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Cited by 254Genetics and Neurodevelopmental DisordersAutism Spectrum Disorder ResearchNeuroscience and Neuropharmacology Research

Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism

Open access
Silverman, Jill L., Smith, Daniel G., Rizzo, Stacey J. Sukoff, Karras, Michael N., Turner, Sarah M., Tolu, Seda S., Bryce, Dianne K., Smith, Deborah L. +3 more·2012·Science Translational Medicine
DOI 10.1126/scitranslmed.3003501PMC PMC4904784
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Abstract

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.

AI snapshot

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.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1126/scitranslmed.3003501

Cites

98 of 98 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 86 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    GRN-529 did not induce sedation in control open field assays at doses that reduced repetitive behaviors in BTBR mice.

    “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).”
    Quote in the paperSubstantial claim
  • Findingown data

    GRN-529 partially reversed the lack of sociability in BTBR mice on some parameters of social approach and reciprocal social interactions.

    “Further, GRN-529 partially reversed the striking lack of sociability in BTBR mice on some parameters of social approach and reciprocal social interactions.”
    Quote in the paperSubstantial claim
  • Findingown data

    GRN-529 reduced repetitive behaviors in three cohorts of BTBR mice.

    “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.”
    Quote in the paperSubstantial claim
  • Findingown data

    GRN-529 reduced spontaneous stereotyped jumping in C58/J mice at nonsedating doses.

    “In addition, the same nonsedating doses reduced the spontaneous stereotyped jumping that characterizes a second inbred strain of mice, C58/J.”
    Quote in the paperSubstantial claim
  • Findingown data

    In three replications by two laboratories, acute administration of GRN-529 significantly reduced repetitive self-grooming scores in BTBR mice at doses that achieved 50 to 90% receptor occupancy.

    “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).”
    Quote in the paperSubstantial claim
  • May combine two claims. 22
  • Classified as probably not a substantial claim. 9

  • May combine two claims.

    Findingown data

    GRN-529 increased sociability in BTBR mice on some parameters, particularly nose-to-nose sniffing and total time spent in social contact, while having no effect in B6 controls.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    During the reciprocal interaction test, B6 mice exhibited high levels of nose-to-nose sniffing, front approach, and total time spent in social contact, whereas BTBR mice displayed lack of sociability on these standard parameters.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The number of entries between chambers was not significantly affected by lower doses of GRN-529 in either strain, but elevated numbers of entries in both strains appeared at 3.0 mg/kg.

    “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).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    A second cohort displayed a similar pattern of responses.

    “A second cohort displayed a similar pattern of responses (fig. S2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    For time spent sniffing the novel mouse versus the novel object, GRN-529 reversed the deficit in BTBR mice, with no detrimental effect on B6 sociability.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    GRN-529 dose-dependently reduced jumping in C58 mice, almost completely abolishing this repetitive behavior at 3.0 mg/kg, a dose that achieved approximately 90% occupancy.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    MTEP reduced repetitive self-grooming in BTBR mice at some doses and had no effect in B6 mice.

    “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).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    More ethologically meaningful parameters of interactive sniffing, nose-to-nose sniffing, and time in social contact were restored in BTBR mice by acute GRN-529, which had no effect in B6 mice.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Parallel attenuation of self-grooming in BTBR mice was confirmed at the high dose of MPEP and for MTEP, although MTEP's dose-response curve was nonlinear.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    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 higher doses in one cohort tested at Pfizer, indicating a moderate increase in general exploratory locomotion.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Small increases in open field scores and number of chamber entries were detected in B6 and BTBR mice after higher doses of GRN-529, although exploratory locomotion was not significantly affected in B6 and BTBR mice engaged in social interaction in the PhenoTyper arena.

    “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.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Only two drugs have been approved by the U.S. Food and Drug Administration for use in patients diagnosed with autism.

    “To date, only two drugs have been approved by the U.S. Food and Drug Administration for use in patients diagnosed with autism.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Risperdal and Abilify do not target the core symptoms of autism but treat irritability.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    Inbred strains with robust behavioral phenotypes relevant to autism but without identified genetic mutations are analogous to individuals with autism for whom the responsible genetic factors remain unknown; more than 75% of autism cases have unknown genetic factors.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Miles JH Autism spectrum disorders—A genetics review Genet Med 13 278 294 2011 21358411 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BTBR mice engage in low levels of reciprocal social interactions, minimal social approach, and low ultrasonic vocalizations compared to standard inbred strains such as C57BL/6J and FVB.

