurs in A1, where it involves delayed perineuronal net formation, the rescue of which is sufficient to improve network hyperactivity (169).”
BackgroundMascio, G., Notartomaso, S., Martinello, K., Liberatore, F., Bucci, D., Imbriglio, T., Cannella, M., Antenucci, N., Scarselli, P., Lattanzi, R., et al. (2022) · Journal of Neuroscience · doi:10.1523/jneurosci.1714-21.2022 · Cited by 32
Toledo, M. A., Wen, T. H., Binder, D. K., Ethell, I. M., & Razak, K. A. (2019) · Behavioural Brain Research · doi:10.1016/j.bbr.2019.112068 · Cited by 31
“We have previously shown that reduction or removal of MMP-9 in the Fmr1 KO mice alleviates auditory cortex hyperexcitability, and corrects abnormal ERP habituation [20,26].”
InfluentialSelf-citationNguyen, A. O., Binder, D. K., Ethell, I. M., & Razak, K. A. (2020) · Journal of Neurophysiology · doi:10.1152/jn.00706.2019 · Cited by 28
“The lack of electrophysiological deficits at P14 indicates abnormal experience-dependent plasticity between P14 and P21, similar to that seen in the auditory cortex (Wen et al. 2018).”
BackgroundInfluentialSelf-citationHooper, A. W. M., Wong, H., Niibori, Y., Abdoli, R., Karumuthil‐Melethil, S., Qiao, C., Danos, O., Bruder, J. T., & Hampson, D. R. (2021) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2021.06.013 · Cited by 31
Burket, J. A., Webb, J. D., & Deutsch, S. I. (2021) · Biomolecules · doi:10.3390/biom11081235 · Cited by 31
“Interestingly, although none of the components of the PNN are known substrates of MMP-9, genetic reduction of MMP-9 in developing Fmr-1 knockout (KO) mice promotes PNN formation around PV-expressing neurons [14,44].”
BackgroundAuditory Dysfunction in Animal Models of Autism Spectrum Disorder
Castro, A. C., & Monteiro, P. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.845155 · Cited by 34
Kulinich, A. O., Reinhard, S. M., Rais, M., Lovelace, J. W., Scott, V., Binder, D. K., Razak, K. A., & Ethell, I. M. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.104622 · Cited by 30
“, 2001), elevated auditory cortical responses (Rotschafer and Razak, 2013; Wen et al., 2018), reduced habituation of ERP to auditory stimuli (Lovelace et al.”
InfluentialSelf-citationYang, X. (2020) · Reviews in the Neurosciences · doi:10.1515/revneuro-2019-0117 · Cited by 31
MiR‐29 coordinates age‐dependent plasticity brakes in the adult visual cortex
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Self-citationJakovljević, A., Tucić, M., Blažíková, M., Korenić, A., Missirlis, Y. F., Stamenković, V., & Anđjus, P. R. (2021) · Cells · doi:10.3390/cells10061345 · Cited by 32
“Likewise, an increased activity of MMP-9 was found in the auditory cortex, promoting degradation of the PNN around PV+ interneurons and leading to sensory hypersensitivity in the Fragile X syndrome animal model [85].”
BackgroundPuścian, A., Winiarski, M., Łęski, S., Charzewski, Ł., Nikolaev, T., Borowska, J., Dzik, J. M., Bijata, M., Lipp, H., Dziembowska, M., et al. (2020) · British Journal of Pharmacology · doi:10.1111/bph.15319 · Cited by 27
A Role for Matrix Metalloproteases in Antidepressant Efficacy
Alaiyed, S., & Conant, K. E. (2019) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2019.00117 · Cited by 26
Pinna, A., & Colasanti, A. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.689473 · Cited by 28
“, 2016) and Fragile X syndrome (Wen et al., 2018), with preliminary evidence of PNN alterations in BPAD (Steullet et al.”
