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Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism
Open accessAbstract
Autism-like behaviors in mice were reversed by a negative modulator of a metabotropic glutamate receptor, suggesting a treatment for symptoms of autism spectrum disorders.
Overview
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Written from the paper’s full text.
TL;DR
The selective mGluR5 negative allosteric modulator GRN-529 reduced repetitive behaviors and partially rescued social deficits in BTBR and C58 inbred mouse models of autism-relevant phenotypes. Effects occurred at nonsedating doses, suggesting mGluR5 modulation may alleviate multiple core diagnostic behavioral symptoms.
Key findings
- GRN-529 significantly reduced repetitive self-grooming in BTBR mice in three replications by two laboratories at doses achieving 50 to 90% mGluR5 receptor occupancy.
- GRN-529 dose-dependently reduced stereotyped vertical jumping in C58 mice, almost completely abolishing it at 3.0 mg/kg, a dose achieving ~90% occupancy.
- GRN-529 partially reversed social deficits in BTBR mice: it reversed sociability deficits at 3.0 mg/kg by time in chamber, and BTBR mice spent significantly more time sniffing a novel mouse than a novel object after 0.3, 1.0, and 3.0 mg/kg.
- No sedation was detected in B6, BTBR, or C58 mice at any dose during a 30-min open field test; higher total distances traveled appeared at 3.0 mg/kg in B6 and BTBR, and no increases in total distance were observed in C58 at any dose.
Methods
- Adult male and female C57BL/6J (B6) and BTBR T+tf/J (BTBR) mice were tested at NIMH; B6, BTBR, and C58/J (C58) mice were tested at Pfizer.
- Behavioral assays included repetitive self-grooming, automated three-chambered social approach, freely moving dyadic reciprocal social interaction, and open field locomotion; scoring was automated or from digital video by investigators uninformed of treatment.
- Pharmacokinetic and ex vivo receptor occupancy assays measured plasma and forebrain GRN-529 concentrations and mGluR5 occupancy; behavioral doses were 0.3 to 3.0 mg/kg, with a 30- to 60-min posttreatment interval. Complete statistical analyses are reported in the Supplementary Materials.
Limitations
- The paper states it remains conceptually possible that increased general exploration could contribute to increased sociability, and notes higher doses increased open field scores and chamber entries in B6 and BTBR.
- The paper states the background genes responsible for autism-relevant behavioral traits in BTBR and C58 remain under investigation, and these inbred strains lack identified genetic mutations.
- Evident from the text: the experiments assessed social and repetitive behaviors but did not test communication phenotypes, despite the abstract framing autism’s three diagnostic behavioral symptoms; effects were also from acute administration only.
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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
“No evidence of sedation was detected in any strain at any dose during a 30-min test session (Fig. 5 and figs. S4 to S6).”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > RESULTS > Absence of sedation
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Further, GRN-529 partially reversed the striking lack of sociability in BTBR mice on some parameters of social approach and reciprocal social interactions.”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“GRN-529 reduced repetitive behaviors in three cohorts of BTBR mice at doses that did not induce sedation in control assays of open field locomotion.”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition, the same nonsedating doses reduced the spontaneous stereotyped jumping that characterizes a second inbred strain of mice, C58/J.”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In three replications by two laboratories, acute administration of GRN-529 significantly reduced repetitive self-grooming scores in BTBR (Fig. 2, B and D, and fig. S1F) at doses that achieved 50 to 90% receptor occupancy (Fig. 1F).”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > RESULTS > Amelioration of repetitive and stereotyped behaviors
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Further, during the freely moving, dyadic reciprocal interaction task, BTBR mice treated with vehicle engaged in much longer bouts of self-grooming and repetitive digging than did B6 mice (Fig. 4, E to H).”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > RESULTS > Improvement in social behaviors
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“A 30- to 60-min timeframe was chosen for occupancy and behavioral experiments because a 2-hour time course of plasma and brain exposure after GRN-529 administration revealed that peak concentrations occurred between 0 and 60 min in B6 mice (Fig. 1E).”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > RESULTS > GRN-529 brain penetration and mGluR5 receptor occupancy
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In the paper
“B6 control mice spent more time in the side chamber containing a novel mouse than in the side chamber containing a novel object, meeting the definition of normal sociability in this task, as extensively reported (22, 62, 64, 72–74, 87–89).”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > RESULTS > Improvement in social behaviors
