Matrix metalloproteinase-9 deletion rescues auditory evoked potential habituation deficit in a mouse model of Fragile X Syndrome

May combine two claims.

In all three genotypes, auditory event-related potentials habituate by the second sound in the train, with no statistical difference between genotypes.

“This indicates that ERPs in all three genotypes of mice habituate to auditory stimuli by the second sound in the train and there is no statistical difference between the genotypes.”

May combine two claims.

The normalized first N1 response does not differ by genotype, repetition rate, or their interaction.

“Two-way ANOVA of genotype and repetition rate reveals no differences for the normalized 1st response between genotype (F(2,123) = 1.482, p = 0.231), repetition rate (F(5,123) = 0.593, p = 0.216), or genotype x repetition rate interaction (F(10,123) = 0.593, p = 0.817) (Figure 2E).”

May combine two claims.

N1 latency differs between wildtype and Mmp-9/Fmr1 double knockout mice, but not between wildtype and Fmr1 knockout mice or between double knockout and Fmr1 knockout mice.

“Post-hoc Bonferroni analysis reveals a difference between WT and Mmp-9/Fmr1 DKO (p = 0.002), but not between WT and Fmr1 KO (p = 0.171), or Mmp-9/Fmr1 DKO and Fmr1 KO mice (p = 0.204).”

May combine two claims.

Raw N1 amplitudes in Mmp-9 knockout mice do not differ from wildtype mice except at 0.25 Hz, where they are lower.

“Additionally, raw amplitudes of Mmp-9 KO mice showed no difference when compared to WT mice using independent samples t-test (all p > 0.5), except at the lowest rate of 0.25Hz, which was significantly lower than WT, p = 0.046 (data not shown).”

May combine two claims.

N1 latency shows a main effect of genotype but not of repetition rate or their interaction.

“Two-way ANOVA on N1 latency of genotype and rate shows a main effect of genotype (F(2,118) = 6.369, p = 0.002), but not of rate (F(5,118) = 2.247, p = 0.054), or genotype x rate interaction (F(10,118) = 0.742, p = 0.683).”

May combine two claims.

The second N1 response does not differ between genotypes, but it does differ by repetition rate, with greater habituation at faster rates in all genotypes.

“A two-way ANOVA of genotype and repetition rate reveals no differences for the 2nd response between genotype (F(2,123) = 2.500, p = 0.086) or a genotype x repetition rate interaction (F(10,123) = 0.746, p = 0.680). However, 2nd responses are different depending on the repetition rate (F(5,123) = 13.898, p < 0.000001), with more habituation occurring at faster rates for all genotypes (Figure 2F).”

May combine two claims.

The Fano factor of N1 latency differs in Mmp-9/Fmr1 double knockout mice compared with wildtype or Fmr1 knockout mice, with no difference between wildtype and Fmr1 knockout mice.

“Post-hoc Bonferroni analysis shows that differences in Fano Factor existed in Mmp-9/Fmr1 DKO mice when compared to WT or Fmr1 KO mice (p = 0.009), with no differences between WT and Fmr1 KO mice (p = 0.9).”

May combine two claims.

The Fano factor of N1 latency shows effects of genotype and repetition rate but no genotype-by-rate interaction.

“The analysis showed that there was an effect of genotype (F(2,117) = 6.953, p = 0.001), and an effect of repetition rate (F(5,117) = 13.152, p < 0.000001), with no genotype x repetition rate interaction (F(10,117) = 0.845, p = 0.587).”

May combine two claims.

At 0.25 Hz, N1 latency was stable across the whole stimulus train in WT, Fmr1 KO, and Mmp-9/Fmr1 DKO mice, and no genotype differences were found (F(2,20)=0.308, p=0.738).

“At 0.25 Hz N1 latencies were extremely stable throughout the entire stimulus train for WT (Fano Factor: 0.00019 ± 0.00008, n = 7), Fmr1 KO (Fano Factor: 0.00052 ± 0.00046, n = 9), and Mmp-9/Fmr1 DKO mice (Fano Factor: 0.00028 ± 0.00024) with no differences observed between genotypes (F(2,20) = 0.308, p = 0.738)”

May combine two claims.