BackgroundBlondiaux, A., Jia, S., Annamneedi, A., Çalışkan, G., Nebel, J., Montenegro‐Venegas, C., Wykes, R. C., Fejtová, A., Walker, M. C., Stork, O., et al. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106324 · Cited by 26
Region-Specific Alterations of Perineuronal Net Expression in Postmortem Autism Brain Tissue
Brandenburg, C., & Blatt, G. J. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.838918 · Cited by 25
Cornez, G., Shevchouk, O. T., Ghorbanpoor, S., Ball, G. F., Cornil, C. A., & Balthazart, J. (2019) · Hormones and Behavior · doi:10.1016/j.yhbeh.2019.104643 · Cited by 25
Gore, S. V., James, E. J., Huang, L.-C., Park, J. J., Berghella, A. P., Thompson, A. C., Cline, H. T., & Aizenman, C. D. (2021) · eLife · doi:10.7554/elife.62147 · Cited by 26
“Recent studies have shown that MMP-9 can rapidly degrade the PNNs surrounding various neurons enabling synaptic and network reorganization during experience dependent plasticity, and could also provide a mechanism by which dysregulation of MMP-9 can lead to abnormal development of neural circuitry (Murase et al., 2019…”
BackgroundPirbhoy, P. S., Jonak, C. R., Syed, R., Argueta, D. A., Perez, P. A., Wiley, M. B., Hessamian, K., Lovelace, J. W., Razak, K. A., DiPatrizio, N. V., et al. (2021) · Journal of Neurodevelopmental Disorders · doi:10.1186/s11689-021-09394-x · Cited by 24
“Altered function of fastspiking parvalbumin (PV) interneurons, which are significantly reduced and exhibit delayed development in the auditory cortex [96, 97] of Fmr1 KO mice, may contribute to abnormal network synchrony and alterations in gamma oscillations [98, 99].”
BackgroundSelf-citationFunctional consequences of postnatal interventions in a mouse model of Fragile X syndrome
Rais, M., Lovelace, J. W., Shuai, X. S., Woodard, W., Bishay, S., Estrada, L., Sharma, A. R., Nguy, A. K., Kulinich, A. O., Pirbhoy, P. S., et al. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105577 · Cited by 25
Self-citationMatrix metalloproteinase‐9: A magic drug target in neuropsychiatry?
Kaczmarek, K. T., Protokowicz, K., & Kaczmarek, L. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.15976 · Cited by 23
“…genetic or pharmacological inhibition of matrix metalloproteinase-9 activity (either during development or in adults) offers a significant therapeutic potential (Dansie et al., 2013; Kokash et al., 2019; Lovelace, Ethell, et al., 2020; Pirbhoy et al., 2020; Toledo et al., 2019; Wen et al., 2017).”
Phenotypic analysis of multielectrode array EEG biomarkers in developing and adult male Fmr1 KO mice
Jonak, C. R., Assad, S. A., Garcia, T. A., Sandhu, M. S., Rumschlag, J. A., Razak, K. A., & Binder, D. K. (2024) · Neurobiology of Disease · doi:10.1016/j.nbd.2024.106496 · Cited by 23
“Normalization of PNNs around PV neurons reduced sound driven firing rates in auditory cortex of Fmr1 KO mice (Wen et al., 2018). study reported increased resting state gamma power in both frontal cortex of Fmr1 KO mice at P30 (Wen et al., 2019), suggesting developmental window as one where broadband gamma power increa…”
BackgroundResultInfluentialSelf-citationMagnesium-based biodegradable microelectrodes for neural recording
Zhang, C., Wen, T. H., Razak, K. A., Lin, J., Xu, C., Seo, C., Villafana, E., Jiménez, H. O. T., & Liu, H. H. (2020) · Materials Science and Engineering C · doi:10.1016/j.msec.2019.110614 · Cited by 22
Self-citationChen, C., & Brumberg, J. C. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.770453 · Cited by 18
“So far, it is not known if the changed level of tPA is the reason that PNNs are impacted by sensory deprivation, or if there are other extracellular matrix factors such as matrix metalloproteinase-9 (MMP-9) that may partake in such regulation of sensory-deprivation induced PNN changes, as recently demonstrated in the…”
BackgroundAuditory processing in rodent models of autism: a systematic review
Wilde, M., Constantin, L., Thorne, P. R., Montgomery, J. M., Scott, E. K., & Cheyne, J. E. (2022) · Journal of Neurodevelopmental Disorders · doi:10.1186/s11689-022-09458-6 · Cited by 19
Nonneuronal contributions to synaptic function
Hodebourg, R., Scofield, M. D., Kalivas, P. W., & Kuhn, B. N. (2025) · Neuron · doi:10.1016/j.neuron.2025.04.004 · Cited by 19
Perineuronal net density in schizophrenia: A systematic review of postmortem brain studies
Lisboa, J. R., Costa, O., Pakes, G. H., Colodete, D. A. E., & Gomes, F. V. (2024) · Schizophrenia Research · doi:10.1016/j.schres.2024.07.023 · Cited by 17
Estrogenic regulation of perineuronal nets in the mouse insular cortex and hippocampus
Nguyen, R., Rahyab, R., Deshpande, A., Legge, E., Almeida, J. F., Herz, S. M., Zylko, A. L., Damaj, M. I., & Lasek, A. W. (2025) · Neuropharmacology · doi:10.1016/j.neuropharm.2025.110641 · Cited by 17
“For example, in the dHPC, E2 enhancement of memory requires the activity of MMP9 (Gross et al., 2022), which has been shown to cleave the PNN protein brevican and attenuate WFA staining (Alaiyed et al., 2019, 2020; Stamenkovic et al., 2017; Wen et al., 2017).”
