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Cited by 1,570Genetics and Neurodevelopmental DisordersAutism Spectrum Disorder ResearchNeuroscience and Neuropharmacology Research

Shank3 mutant mice display autistic-like behaviours and striatal dysfunction

Open access
Peça, João, Feliciano, Cátia, Ting, Jonathan T., Wang, Wenting, Wells, Michael F., Venkatraman, Talaignair N., Lascola, Christopher D., Fu, Zhanyan +1 more·2011·Nature
DOI 10.1038/nature09965PMC PMC3090611
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Abstract

Autism spectrum disorders (ASDs) comprise a range of disorders that share a core of neurobehavioural deficits characterized by widespread abnormalities in social interactions, deficits in communication as well as restricted interests and repetitive behaviours. The neurological basis and circuitry mechanisms underlying these abnormal behaviours are poorly understood. SHANK3 is a postsynaptic protein, whose disruption at the genetic level is thought to be responsible for the development of 22q13 deletion syndrome (Phelan-McDermid syndrome) and other non-syndromic ASDs. Here we show that mice with Shank3 gene deletions exhibit self-injurious repetitive grooming and deficits in social interaction. Cellular, electrophysiological and biochemical analyses uncovered defects at striatal synapses and cortico-striatal circuits in Shank3 mutant mice. Our findings demonstrate a critical role for SHANK3 in the normal development of neuronal connectivity and establish causality between a disruption in the Shank3 gene and the genesis of autistic-like behaviours in mice.

AI snapshot

Written from the paper’s full text.

TL;DR

Mice lacking Shank3 show autistic-like behaviors, especially excessive self-injurious grooming and impaired social interaction, together with structural and functional defects at striatal synapses. The findings link Shank3 disruption to cortico-striatal dysfunction and support a causal role for Shank3 in autism-related phenotypes in mice.

Key findings

  • Shank3B−/− mice developed self-inflicted skin lesions, with penetrance around 35% in the general colony and 100% in mating females that had produced 4–6 litters; they also spent more time grooming than controls.
  • Shank3B−/− mice showed abnormal social behavior, including preferring an empty cage over a social partner and spending more time in the center chamber during social novelty testing, while Shank3A−/− mice had normal social initiation but impaired social novelty recognition.
  • Striatal PSDs from Shank3B−/− mice had reduced SAPAP3, Homer-1b/c, PSD93, GluR2, NR2A, and NR2B; Shank3B−/− medium spiny neurons showed increased dendritic complexity and length but reduced spine density and thinner/shorter PSDs.
  • Cortico-striatal field population spikes and AMPAR-mEPSC frequency and amplitude were reduced in Shank3B−/− mice, whereas hippocampal learning and CA1 synaptic measures were largely unaffected; caudate volume was slightly but significantly enlarged.

Methods

  • Two Shank3 mutant lines were generated by homologous recombination: Shank3A targeted the ankyrin-repeat region and Shank3B targeted the PDZ domain. The study focused mainly on Shank3B−/− mice, using F5 isogenic hybrids from homozygous × homozygous matings to reduce size confounds.
  • Behavioral assays included grooming videotaping, open field, elevated zero maze, light-dark emergence, rotarod, three-chamber social interaction, dyadic social interaction, and Morris water maze; most behavioral tests used 5–6 week old mice, while lesion scoring used 4–5 month old mice.
  • Biochemical, morphological, imaging, and electrophysiological methods included striatal PSD Western blotting, Golgi staining with Sholl analysis, Lucifer Yellow cell filling for spine measurements, electron microscopy for PSD morphology, 7T MRI for caudate volumetry, and extracellular/whole-cell recordings in striatal and hippocampal slices.

Limitations

  • The paper states that clinical 22q13 deletions and autism-associated Shank3 mutations are heterozygous, whereas this study used homozygous mutants; further work is needed to assess deficits from Shank3 haploinsufficiency.
  • The authors note that the two mutant lines differed in severity and that analysis focused mainly on Shank3B−/− because of its stronger behavioral and physiological phenotypes, with Shank3A−/− showing milder defects.
  • Evident from the text: behavioral experiments used only aged-matched male mice, and some Shank3A field recordings used an older slice-preparation protocol with reduced slice viability, although procedures were standardized within each dataset.