Fmr1 KO mice had a habituation deficit across repeated sounds at 5 Hz, but no differences were observed in responses to the deviant noise or the following tone.

“These results indicate that while Fmr1 KO mice have a deficit in habituation across repeated sounds for a 5 Hz repetition rate, no differences in response to the deviant noise or the tone following the deviant noise were observed.”

• AssumptionRests on an assumption: The fixed-position deviant sound paradigm is adequate to detect stimulus contrast detection deficits in Fmr1 KO mice.

May combine two claims.

Independent t-tests on each train stimulus showed some WT versus Fmr1 KO and DKO versus Fmr1 KO differences, but no WT versus DKO difference at any position (p>0.05).

“Comparison of the responses to each stimulus in the train in isolation using independent samples t-tests revealed some differences between WT and Fmr1 KO mice and between Mmp-9/Fmr1 DKO and Fmr1 KO mice (Figure 6A), but no difference between WT and Mmp-9/Fmr1 DKO at any position (p>0.05).”

May combine two claims.

Post-hoc tests attributed the genotype effect to differences between Fmr1 KO and WT or DKO mice (p<0.000001), with no WT versus DKO difference (p=0.9).

“Post-hoc analysis showed that the effect of genotype is due to the differences between Fmr1 KO mice and WT or Mmp-9/Fmr1 DKO mice (p < 0.000001), but no differences between WT and Mmp-9/Fmr1 DKO mice (p = 0.9).”

May combine two claims.

No early-train differences appeared between genotypes, consistent with similar early habituation, while impaired responses occurred only in Fmr1 KO mice during later steady-state habituation.

“It should also be noted that no differences are seen early in the train between any genotypes, which is consistent with earlier results showing similar early habituation between genotypes, but impaired responses only in Fmr1 KO genotype during later, steady state habituation.”

May combine two claims.

Responses reached a stable asymptote after two to three repetitions, but the asymptote amplitude was significantly higher in Fmr1 KO than WT mice.

“The responses asymptote to a stable level after the first two to three repetitions, but the asymptote amplitude was significantly higher in Fmr1 KO than WT mice.”

May combine two claims.

At some repetition rates, Mmp-9/Fmr1 DKO mice had larger N1 amplitudes, shorter latencies, and less latency variability.

“at some rates, the N1 amplitudes were larger, and latencies shorter and less variable, in the Mmp-9/Fmr1 DKO mice.”

May combine two claims.

Sound-evoked cortical N1 amplitudes decreased rapidly and in a repetition-rate-dependent way in all three genotypes.

“Sound evoked cortical N1 amplitudes showed a rapid and repetition rate-dependent reduction across all three genotypes.”

May combine two claims.

In all three genotypes, the second response to a paired sound was reduced relative to the first, with no significant genotype difference.

“The response amplitude to the second sound of a pair is normally reduced compared to the first. This was seen in all three genotypes with no significant difference between them suggesting normal sensory gating in Fmr1 KO mice.”

May combine two claims.

Discrimination indices for the 5th-6th and 6th-7th transitions showed no differences (F(2,18)=0.725, p=0.498; F(2,18)=0.255, p=0.778).

“No differences were observed for either 5th −6th transition (F(2,18) = 0.725, p = 0.498) or from 6th-7th transition (F(2,18) = 0.255, p = 0.778)”

May combine two claims.

Removal of MMP-9 in Mmp9 KO mice mostly did not affect auditory ERP N1 amplitude or habituation, although MMP-9 is involved in sensory system development (Reinhard et al., 2015).

“Although MMP-9 is involved in sensory system development (reviewed in Reinhard et al., 2015), we found that auditory ERP N1 amplitude and habituation are mostly unaffected by the removal of MMP-9 (Mmp9 KO mice).”

• cites Reinhard et al., 2015 sourceNot checked yet

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May combine two claims.