Fragile X Syndrome as an interneuronopathy: a lesson for future studies and treatments
Tempio, A., Boulksibat, A., Bardoni, B., & Delhaye, S. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1171895 · Cited by 17
Developmental delays in cortical auditory temporal processing in a mouse model of Fragile X syndrome
Croom, K., Rumschlag, J. A., Erickson, M. A., Binder, D. K., & Razak, K. A. (2023) · Journal of Neurodevelopmental Disorders · doi:10.1186/s11689-023-09496-8 · Cited by 19
“There is also a developmental delay in the maturation of parvalbuminexpressing inhibitory neurons and the perineuronal nets that surround them [59].”
BackgroundInfluentialSelf-citationYang, P., Davidson, J. O., Fowke, T. M., Galinsky, R., Wassink, G., Karunasinghe, R. N., Prasad, J. D., Ranasinghe, S., Green, C. R., Bennet, L., et al. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21186475 · Cited by 17
Negwer, M., Piera, K., Hesen, R., Lütje, L., Aarts, L., Schubert, D., & Kasri, N. N. (2020) · Brain Structure and Function · doi:10.1007/s00429-020-02149-9 · Cited by 15
“In the Fmr1−/y mouse, a delay of both PV+ and PNN development is visible, which in this mouse is caused by an overproduction of the PNN modifier MMP-9 during the auditory critical period (Wen et al. 2018).”
BackgroundKudo, T., Takuwa, H., Takahashi, M., Urushihata, T., Shimojo, M., Sampei, K., Yamanaka, M., Tomita, Y., Sahara, N., Suhara, T., et al. (2023) · iScience · doi:10.1016/j.isci.2023.106342 · Cited by 16
Urokinase plasminogen activator mediates changes in human astrocytes modeling fragile X syndrome
Peteri, U., Pitkonen, J., de Toma, I., Nieminen, O., Utami, K. H., Strandin, T. M., Corcoran, P., Roybon, L., Vaheri, A., Ethell, I., et al. (2021) · Glia · doi:10.1002/glia.24080 · Cited by 16
Self-citationReinhard, S. M., Abundez-Toledo, M., Espinoza, K., & Razak, K. A. (2019) · Hearing Research · doi:10.1016/j.heares.2019.107781 · Cited by 15
Self-citationWoo, A. M., & Sontheimer, H. W. (2023) · Frontiers in Molecular Medicine · doi:10.3389/fmmed.2023.1198021 · Cited by 17
Bozzelli, P. L., Caccavano, A., Avdoshina, V., Mocchetti, I., Wu, J., & Conant, K. E. (2019) · Experimental Neurology · doi:10.1016/j.expneurol.2019.113077 · Cited by 15
Mascio, G., Bucci, D., Notartomaso, S., Liberatore, F., Antenucci, N., Scarselli, P., Imbriglio, T., Caruso, S., Gradini, R., Cannella, M., et al. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01210-3 · Cited by 14
The Pathophysiological Underpinnings of Gamma-Band Alterations in Psychiatric Disorders
Palmisano, A., Pandit, S., Smeralda, C. L., Demchenko, I., Rossi, S., Battelli, L., Rivolta, D., Bhat, V., & Santarnecchi, E. (2024) · Life · doi:10.3390/life14050578 · Cited by 17
“Kigawa and colleagues [300] also found that combined exposure to prenatal and adolescent stress reduces PV+ interneurons.”
BackgroundAmontree, M., Nelson, M., Stefansson, L., Pak, D. T. S., Maguire-Zeiss, K., Turner, R., & Conant, K. (2024) · Journal of Neurochemistry · doi:10.1111/jnc.16031 · Cited by 13
“MMP-9 can also promote dendritic arborization and attenuate plasticity-restricting perineuronal nets (PNNs) (Alaiyed et al., 2020 ; Murase et al., 2017; Wen et al., 2018 ).”
Cheung, S. W., Willis, E. F., Simmons, D. G., Bellingham, M. C., & Noakes, P. G. (2024) · Neurobiology of Disease · doi:10.1016/j.nbd.2024.106614 · Cited by 13
“MMP-9 has been shown to degrade PNNs by cleaving aggrecan, a core proteoglycan (Lark et al., 1995; Murase et al., 2017; Wen et al., 2017; Madsen et al., 2010).”