Load-bearingStrength:boosted· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The effects in C58 were not attributable to reduced locomotion or sedation (Fig. 2F and fig. S6).”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > RESULTS > Amelioration of repetitive and stereotyped behaviors
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“GRN-529 and the prototypic mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) reduced the high levels of repetitive self-grooming that characterizes the BTBR strain.”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > RESULTS > Amelioration of repetitive and stereotyped behaviors
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- It may state two separate claims as one. 22
- Probably not a substantial claim. 9
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
“GRN-529 increased sociability in BTBR on some of these parameters, particularly on the most sensitive measures, nose-to-nose sniffing (Fig. 4B) and total time spent in social contact (Fig. 4D), while having no effect in B6 controls (Fig. 4, A and C, and fig. S3, A, C, and E).”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > RESULTS > Improvement in social behaviors
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“During the reciprocal interaction test, B6 mice consistently exhibited high levels of nose-to-nose sniffing, front approach, and total time spent in social contact (Fig. 4, A and C, and fig. S3A), whereas BTBR mice displayed lack of sociability on these standard parameters (Fig. 4, B and D, and fig. S3B), consistent with previous reports (60, 78, 91).”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > RESULTS > Improvement in social behaviors
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The number of entries between chambers, an internal control for general exploration, was not significantly affected by the lower doses of GRN-529 in either strain, but elevated numbers of entries in both strains appeared at a dose of 3.0 mg/kg (Fig. 3, E and F).”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > RESULTS > Improvement in social behaviors
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“A second cohort displayed a similar pattern of responses (fig. S2).”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > RESULTS > Improvement in social behaviors
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A 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
“For time spent sniffing the novel mouse versus the novel object, which is a more precise and sensitive measure of true social interaction (87, 90), GRN-529 reversed the deficit in BTBR, again with no detrimental effect on B6 sociability (Fig. 3, A and C).”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > RESULTS > Improvement in social behaviors
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“GRN-529 dose-dependently reduced jumping in C58, almost completely abolishing this repetitive behavior at 3.0 mg/kg, a dose that achieved ~90% occupancy (Fig. 1F).”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > RESULTS > Amelioration of repetitive and stereotyped behaviors
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“3-((2-Methyl-4-thiazolyl)ethynyl)pyridine (MTEP), another standard mGluR5 antagonist, similarly reduced repetitive self-grooming in BTBR at some doses (fig. S1D) and similarly had no effect in B6 mice (fig. S1C), consistent with current and previous findings with the less selective mGluR5 antagonist MPEP (fig. S1, A and B) (72).”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > RESULTS > Amelioration of repetitive and stereotyped behaviors
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In particular, the more ethologically meaningful parameters of time engaged in interactive sniffing of a novel mouse versus time spent sniffing a novel object during social approach, bouts of nose-to-nose sniffing and time in social contact during reciprocal interactions, were restored in BTBR by the acute pharmacological intervention, which had no effect in the normal control B6 strain.”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Parallel attenuation of self-grooming in BTBR was confirmed at the high dose of MPEP, and for the more brain penetrant and selective mGluR5 analog MTEP, although its dose-response curve was nonlinear.”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > DISCUSSION
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Higher total distances traveled were seen in both strains at a dose of 3.0 mg/kg, and higher vertical and center time scores were seen in BTBR at the higher doses in one cohort tested at Pfizer, indicating a moderate increase in general exploratory locomotion.”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > RESULTS > Absence of sedation
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Small increases in open field scores, and on number of chamber entries in the three-chambered apparatus, were detected in B6 and BTBR mice after the higher doses of GRN-529, although exploratory locomotion was not significantly affected by GRN-529 in B6 and BTBR mice engaged in social interaction in the PhenoTyper arena.”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > DISCUSSION
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None of the sources cited for this claim have been checked yet.