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

Integrity signals

Registry

Crossref · 10.1038/nature09965

Cites

42 of 42 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 29 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Cellular, electrophysiological and biochemical analyses found defects at striatal synapses and cortico-striatal circuits in Shank3 mutant mice.

    “Cellular, electrophysiological and biochemical analyses uncovered defects at striatal synapses and cortico-striatal circuits in Shank3 mutant mice.”
    Quote in the paperSubstantial claim
  • Findingown data

    Biochemical, morphological and electrophysiological studies revealed synaptic dysfunction at cortico-striatal synapses.

    “Biochemical, morphological and electrophysiological studies revealed synaptic dysfunction at cortico-striatal synapses, part of the neural circuits strongly implicated as dysfunctional in ASDs.”
    Quote in the paperSubstantial claim
  • Findingown data

    In the rotarod motor test, Shank3B−/− and control animals performed at similar levels.

    “In the rotarod motor test, Shank3B−/− and control animals performed at similar levels (Supplementary Fig. 2).”
    Quote in the paperNot a substantial claim
  • Findingown data

    In Shank3A mutant mice, the Shank3β and Shank3γ isoforms were not affected.

    “However, the other two isoforms were not affected (here named Shank3β and Shank3γ).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Wildtype mice displayed a preference for the novel animal, shown by increased time in the compartment containing Stranger 2.

    “Wildtype mice displayed a preference for the novel animal, as shown by the increase in time spent in the compartment containing “Stranger 2”.”
    Quote in the paperSubstantial claim
  • May combine two claims. 29
  • Classified as probably not a substantial claim. 36
  • The quote only partly states this claim. 2

  • May combine two claims.

    Findingown data

    Genetic disruption of Shank3 in mice leads to compulsive or repetitive behaviour and impaired social interaction, resembling two cardinal features of ASD.

    “Here we demonstrate that genetic disruption of Shank3 in mice leads to compulsive/repetitive behaviour and impaired social interaction, resembling two of the cardinal features of ASD.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The repetitive grooming and social interaction deficits observed in Shank3 mutant mice correspond to autistic-like behaviours in humans.

  • May combine two claims.

    Findingown data

    Mice carrying Shank3 gene deletions show repetitive self-injurious grooming and impaired social interaction.

    “Here we show that mice with Shank3 gene deletions exhibit self-injurious repetitive grooming and deficits in social interaction.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The repetitive grooming and social interaction deficits observed in Shank3 mutant mice correspond to autistic-like behaviours in humans.

  • May combine two claims.

    Findingown data

    In the light-dark emergence test, Shank3B−/− mice had increased latency to cross into the brightly lit area, while time spent on each side was similar to controls.

    “In the light-dark emergence test, the Shank3B−/− mice displayed an increased latency to cross into the brightly lit area, although the time spent in each side of the box was similar between mutant animals and controls (Supplementary Fig. 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    By 3-6 months of age, Shank3B−/− mice developed pronounced skin lesions with about 35% penetrance in the general holding colony (p<0.0001) and 100% penetrance in mating females that had produced 4-6 litters.

    “By the age of 3–6 months, Shank3B−/− mice developed pronounced skin lesions with varying degrees of phenotypical penetrance: approximately 35% in the general holding colony (Fishers exact test, p<0.0001), and 100% in mating females that have produced 4–6 litters.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the open field test, Shank3B−/− mice showed similar levels of activity and thigmotaxis to controls.

    “In the open field test, when compared to controls, Shank3B−/− mice showed similar levels of activity and thigmotaxis (Supplementary Fig. 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The lesions were not due to excessive allogrooming, because no lesions were found in wildtype or Shank3B+/− mice housed from birth with Shank3B−/− animals.

    “The lesions were self-inflicted, as they were present in animals socially isolated at weaning age, and not due to excessive allogrooming, as no lesions were found in wildtype or Shank3B+/− mice housed from birth with Shank3B−/− animals.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The skin lesions in Shank3B−/− mice were self-inflicted, as they appeared in animals socially isolated at weaning age.

    “The lesions were self-inflicted, as they were present in animals socially isolated at weaning age, and not due to excessive allogrooming, as no lesions were found in wildtype or Shank3B+/− mice housed from birth with Shank3B−/− animals.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Shank3A−/− mice displayed no lesions or anxiety-like behaviour.