    “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).”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [76] Chadman KK Fluoxetine but not risperidone increases sociability in the BTBR mouse model of autism Pharmacol Biochem Behav 97 586 594 2011 20863848

      Not checked in the free run.

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

    Premisereasoning

    Inbred strains can incorporate multiple background genes that influence behavioral deficits, allowing evaluation of two-hit and multiple-hit hypotheses of autism spectrum disorders.

    “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.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The background genes responsible for autism-relevant behavioral traits in these inbred strains remain under investigation.

    “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).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    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.

    “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.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Mouse models of autism spectrum disorders can serve as tools to evaluate the therapeutically relevant efficacy of experimental agents.

  • May combine two claims.

    Interpretationreasoning

    Social interaction and communication deficits in BTBR represent face validity to the first and second diagnostic symptoms of autism.

    “Social interaction and communication deficits in BTBR represent face validity to the first and second diagnostic symptoms of autism, respectively.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Long bouts of repetitive self-grooming are the third major characteristic of BTBR and represent face validity to the third diagnostic symptom of autism.

    “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.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Therapeutic efficacy is currently evaluated by improvement in the diagnostic behavioral symptoms.

    “Therefore, therapeutic efficacy is currently evaluated by improvement in the diagnostic behavioral symptoms (11, 50, 95).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [95] Dawson G Early behavioral intervention, brain plasticity, and the prevention of autism spectrum disorder Dev Psychopathol 20 775 803 2008 18606031 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GRN-529 is a negative allosteric modulator of mGluR5 with high affinity (Ki = 5.4 ± 0.43 nM), antagonizes glutamate-induced increases in calcium signaling, and does not directly bind to the orthosteric binding site or affect the affinity of glutamate for this site.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

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

    Premisecitation

    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.

    “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).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Magnitudes of reduction in self-grooming were consistent with a previous report with MPEP, which required higher doses and is known to also act at NMDA receptors.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

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

    Premisecitation

    One strategy is modulation of glutamatergic neurotransmission through the mGluR5 receptor, which is under investigation for the treatment of fragile X.

    “One such strategy is modulation of glutamatergic neurotransmission through the mGluR5 receptor (96), which is under investigation for the treatment of fragile X (55).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Total distance traversed in the open field was not affected by GRN-529 in C58 mice, did not reach the range considered hyperactive for B6 mice, and did not mimic the qualitative type of fast, unstructured activity that characterizes rodent responses to psychostimulants.

    “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.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Behavioral parameters were scored with automated equipment or from digital videotapes by investigators uninformed of treatment.

    “Behavioral parameters were scored with automated equipment or from digital videotapes by investigators uninformed of treatment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The results show that negative allosteric modulation of the mGluR5 receptor improves social interactions, reduces high levels of repetitive behaviors in BTBR mice, and reduces stereotyped behaviors in C58 mice, relevant to the first and third diagnostic symptoms of autism.

    “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.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Mouse models of autism spectrum disorders can serve as tools to evaluate the therapeutically relevant efficacy of experimental agents.

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

    Study design and conductnone given

    To ensure absence of unconscious bias by the raters, identities of subject mice were recorded from paw tattoos only after the behavioral test session ended.

    “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.”
    Quote in the paperNot a substantial claim
29 of 29

  • 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.”
3 of 3

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Cites

1 retracted

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Research works printed but not linked: 1

  1. Terranova M. L. Laviola G. Scoring of Social Interactions and Play in Mice During Adolescence (John Wiley & Sons Inc. Hoboken NJ 2005). · DOI

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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
Publisher
American Association for the Advancement of Science (AAAS)
Published
2012-04-25
Volume
4
Issue
131
Pages
131ra51-131ra51
ISSN
  • 1946-6234 (ISSN-L)
  • 1946-6242
DOI
10.1126/scitranslmed.3003501
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
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

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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