In the paper
“To date, only two drugs have been approved by the U.S. Food and Drug Administration for use in patients diagnosed with autism.”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > INTRODUCTION
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“These two agents, Risperdal and Abilify (11), do not target the core symptoms, but rather treat a cluster of associated symptoms referred to as irritability.”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > INTRODUCTION
What the sources say
- Not checked yetcites [11] McPheeters ML Warren Z Sathe N Bruzek JL Krishnaswami S Jerome RN Veenstra-Vanderweele J A systematic review of medical treatments for children with autism spectrum disorders Pediatrics 127 e1312 e1321 2011 21464191 source
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In the paper
“Inbred strains with robust behavioral phenotypes relevant to the defining symptoms of autism, but without identified genetic mutations, are analogous to individuals with autism for whom the responsible genetic factor(s) remains unknown; at present, this is more than 75% of the cases of autism (21).”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > INTRODUCTION
What the sources say
- Not checked yetcites [21] Miles JH Autism spectrum disorders—A genetics review Genet Med 13 278 294 2011 21358411 source
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None of the sources cited for this claim have been checked yet.
In the paper
“BTBR engages in low levels of reciprocal social interactions as juveniles and adults, minimal social approach by both males and females, and low levels of ultrasonic vocalizations in response to social olfactory cues and during reciprocal social interactions compared to other standard inbred strains such as C57BL/6J (B6) and FVB (60–62, 64, 66, 68–70, 74, 76–78).”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > INTRODUCTION
What the sources say
- Not checked yetcites [60] Bolivar VJ Walters SR Phoenix JL Assessing autism-like behavior in mice: Variations in social interactions among inbred strains Behav Brain Res 176 21 26 2007 17097158 PMC1831820
- Not checked yetcites [61] Moy SS Nadler JJ Young NB Perez A Holloway LP Barbaro RP Barbaro JR Wilson LM Threadgill DW Lauder JM Magnuson TR Crawley JN Mouse behavioral tasks relevant to autism: Phenotypes of 10 inbred strains Behav Brain Res 176 4 20 2007 16971002 PMC1857288
- Not checked yetcites [62] Yang M Zhodzishsky V Crawley JN Social deficits in BTBR T + tf/J mice are unchanged by cross-fostering with C57BL/6J mothers Int J Dev Neurosci 25 515 521 2007 17980995 PMC2194756
- Not checked yetcites [64] McFarlane HG Kusek GK Yang M Phoenix JL Bolivar VJ Crawley JN Autism-like behavioral phenotypes in BTBR T+tf/J mice Genes Brain Behav 7 152 163 2008 17559418 source
- Not checked yetcites [66] Scattoni ML Gandhy SU Ricceri L Crawley JN Unusual repertoire of vocalizations in the BTBR T+tf/J mouse model of autism PLoS One 3 e3067 2008 18728777 PMC2516927
- Not checked yetcites [68] Defensor EB Pearson BL Pobbe RL Bolivar VJ Blanchard DC Blanchard RJ A novel social proximity test suggests patterns of social avoidance and gaze aversion-like behavior in BTBR T+ tf/J mice Behav Brain Res 217 302 308 2011 21055421 PMC3124342
- Not checked yetcites [69] Pearson BL Pobbe RL Defensor EB Oasay L Bolivar VJ Blanchard DC Blanchard RJ Motor and cognitive stereotypies in the BTBR T+tf/J mouse model of autism Genes Brain Behav 10 228 235 2011 21040460 PMC3037433
- Not checked yetcites [70] Wöhr M Roullet FI Crawley JN Reduced scent marking and ultrasonic vocalizations in the BTBR T+tf/J mouse model of autism Genes Brain Behav 10 35 43 2011 20345893 PMC2903641
- Not checked yetcites [74] Yang M Scattoni ML Zhodzishsky V Chen T Caldwell H Young WS McFarlane HG Crawley JN Social approach behaviors are similar on conventional versus reverse lighting cycles, and in replications across cohorts, in BTBR T+ tf/J, C57BL/6J, and vasopressin receptor 1B mutant mice Front Behav Neurosci 1 1 2007 18958184 PMC2525856
- Not checked yetcites [76] Chadman KK Fluoxetine but not risperidone increases sociability in the BTBR mouse model of autism Pharmacol Biochem Behav 97 586 594 2011 20863848