    “In contrast, Shank3A−/−mice displayed no lesions or anxiety-like behaviour (Supplementary Fig. 3).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims. The quote only partly states this claim.

    Findingown data

    Shank3B−/− mice rarely exhibited seizures during handling, and spontaneous seizures were never observed.

    “However, spontaneous seizures were never observed.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In an open arena test, freely interacting wildtype-Shank3B−/− dyads spent less time in reciprocal interaction and had lower frequencies of nose-to-nose interaction and anogenital sniffing than wildtype-wildtype pairs.

    “Additionally, in an open arena test, freely interacting dyadic pairs of wildtype-Shank3B−/−mice displayed less time spent in reciprocal interaction, a lower frequency of nose-to-nose interaction and anogenital sniffing when compared to wildtype-wildtype pairs (Supplementary Fig. 5).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Findingnone given

    Shank3 is the most abundant Shank family member expressed in the striatum.

    “Shank3 is the most abundant Shank family member expressed in the striatum and Shank3B−/−mice exhibit excessive/repetitive grooming leading to skin lesions.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Shank family proteins bind SAPAP directly to form the PSD95/SAPAP/Shank complex.

    “Shank family proteins (Shank1–3) directly bind SAPAP to form the PSD95/SAPAP/Shank complex14,15.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [14] Kim, E. et al. GKAP, a novel synaptic protein that interacts with the guanylate kinase-like domain of the PSD-95/SAP90 family of channel clustering molecules. J. Cell Biol. 136, 669–678 (1997) source

      Not checked in the free run.

    • cites [15] Takeuchi, M. et al. SAPAPs. A family of PSD-95/SAP90-associated proteins localized at postsynaptic density. J. Biol. Chem. 272, 11943–11951 (1997) source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisenone given

    The PSD95/SAPAP/Shank core is thought to act as a scaffold that organizes assembly of the macromolecular postsynaptic signaling complex at glutamatergic synapses.

    “This core of proteins is thought to function as a scaffold, orchestrating the assembly of the macromolecular postsynaptic signaling complex at glutamatergic synapses.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Shank3B−/− mice display anxiety-like behaviour and excessive, self-injurious grooming.

    “Thus, the Shank3B−/− mice display an anxiety-like behaviour and excessive, self-injurious grooming.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Shank3B−/− mice display excessive grooming and self-injurious behaviour.

    “These observations indicate that Shank3B−/− mice display excessive grooming and self-injurious behaviour.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Shank family members have been proposed as key regulators of the PSD at glutamatergic synapses.

    “Shank family members have been proposed as key regulators of the PSD at glutamatergic synapses18.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Hung, A. Y. et al. Smaller dendritic spines, weaker synaptic transmission, but enhanced spatial learning in mice lacking Shank1. J. Neurosci. 28, 1697–1708 (2008) source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Data from both social interaction tests indicate that Shank3B−/− mice display abnormal social interaction and deficits in discriminating social novelty.

    “Thus, data from both social interaction tests indicate that Shank3B−/− mice display abnormal social interaction as well as deficits in discriminating social novelty.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    These results suggest an altered molecular composition of postsynaptic machinery in the striatum and possible disruption of glutamatergic signalling.

    “These results suggest an altered molecular composition of postsynaptic machinery in the striatum and a possible disruption of glutamatergic signalling.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The reduction in total field responses was most likely due to postsynaptic impairment and/or a reduction in the number of functional synapses.

    “These results indicate that the reduction in total field responses was most likely due to a postsynaptic impairment in synaptic function and/or a reduction in the number of functional synapses.”
    Quote in the paperSubstantial claim

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

    Premisenone given

    In clinical conditions, 22q13 deletions and autism-associated Shank3 mutations are heterozygous.

    “We should note that, in clinical conditions, the 22q13 deletions and the autism-associated Shank3 mutations are heterozygous, whereas in our current study, we used homozygous mutant mice to get a clear understanding of the physiological role of the Shank3 gene and the underlying functional consequences of its disruption.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    PSD95-SAPAP-Shank proteins form a key postsynaptic scaffold at glutamatergic synapses that interacts with many synaptic proteins, including the Neurexin-Neuroligin complex.