BackgroundPerineuronal Net Alterations Following Early-Life Stress: Are Microglia Pulling Some Strings?
Rahimian, R., Belliveau, C., Simard, S., Turecki, G., & Mechawar, N. (2024) · Biomolecules · doi:10.3390/biom14091087 · Cited by 18
“Studies reveal that MMP9 released by glia and neurons is directly responsible for PNN degradation, as evidenced by the increased densities of PNNs following genetic deletion of the MMP9 gene in Fmr1 knockout mice, a model of fragile X syndrome [73].”
BackgroundTao, X., Newman‐Tancredi, A., Varney, M. A., & Razak, K. A. (2022) · Neuroscience · doi:10.1016/j.neuroscience.2022.11.014 · Cited by 13
Self-citationAxonal and presynaptic FMRP: Localization, signal, and functional implications
Wang, X., Sela‐Donenfeld, D., & Wang, Y. (2023) · Hearing Research · doi:10.1016/j.heares.2023.108720 · Cited by 13
Papatheodoropoulos, C. (2025) · Biology · doi:10.3390/biology14040363 · Cited by 15
Targeted therapy of cognitive deficits in fragile X syndrome
Puścian, A., Winiarski, M., Borowska, J., Łęski, S., Górkiewicz, T., Chaturvedi, M., Nowicka, K., Wołyniak, M., Chmielewska, J. J., Nikolaev, T., et al. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01527-5 · Cited by 11
Longitudinal in vivo imaging of perineuronal nets
Benbenishty, A., Peled-Hajaj, S., Krishnaswamy, V. R., Har-Gil, H., Havusha-Laufer, S., Ruggiero, A., Slutsky, I., Blinder, P., & Sagi, I. (2023) · Neurophotonics · doi:10.1117/1.nph.10.1.015008 · Cited by 11
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Kaczmarek, L. (2018) · Postępy Biochemii · doi:10.18388/pb.2018_119 · Cited by 11
Song, Y. J., Xing, B., Barbour, A. J., Zhou, C., & Jensen, F. E. (2021) · Cerebral Cortex · doi:10.1093/cercor/bhab203 · Cited by 10
“Wen et al. (2018) reported reduced P14 auditory cortex parvalbumin cell numbers in Fmr1 KO mice, and we found reduced P12 GABAAR α3-subunit expression.”
BackgroundInfluentialModulation of stress-, pain-, and alcohol-related behaviors by perineuronal nets
Aguilar, J. S., & Lasek, A. W. (2024) · Neurobiology of Stress · doi:10.1016/j.ynstr.2024.100692 · Cited by 11
“…motifs (ADAMTSs), and the cathepsins family of proteinases, all of which cleave proteoglycans, thus allowing for new synapse formation and heightened plasticity (Bonnans et al., 2014; Dubey et al., 2017; Stamenkovic et al., 2017; Tran et al., 2018; Valenzuela et al., 2014; Wen et al., 2018).”
Croom, K., Rumschlag, J. A., Erickson, M. A., Binder, D. K., & Razak, K. A. (2024) · Journal of Neurodevelopmental Disorders · doi:10.1186/s11689-024-09539-8 · Cited by 11
“The peri-pubertal window is a critical period of development in Fmr1 KO mice that is marked by cortical hyperexcit-ability and reduced inhibitory interneuron function [70, 75, 138].”
BackgroundSelf-citationKourdougli, N., Nomura, T., Wu, M. W., Heuvelmans, A. M., Dobler, Z., Contractor, A., & Portera‐Cailliau, C. (2024) · Biological Psychiatry · doi:10.1016/j.biopsych.2024.06.023 · Cited by 10
Perineuronal nets in the developing brain: implications for neurodevelopmental disorders
Ackerman, J. M., Ford, T. J. L., Kattewar, S. S., & Kim, W.-Y. (2025) · Molecular Brain · doi:10.1186/s13041-025-01261-3 · Cited by 10
“ASD has been previously associated with disruptions in cortical interneuron development across various genetic models [54, 57, 143, 150].”
Liu, P., Zhao, Y., Xiong, W., Pan, Y., Zhu, M., & Zhu, X. (2022) · Neuroscience · doi:10.1016/j.neuroscience.2022.12.024 · Cited by 10
Orchestrating the Matrix: The Role of Glial Cells and Systemic Signals in Perineuronal Net Dynamics
Totaro, V., Pizzorusso, T., & Tognini, P. (2025) · Neurochemical Research · doi:10.1007/s11064-025-04506-8 · Cited by 9
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
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