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“In addition, inbred strains can incorporate multiple background genes that influence their behavioral deficits, allowing evaluation of two-hit and multiple-hit hypotheses of autism spectrum disorders.”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > INTRODUCTION
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Unlike mouse models based on identified genetic mutations, the background genes responsible for autism-relevant behavioral traits in these inbred strains of mice remain under investigation (64, 83–85).”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > INTRODUCTION
What the sources say
- Not checked yetcites [64] McFarlane HG Kusek GK Yang M Phoenix JL Bolivar VJ Crawley JN Autism-like behavioral phenotypes in BTBR T+tf/J mice Genes Brain Behav 7 152 163 2008 17559418 source
- Not checked yetcites [83] Bolivar V Solanki M Du W Day S Manley K Autism-Like Behaviors in Mice Are Modified by Genetic Background, Sex and Testing Protocol Society for Neuroscience Washington, DC 2011
- Not checked yetcites [84] Bothe G Solanki M Du W Kusek G Auerbach R Manley K Bolivar V Genetic Investigations of Corpus Callosum Abnormalities in BTBR T+ tf/J Mice Society for Neuroscience Washington, DC 2011
- Not checked yetcites [85] Jones-Davis D Yang M Rider E Sen S Crawley J Sherr E Identification of Loci Associated with Autism-Relevant Behavioral Traits in the BTBR Strain of Mouse Society for Neuroscience Washington, DC 2011
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“A treatment that attenuates different forms of repetitive behaviors in two different inbred strains is likely to generalize across a range of repetitive behaviors and potentially to generalize across species.”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > INTRODUCTION
Tests✓ Asserted: passes? Checkable: unclear✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Mouse models of autism spectrum disorders can serve as tools to evaluate the therapeutically relevant efficacy of experimental agents.
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
“Social interaction and communication deficits in BTBR represent face validity to the first and second diagnostic symptoms of autism, respectively.”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > INTRODUCTION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Long bouts of repetitive self-grooming are the third major characteristic of BTBR, representing face validity to the third diagnostic symptom of autism, spontaneous stereotyped and repetitive patterns of behavior.”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > INTRODUCTION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Therefore, therapeutic efficacy is currently evaluated by improvement in the diagnostic behavioral symptoms (11, 50, 95).”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > DISCUSSION
What the sources say
- Not checked yetcites [11] McPheeters ML Warren Z Sathe N Bruzek JL Krishnaswami S Jerome RN Veenstra-Vanderweele J A systematic review of medical treatments for children with autism spectrum disorders Pediatrics 127 e1312 e1321 2011 21464191 source
- Not checked yetcites [50] Ehninger D Li W Fox K Stryker MP Silva AJ Reversing neurodevelopmental disorders in adults Neuron 60 950 960 2008 19109903 PMC2710296 source
- Not checked yetcites [95] Dawson G Early behavioral intervention, brain plasticity, and the prevention of autism spectrum disorder Dev Psychopathol 20 775 803 2008 18606031 source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“As demonstrated by Hughes and colleagues (97), in competition binding experiments, GRN-529 competes for [3H]MPEP binding at mGluR5 with high affinity [inhibition constant (Ki) = 5.4 ± 0.43 nM], antagonizes glutamate-induced increases in calcium signaling, but does not directly bind to the orthosteric binding site or affect the affinity of glutamate for this site, consistent with negative allosteri”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > DISCUSSION
What the sources say