    “PSD95-SAPAP-Shank proteins form a key postsynaptic scaffold at glutamatergic synapses which interacts with many synaptic proteins including the Neurexin-Neuroligin complex25.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Irie, M. et al. Binding of neuroligins to PSD-95. Science 277, 1511–1515 (1997) source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    These data suggest that the observed behavioural and synaptic defects are specific to discrete brain regions and are not part of an overall CNS dysfunction.

    “These data suggest that the observed behavioral and synaptic defects are specific to discrete brain regions and are not part of an overall CNS dysfunction.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Shank2, SAPAP2, Neurexin-1, Neuroligin-3 and Neuroligin-4 have been implicated in human ASDs.

    “In addition to Shank39, it is worth noting that Shank26,8, SAPAP26, Neurexin-126, Neuroligin-3 and −427 have all been implicated in human ASDs.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [26] Kim, H. G. et al. Disruption of neurexin 1 associated with autism spectrum disorder. Am. J. Hum. Genet. 82, 199–207 (2008) source

      Not checked in the free run.

    • cites [27] Jamain, S. et al. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nature Genet. 34, 27–29 (2003) source

      Not checked in the free run.

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

    Premisecitation

    Repetitive behaviours are often seen in autistic patients and in some mouse models of ASDs.

    “Repetitive behaviours are also often seen in autistic patients and in some mouse models of ASDs34–36.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [34] McFarlane, H. G. et al. Autism-like behavioral phenotypes in BTBR T+tf/J mice. Genes Brain Behav. 7, 152–163 (2008) source

      Not checked in the free run.

    • cites [35] Blundell, J. et al. Neuroligin-1 deletion results in impaired spatial memory and increased repetitive behavior. J. Neurosci. 30, 2115–2129 (2010) source

      Not checked in the free run.

    • cites [36] Etherton, M. R., Blaiss, C. A., Powell, C. M. & Sudhof, T. C. Mouse neurexin-1α deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments. Proc. Natl Acad. Sci. USA 106, 17998–18003 (2009) source

      Not checked in the free run.

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

    Study design and conductnone given

    All procedures were conducted in compliance with PHS policy on animal welfare and approved by the Duke University IACUC.

    “All procedures were conducted in compliance with the Public Health Service (PHS) Policy on Humane Care and Use of Laboratory Animals policies on animal welfare and approved by the Duke University IACUC.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The release of animals and the relative position of social and inanimate targets were counterbalanced.

    “The release of the animals and relative position of social and inanimate targets was counterbalanced.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Unless otherwise noted, all tests were conducted with naive cohorts of mice.

    “Unless otherwise noted, all tests were conducted with naive cohorts of mice.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The observer was blinded to genotype in the zero maze test.

    “The observer was blinded to genotype.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    All experiments were done blind to genotypes.

    “All experiments were done blind to genotypes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Deletion of SAPAP3 leads to cortico-striatal circuitry dysfunction in mice and OCD-like behaviours including repetitive/compulsive grooming.

    “We previously found that deletion of SAPAP3, which directly interacts with Shank3 and is highly expressed in the striatum, leads to cortico-striatal circuitry dysfunction in mice and OCD-like behaviours including repetitive/compulsive grooming31.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Welch, J. M. et al. Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice. Nature 448, 894–900 (2007) source

      Not checked in the free run.

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

    Premisecitation

    Genetic makeup is thought to play a key role in the phenotypical manifestation of social behaviours.

    “Similarly, genetic makeup is thought to play a key role in the phenotypical manifestation of social behaviours38.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Ebstein, R. P., Israel, S., Chew, S. H., Zhong, S. & Knafo, A. Genetics of human social behavior. Neuron 65, 831–844 (2010) source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Quantification of social behaviours in the dyadic test was performed by a researcher blinded to the genotype of the target animals.

    “Quantification of social behaviors was performed using Noldus Observer software (Leesburg, VA) by a researcher blinded to the genotype of the target animals.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The regulation of social behaviours and social interaction is thought to be controlled by several brain regions and circuits.

    “The regulation of social behaviours and social interaction is thought to be controlled by several brain regions and circuits37.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Insel, T. R. & Fernald, R. D. How the brain processes social information: searching for the social brain. Annu. Rev. Neurosci. 27, 697–722 (2004) source

      Not checked in the free run.

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

    Study design and conductnone given

    The observer was blinded to genotype during scoring of grooming videotapes.