In that paradigm, there was a main effect of genotype (F(2,162)=30.631, p<0.000001) and no genotype by position interaction (F(16,162)=0.725, p=0.766).

“Additionally, a main effect of genotype was found (F(2,162) = 30.631, p < 0.000001), with no genotype x position interaction (F(16,162) = 0.725, p = 0.766).”

May combine two claims.

Not all ERP properties were similar between Mmp-9/Fmr1 DKO and WT mice; DKO mice had shorter N1 latencies at 0.25 and 0.5 Hz, smaller latency variance, and higher N1 amplitude than WT and Fmr1 KO mice at some rates.

“It must be noted that not all ERP properties were similar between the Mmp-9/Fmr1 DKO and WT mice. Mmp-9/Fmr1 DKO mice had shorter N1 latencies at the slowest (0.25 and 0.5 Hz) repetition rates, smaller variance in latency and higher N1 amplitude than the WT and Fmr1 KO mice for some repetition rates.”

May combine two claims.

WT and Fmr1 KO mice did not differ significantly in N1 amplitude or latency.

“there were no significant differences in N1 amplitude or latency between the WT and Fmr1 KO mice”

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

MMP-9 is an endopeptidase that can cleave extracellular matrix.

“MMP-9 is an endopeptidase that can cleave extracellular matrix (Ethell and Ethell, 2007)”

• cites Ethell and Ethell, 2007Not checked yet

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May combine two claims.

Fmr1 knockout mice exhibit auditory hypersensitivity, including audiogenic seizures and enhanced cortical responses to sounds.

“Fmr1 knockout (KO) mouse, a pre-clinical model of FXS, also exhibits auditory hypersensitivity including audiogenic seizures (Chen and Toth, 2001; Musumeci et al., 2007) and enhanced cortical responses to sounds (Rotschafer and Razak, 2013).”

• cites Chen and Toth, 2001Not checked yet

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• cites Musumeci et al., 2007 sourceNot checked yet

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• cites Rotschafer and Razak, 2013Not checked yet

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

Fragile X Syndrome results from expansion and hyper-methylation of CGG trinucleotide repeats in the FMR1 gene, leading to reduced FMRP.

“FXS results from expansion and hyper-methylation of CGG trinucleotide repeats in the un-translated 5’ region of the Fragile X Mental Retardation (FMR1) gene, leading to reduced FMR1 protein (FMRP) (Bailey et al., 1998; O'Donnell and Warren, 2002).”

• cites Bailey et al., 1998 sourceNot checked yet

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• cites O'Donnell and Warren, 2002Not checked yet

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Classified as probably not a substantial claim.

Auditory event-related potential habituation deficits in humans with Fragile X Syndrome are reversed by minocycline treatment.

“The ERP habituation deficits in humans with FXS are reversed by minocycline treatment but the underlying mechanisms are not known (Schneider et al. 2013).”

• cites Schneider et al. 2013 sourceNot checked yet

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May combine two claims.

Genetic deletion of Mmp-9 in Fmr1 knockout mice reverses some molecular and physiological hippocampal deficits and Fragile X Syndrome-associated behaviors.

“Genetic deletion of Mmp-9 in Fmr1 KO mice reverses some molecular and physiological hippocampal deficits and FXS-associated behaviors (Sidhu et al., 2014).”

• cites Sidhu et al., 2014 sourceNot checked yet

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Classified as probably not a substantial claim.

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

“All genotypes were confirmed by PCR analysis of genomic DNA isolated from mouse tails.”

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

The order of broadband noise stimulus trains at different repetition rates was selected at random.

“The order in which BBN stimulus trains with different repetition rates were presented was selected at random.”

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

Minocycline can reduce the levels and activity of MMP-9.

“Beside its antibiotic and anti-inflammatory activity, minocycline can reduce the levels and activity of matrix metalloproteinase-9 (MMP-9) (Lee et al., 2006; Bilousova et al., 2009; Dziembowska et al 2013).”