- Not checked yetcites [97] Hughes Z Neal SJ Smith DL Sukoff Rizzo SJ Pulicicchio CM Lotarski S Lu S Dwyer JM Brennan J Olsen M Bender CN Kouranova E Andree TH Harrison JE Whiteside GT Springer D O’Neil SV Leonard SK Schechter LE Dunlop J Rosenzweig-Lipson S Ring RH Negative allosteric modulation of metabotropic glutamate receptor 5 results in broad spectrum activity relevant to treatment resistant depression Neuropharmacology 10.1016/j.neuropharm.2012.04.007 2012 22551786
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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In the paper
“Target strategies draw from therapeutics under investigation for other neurodevelopmental disorders and hypotheses emerging from mutations in synaptic genes identified in small numbers of individuals with autism spectrum disorders (43, 49, 52).”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > DISCUSSION
What the sources say
- Not checked yetcites [43] Peñagarikano O Abrahams BS Herman EI Winden KD Gdalyahu A Dong H Sonnenblick LI Gruver R Almajano J Bragin A Golshani P Trachtenberg JT Peles E Geschwind DH Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits Cell 147 235 246 2011 21962519 PMC3390029 source
- Not checked yetcites [49] Ehninger D Han S Shilyansky C Zhou Y Li W Kwiatkowski DJ Ramesh V Silva AJ Reversal of learning deficits in a Tsc2+/− mouse model of tuberous sclerosis Nat Med 14 843 848 2008 18568033 PMC2664098 source
- Not checked yetcites [52] Zhou J Blundell J Ogawa S Kwon CH Zhang W Sinton C Powell CM Parada LF Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice J Neurosci 29 1773 1783 2009 19211884 PMC3904448 source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Magnitudes of reduction were consistent with a previous report with the prototypic mGluR5 antagonist MPEP, which required higher doses and is known to also act at N-methyl-D-aspartate (NMDA) receptors (72).”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > DISCUSSION
What the sources say
- Not checked yetcites [72] Silverman JL Tolu SS Barkan CL Crawley JN Repetitive self-grooming behavior in the BTBR mouse model of autism is blocked by the mGluR5 antagonist MPEP Neuropsychopharmacology 35 976 989 2010 20032969 PMC2827881
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“One such strategy is modulation of glutamatergic neurotransmission through the mGluR5 receptor (96), which is under investigation for the treatment of fragile X (55).”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > DISCUSSION
What the sources say
- Not checked yetcites [96] Gasparini F Bilbe G Gomez-Mancilla B Spooren W mGluR5 antagonists: Discovery, characterization and drug development Curr Opin Drug Discov Devel 11 655 665 2008 18729017
- Not checked yetcites [55] Krueger DD Bear MF Toward fulfilling the promise of molecular medicine in fragile X syndrome Annu Rev Med 62 411 429 2011 21090964 PMC3100156
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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
“Total distance traversed in the open field was not affected by GRN-529 in C58, did not reach the range considered hyperactive for B6, and did not mimic the qualitative type of fast, unstructured activity that characterizes rodent responses to psychostimulants.”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > DISCUSSION
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Behavioral parameters were scored with automated equipment or from digital videotapes by investigators uninformed of treatment.”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > MATERIALS AND METHODS
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
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
“Our results show that negative allosteric modulation of the mGluR5 receptor improves social interactions, reduces high levels of repetitive behaviors in BTBR, and reduces stereotyped behaviors in C58, relevant to the first and third diagnostic symptoms of autism.”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Mouse models of autism spectrum disorders can serve as tools to evaluate the therapeutically relevant efficacy of experimental agents.