    “The observer was blinded to genotype during the scoring of the videotapes.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Brain volumes were computed in Osirix from the average of two segmentations.

    “As with striatal volumes, brain volumes were computed in Osirix from the average of two segmentations.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Hippocampal slices were prepared from one wild-type and one knockout pair each day, with the experimenter blind to genotype.

    “Slices were prepared in a 20–30 degree off-horizontal cutting angle (optimal for CA1 region) from one WT and one KO pair each day and the experimenter was blind to the genotypes of the animals.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    All whole-cell electrophysiology procedures used 5-6 week old mice and were performed by an experimenter blind to genotype.

    “Mice 5–6 week old were used for all whole-cell electrophysiology procedures by an experimentalist blinded to genotype.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Two separate striatal segmentations were obtained per animal, and their average volume was used.

    “Two separate striatal segmentations were obtained for each animal, with the average volume then taken.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Mice were coded before dissection so that genotype remained blinded throughout dissection, cell filling, imaging, and quantification.

    “Mice were assigned a code previous to dissection, as to maintain a blinded genotype across all procedures, including dissection, cell filling, imaging and quantification.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    All spine metric analyses were performed by observers blind to animal genotype.

    “All analysis of spine metrics were performed by observers that were blinded to the genotypes of the animals.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    PSD measurements were made with ImageJ by an observer blind to sample genotype.

    “PSD measurements were performed using ImageJ (NIH, Bethesda, Maryland) by an observer that was blinded to the genotype of the samples.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    For electron microscopy, mice were coded before dissection so that genotype remained blinded throughout dissection, sample processing, imaging, and quantification.

    “Mice were assigned a code previous to dissection, as to maintain a blinded genotype across all procedures, including dissection, sample processing, imaging and quantification.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Animals were assigned a blinding code that was maintained during MR data acquisition and analysis.

    “Animals were assigned a blinding code, which was maintained during magnetic resonance (MR) data acquisition and analysis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). The quote only partly states this claim.

    Study design and conductown data

    Intrarater reliability for brain volume segmentation had a kappa value greater than 0.99.

    “Intrarater reliability (kappa value) was > 0.99.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Each day, slices were prepared from one wild-type and one knockout mouse pair, with the experimenter blind to genotype.

    “Slices were prepared from one WT and one KO pair each day and the experimenter was blind to the genotype.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Series resistance was kept below 20 MΩ.

    “The series-resistance was < 20 MΩ.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    MR volumetric analysis was performed in Osirix, with the left caudate-putamen manually segmented by an investigator blind to genotype.

    “Volumetric analysis of MR data sets was performed in Osirix software, an open source image processing application developed and maintained by Pixmeo (Geneva, SUI). The left caudate-putamen was manually segmented in each animal by an investigator blinded to genotype.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The measurements primarily reflect corticostriatal transmission but are not pure corticostriatal responses.

    “Thus, although we refer to our measurements as primarily reflecting corticostriatal transmission, our measurements are not “pure” corticostriatal responses.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Data analysis was performed with the analyst blind to genotype using Clampfit.

    “Data analysis was performed blind of genotype in Clamp fit (Axon Instruments/Molecular Devices).”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Brains and sections were coded so that the experimenter remained blind to genotype until all data collection and analysis were complete.

    “All brains and collected sections were coded in order to blind the experimenter of the genotype until after all data was collected and analyzed.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    A relatively smaller contribution from thalamostriatal axon activation cannot be excluded.

    “we are unable to exclude the possibility of a relatively smaller contribution arising from activation of thalamostriatal axons that have distal terminals in dorsolateral striatum nearby to the stimulated region.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Spine density data passed the Lilliefors and D'Agostino & Pearson omnibus normality tests.

    “The data from spine density passed the Lilliefors Normality Test and D’Agostino & Pearson Omnibus Normality Test.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Intrarater reliability for striatal segmentation had a kappa value of 0.97.

    “Intrarater reliability (kappa value) was = 0.97.”
    Quote in the paperNot a substantial claim
53 of 53

  • The paper relies on this without support.

    Shank3 is a key postsynaptic density protein at glutamatergic synapses.

    “Shank3, which codes for a key postsynaptic density (PSD) protein at glutamatergic synapses.”

  • The authors state this as an assumption.