• cites Lee et al., 2006 sourceNot checked yet

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• cites Bilousova et al., 2009 sourceNot checked yet

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• cites Dziembowska et al 2013 sourceNot checked yet

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

Speaker output fluctuation was within +/- 3 dB for frequencies between 5 and 35 kHz, as measured with a 1/4 inch B&K microphone.

“The speaker output fluctuation was within +/− 3 dB for frequencies between 5 and 35 kHz as measured using a ¼ inch B&K microphone.”

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

Differences in repetition rates, anesthesia, and scalp versus cortical recordings may explain the human-mouse N1 amplitude discrepancy.

“Factors such as differences in repetition rates, anesthesia and scalp versus cortical recordings may contribute to these differences.”

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

Mismatch negativity amplitude is lower in humans with FXS (Van der Molen et al., 2012b).

“The amplitude of mismatch negativity is lower in humans with FXS (Van der Molen et al., 2012b)”

• cites Van der Molen et al., 2012bNot checked yet

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May combine two claims.

The second response in a stimulus train measures early habituation, a process linked to sensory gating (Rosburg et al., 2004).

“In response to a stimulus train, the amplitude of the second response in the train is a measure of early habituation, a process related to sensory gating (Rosburg et al., 2004).”

• cites Rosburg et al., 2004 sourceNot checked yet

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

If non-stimulus-driven artifacts occurred during a sound train, the entire train was removed from subsequent analysis.

“If during sound train presentation, non-stimulus driven artifacts were observed, the entire train was removed from subsequent analysis.”

May combine two claims.

When sound is repeated, more cortical neurons may be activated in a sustained way in Fmr1 KO mice due to reduced synaptic inhibition and enhanced intrinsic excitability, producing hyperexcitability in FXS.

“Thus when a sound is repeated, more neurons across the cortex may be activated in a sustained fashion in Fmr1 KO mice due to a combination of reduced synaptic inhibition and enhanced intrinsic excitability resulting in hyperexcitability in FXS.”

May combine two claims.

Reduced N1 habituation in Fmr1 KO mice resembles human FXS observations, providing an analogous functional sensory outcome measure in mice and humans (Castren et al., 2003; Van der Molen et al., 2012; Schneider et al., 2013).

“The reduced habituation of N1 amplitude in Fmr1 KO mice is similar to observations in humans with FXS providing, for the first time, an analogous functional sensory outcome measure in mice and humans (Castren et al., 2003; Van der Molen et al., 2012; Schneider et al., 2013).”

• cites Castren et al., 2003 sourceNot checked yet

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• cites Van der Molen et al., 2012Not checked yet

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• cites Schneider et al., 2013 sourceNot checked yet

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• AssumptionRests on an assumption: The Fmr1 KO mouse is a valid model for human FXS auditory phenotypes.
• AssumptionRests on an assumption: N1 ERP habituation in mice and humans reflects the same underlying neural process.

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

This lower mismatch negativity may reflect reduced habituation of the steady-state response.

“that may also reflect a reduced habituation of steady state response.”

May combine two claims.

The sustained response component was mostly absent in WT neurons but significant in Fmr1 KO neurons.

“The sustained component of the response, which was mostly absent in WT neurons, was significant in Fmr1 KO neurons.”

• cites Rotschafer and Razak, 2013Not checked yet

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

ERP studies typically average hundreds of trials for high signal-to-noise; average amplitude differences can arise from different individual response amplitudes or from latency jitter smearing the average (Mouraux and Ionnetti, 2008).

“Averaging of 100s of trials is typically performed to obtain high signal to noise ratios in ERP studies. Using an averaging approach, differences in average amplitudes could be either because the individual responses have different amplitudes or because of increased latency jitter of individual responses, which then “smear” the average (Mouraux and Ionnetti, 2008).”

• cites Mouraux and Ionnetti, 2008Not checked yet

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

Reduced cortical GABA-A mediated inhibition in Fmr1 KO cortex may also contribute to broader tuning curves (Wang et al., 2000).

“Reduced cortical GABA-A mediated inhibition observed in Fmr1 KO cortex may also contribute to broader tuning curves in the Fmr1 KO mice (Wang et al., 2000).”