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
“To further ensure absence of unconscious bias by the raters, we recorded identities of subject mice from paw tattoos only after the behavioral test session ended.”
§ Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism > MATERIALS AND METHODS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
Mouse models of autism spectrum disorders can serve as tools to evaluate the therapeutically relevant efficacy of experimental agents.
“Mouse models of autism spectrum disorders can serve as tools to evaluate the therapeutically relevant efficacy of experimental agents.”
The paper relies on this without support.
The primary symptoms of autism and fragile X differ in qualitative features, and mouse models of autism and fragile X display sharply divergent phenotypes.
“Because the primary symptoms of autism and fragile X differ in qualitative features, and mouse models of autism and fragile X display sharply divergent phenotypes, testing mGluR5 antagonists in specific assays of mouse behavioral phenotypes that optimize relevance to the diagnostic symptoms of autism would be most informative for translational goals.”
The paper relies on this without support.
Compelling neuropharmacological targets for autism remain to be identified.
“Compelling neuropharmacological targets for autism remain to be identified.”
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
“Studies of FXS and ASD mechanisms may also inform each other, as mutations in mGluR5 can contribute to the diagnosis of FXS or ASD, and mGluR5 antagonists have shown promise in alleviating ASD symptoms in mouse models (Silverman et al., 2012) as well as FXS pathology.”
From Oxytocin and vasopressin systems in genetic syndromes and neurodevelopmental disorders (2014) · cites this paper as Silverman et al., 2012
In the citing paper
“In contrast to C57Bl6J mice, BTBR mice show no social preference in the test (Fig. 1c, d).20,21”
From Enhancement of anandamide-mediated endocannabinoid signaling corrects autism-related social impairment (2016) · cites this paper as [21]
In the citing paper
“Previously established methods were followed.21”
From Enhancement of anandamide-mediated endocannabinoid signaling corrects autism-related social impairment (2016) · cites this paper as [21]
Citations
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Self-citationLoss of mGluR5 in D1 Receptor-Expressing Neurons Improves Stress Coping
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Metadata
- Authors
- Silverman, J. L., Smith, D. G., Rizzo, S. J. S., Karras, M. N., Turner, S. M., Tolu, S. S., Bryce, D. K., Smith, D. L., Fonseca, K., Ring, R. H., & Crawley, J. N.
- Affiliations
- National Institute of Mental Health (US)
- Pfizer (United States) (US)
- Corresponding author
- Ring, Robert H.
- Crawley, Jacqueline N.
- ORCID
- Venue
- Science Translational Medicine
- Published
- 2012-04-25
- Volume
- 4
- Issue
- 131
- Pages
- 131ra51-131ra51
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- PMC
- PMC4904784
- OpenAlex
- W2117928188
- Semantic Scholar
- 7e8f4c22a6e6b40e25c440a2784068dedc3c9a19
- Cited by
- 251
- References
- 98
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 10 · 2023: 14 · 2022: 9 · 2021: 10 · 2020: 10 · 2019: 17 · 2018: 9 · 2017: 20 · 2016: 21 · 2015: 33 · 2014: 27 · 2013: 36 · 2012: 22
- FWCI
- 22.86
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (Z99 MH999999)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- mGluR5, negative allosteric modulators, autism spectrum disorder, repetitive behavior, social dysfunction, BTBR T+tf/J mice, fragile X syndrome, metabotropic glutamate receptors, pharmacological interventions, sociability
- MeSH terms
- Animals, Behavior, Animal, Blood-Brain Barrier, Brain, Capillary Permeability, Child Development Disorders, Pervasive, Child, Preschool, Disease Models, Animal, Female, Humans, Male, Mice, Inbred C57BL, Motor Activity, Sleep, Social Behavior, Stereotyped Behavior, Time Factors, Video Recording, Receptors, Metabotropic Glutamate, Excitatory Amino Acid Antagonists, Mice, Receptor, Metabotropic Glutamate 5
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
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