    The size difference between homozygous knockout mice and wildtype littermates from heterozygous x heterozygous matings would influence the behavioural tests.

    “We postulated that this size difference would influence our behavioral tests.”

  • The paper relies on this without support.

    The repetitive grooming and social interaction deficits observed in Shank3 mutant mice correspond to autistic-like behaviours in humans.

    “Here we demonstrate that genetic disruption of Shank3 in mice leads to compulsive/repetitive behaviour and impaired social interaction, resembling two of the cardinal features of ASD.”
3 of 3

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?

  • Atypicalities in these brain regions are associated with autism, according to recent neuroimaging, postmortem, and animal-model studies.

    “Indeed, the emerging picture from recent neuro-imaging, postmortem, and animal-model studies is that atypicalities in these regions are associated with autism (75 -80).”

    From Autism as a disorder of prediction (2014) · cites this paper as [76]

  • Animal models of ASD with mutations in ASD-relevant neural cell adhesion molecules show deficits in social affiliative behaviors and glutamatergic synaptic structure in various brain regions including reward pathways.

    “emerging animal models of ASD, with mutations in ASD-relevant neural cell adhesion molecules, have shown deficits in both the development of social affiliative behaviors and in glutamatergic synaptic structure in various brain regions, including circuits that may involve reward pathways [83,84]”

    From The social motivation theory of autism (2012) · cites this paper as [83]

  • Patients with mutations in similar genes might actually show the opposite synaptic defects, as observed in Shank2 (increased NMDA) and Shank3 (decreased NMDA) knockout mice.

    “second, patients with mutations in similar genes might actually show the opposite synaptic defects, as observed in Shank2 (increased NMDA) and Shank3 (decreased NMDA) knockout mice 17,18,51 .”

    From Progress toward treatments for synaptic defects in autism (2013) · cites this paper as [18]

  • SHANK3 mutant mice show a hypertrophy of medium spiny neurons with an increase in the complexity of dendritic arbors and total dendritic length.

    “Similarly, SHANK3 mutant mice show a hypertrophy of medium spiny neurons with an increase in the complexity of dendritic arbors and total dendritic length 17,18 .”

    From Progress toward treatments for synaptic defects in autism (2013) · cites this paper as [18]

  • Knockout mice with deletions in Shank family genes show behaviours resembling those seen in ASD.

    “Knockout mice with deletions in members of the Shank family of genes exhibit behaviours similar to those observed in ASD.”

    From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [47]

Cites

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Research works printed but not linked: 1

  1. Bourgeron, T. A synaptic trek to autism. Curr. Opin. Neurobiol. 19, 231–234 (2009) · DOI · Paper page

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Authors
Peça, J., Feliciano, C., Ting, J. T., Wang, W., Wells, M. F., Venkatraman, T. N., Lascola, C. D., Fu, Z., & Feng, G.
Affiliations
  • Duke Medical Center (US)
  • Duke University (US)
  • McGovern Institute for Brain Research (US)
  • Broad Institute (US)
Corresponding author
Feng, Guoping
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2011-03-20
Volume
472
Issue
7344
Pages
437-442
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature09965
PMC
PMC3090611
OpenAlex
W2109002457
Cited by
1,570
References
42
Citations by year
2026: 94 · 2025: 119 · 2024: 133 · 2023: 116 · 2022: 105 · 2021: 113 · 2020: 113 · 2019: 102 · 2018: 97 · 2017: 94 · 2016: 104 · 2015: 87 · 2014: 80 · 2013: 80 · 2012: 91
FWCI
57.94
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
  • PMC
Funders
National Institute of Mental Health (R03MH085224, F32MH084460, R01MH081201)
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
SHANK3, autism spectrum disorder, 22q13 deletion syndrome, Phelan-McDermid syndrome, social interaction deficits, self-harm, corticostriatal circuits, postsynaptic density, glutamatergic synapses, neuronal connectivity, gene deletion mice
MeSH terms
Animals, Autistic Disorder, Carrier Proteins, Compulsive Behavior, Female, Grooming, Male, Microfilament Proteins, Nerve Tissue Proteins, Neural Pathways, RNA, Messenger, Social Behavior, Synapses, Self-Injurious Behavior, Neostriatum, Gene Deletion, Mutant Proteins, Mice

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