• cites Wang et al., 2000 sourceNot checked yet

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May combine two claims.

The data suggest that enhanced steady-state cortical activation during repeated acoustic stimulation may contribute to auditory hypersensitivity in FXS, and that abnormal MMP-9 levels may lead to that hypersensitivity.

“These data suggest that enhanced steady state cortical activation in the presence of repeated acoustic stimulation may contribute to auditory hypersensitivity in FXS and suggest that abnormal MMP-9 levels may lead to the auditory hypersensitivity in FXS.”

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

The higher average N1 amplitude in human FXS may relate to reduced habituation when responses are averaged over repetitions and to N1 latency variability.

“The higher average N1 amplitude in human FXS may be related to the reduced habituation when responses are averaged over multiple repetitions and variability of N1 latency”

May combine two claims.

In Fmr1 KO somatosensory cortex, PV neurons receive reduced excitatory drive, causing reduced network inhibition and increased UP states (Selby et al., 2007; Gibson et al., 2008).

“In the somatosensory cortex of Fmr1 KO mice, PV neurons receive reduced excitatory drive resulting in reduced inhibition in the network and increased UP states (Selby et al., 2007; Gibson et al., 2008).”

• cites Selby et al., 2007 sourceNot checked yet

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• cites Gibson et al., 2008 sourceNot checked yet

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

Smaller latency variance may increase N1 amplitude through greater synchrony.

“The smaller latency variance may contribute to the larger N1 amplitude because of increased synchrony.”

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

At each recording location, habituation and oddball testing began only after reliable sound-driven event-related potentials with an N1 component at about 45 ms latency were produced.

“At each recording location, habituation and oddball testing began only after sound-driven ERPs with an N1 component with ~45 ms latency could be reliably produced.”

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

Sound delivery was synchronized with EEG recording using a 5 ms digital TTL pulse to mark sound onset.

“Data were sampled at a rate of either 5 or 20 kHz using Acqknowledge software, and sound delivery was synchronized with EEG recording using a 5 ms digital TTL pulse to mark the onset of each sound in a train.”

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

All mouse studies were done according to NIH and Institutional Animal Care and Use Committee guidelines.

“All mouse studies were done according to NIH and Institutional Animal Care and Use Committee guidelines.”

Classified as probably not a substantial claim.

A prior in vivo auditory cortex study found hyper-responsive neurons in Fmr1 KO mice (Rotschafer and Razak, 2013).

“A previous in vivo study of the auditory cortex revealed hyper-responsive neurons in Fmr1 KO mice (Rotschafer and Razak, 2013).”

• cites Rotschafer and Razak, 2013Not checked yet

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

Toe pinch reflex was used to measure anesthetic state every 20-30 minutes and isoflurane levels were adjusted as needed.

“Toe pinch reflex was used to measure anesthetic state every 20–30 minutes throughout the experiment, and isoflurane levels were adjusted as needed.”

May combine two claims.

Mmp-9/Fmr1 DKO mice had habituation responses similar to WT, indicating that deleting Mmp-9 reversed the Fmr1 KO deficit at 5 Hz.

“Habituation responses in Mmp-9/Fmr1 DKO mice were similar to WT, indicating that a genetic deletion of Mmp-9 reversed the deficits in Fmr1 KO mice at a stimulus repetition rate of 5 Hz.”

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

The smaller N1 latency Fano factor in DKO recordings suggests latency jitter may explain their larger N1 amplitude.

“The smaller N1 latency Fano factor of the Mmp-9/Fmr1 DKO recordings suggest the latter may be the reason here.”

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

The location of core auditory cortex was identified using vasculature and confirmed with extracellular recordings in response to sounds.

“Location of core auditory cortex was identified using vasculature, and confirmed with extracellular recordings in response to sounds.”

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

Recovery windows during repeated auditory cortex stimulation may also depend on intrinsic excitability and presynaptic BK channel deficits in Fmr1 KO mice (Deng et al., 2013), contributing to the habituation phenotype.

“Recovery windows during repeated stimulation in the auditory cortex may also depend on intrinsic excitability and deficits in presynaptic BK channels in Fmr1 KO mice (Deng et al., 2013) contributing to the habituation phenotype.”

• cites Deng et al., 2013 sourceNot checked yet

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

The amplifier gain was kept the same at 10,000x between all recordings.

“Normal EEG output data was collected, alpha detection mode was not used and gain was kept the same (10,000×) between all recordings.”

May combine two claims.

Although ERPs have low spatial resolution for circuit, cortical depth, or single-neuron mechanisms, the human-mouse similarity in habituation deficits provides a translation-relevant functional biomarker.

“Although ERPs have low spatial resolution to address mechanisms at the circuit, cortical depth or single neuron level, the similarity of the habituation deficits between humans and mice provides a functional biomarker that is translation relevant.”

• AssumptionRests on an assumption: The Fmr1 KO mouse is a valid model for human FXS auditory phenotypes.
• AssumptionRests on an assumption: N1 ERP habituation in mice and humans reflects the same underlying neural process.

May combine two claims.

FMRP is expressed throughout the auditory system, and the cortical habituation deficits may have multiple origins (Strumbos et al., 2010; Wang et al., 2014; Rotschafer et al., 2015).

“However, FMRP is expressed across the auditory system and the observed cortical habituation deficits may have multiple origins (Strumbos et al., 2010; Wang et al., 2014; Rotschafer et al., 2015).”

• cites Strumbos et al., 2010 sourceNot checked yet

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• cites Wang et al., 2014 sourceNot checked yet

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• cites Rotschafer et al., 2015 sourceNot checked yet

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

Abnormally high or low MMP-9 levels may cause auditory circuit differences.

“and abnormally high or low levels may result in auditory circuit differences.”

May combine two claims.

Deleting MMP-9 from Fmr1 KO mice reverses molecular and synaptic hippocampal deficits and some FXS-associated behaviors (Sidhu et al., 2014).

“Deletion of MMP-9 from Fmr1 KO mice results in reversal of molecular and synaptic deficits in the hippocampus of Fmr1 KO mice as well as some FXS-associated behaviors (Sidhu et al., 2014).”

• cites Sidhu et al., 2014 sourceNot checked yet

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Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

Because similar sensory processing deficits occur in FXS and ASD, auditory ERP habituation may serve as a broader preclinical model for drug discovery in autism.

“Given that similar sensory processing deficits are seen in FXS and ASD, auditory ERP habituation may serve more broadly as a pre-clinical model for drug discovery in autism.”

• AssumptionRests on an assumption: The Fmr1 KO mouse is a valid model for human FXS auditory phenotypes.
• AssumptionRests on an assumption: N1 ERP habituation in mice and humans reflects the same underlying neural process.

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

MMP-9 regulates normal sensory cortex development (Kaliszewska et al., 2012).

“MMP-9 regulates normal development of sensory cortex (Kaliszewska et al., 2012)”

• cites Kaliszewska et al., 2012 sourceNot checked yet

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May combine two claims.

High MMP-9 may reduce PNN formation around PV interneurons, affecting their activity (Cabungcal et al., 2013), leading to impaired inhibition (Selby et al., 2007; Gibson et al., 2008) and enhanced excitability in Fmr1 KO auditory cortex.

“High MMP-9 levels may result in reduced PNN formation around PV interneurons affecting their activity (Cabungcal et al., 2013) and leading to impaired inhibition (Selby et al., 2007; Gibson et al., 2008), and enhanced excitability in Fmr1 KO auditory cortex.”

• cites Cabungcal et al., 2013 sourceNot checked yet

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• cites Selby et al., 2007 sourceNot checked yet

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• cites Gibson et al., 2008 sourceNot checked yet

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May combine two claims.

MMP-9 targets perineuronal nets (PNNs), which preferentially surround PV-expressing inhibitory interneurons in cortex.

“MMP-9 targets components of the extracellular matrix known as perineuronal nets (PNNs), which preferentially surround PV-expressing inhibitory interneurons in the cortex.”