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Shank3 mutant mice display autistic-like behaviours and striatal dysfunction
Open accessAbstract
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.
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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.
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55 Own result · 25 Own method · 21 Own interpretation · 14 Not checked yet · 3 No basis given · 1 Partly supported · accuracy not yet measured
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In the paper
“We used mice with a hybrid genetic background to avoid the potential contribution to behavioral phenotypes of homozygous genetic variants on a pure inbred background7,16.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Shank3B−/− mice display repetitive grooming
What the sources say
- Could not verifycites [7] Tabuchi, K. et al. A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science 318, 71–76 (2007) sourceExperimental — accuracy not yet measured
The passage headed “An increase in inhibitory synapse markers in R451C-mutant mice” describes the mice’s genotype and breeding cross, but does not identify a hybrid genetic background. Searches for “hybrid background” and for inbred, homozygous variants and behavioral phenotypes found no passage explaining the claimed rationale. (LLM, conf=0.74)
- Supportedcites [16] Zoghbi, H. Y. & Warren, S. T. Neurogenetics: advancing the “next-generation” of brain research. Neuron 68, 165–173 (2010) source
In “On Animal Models” (page not provided), the source recommends F1 hybrids from two pure isogenic backgrounds to control for strain-specific deficits that could confound behavioral phenotypes. The citing authors’ statement that they used such mice describes their own method; the source supports the reason they give for it. (LLM, conf=0.90)
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In the paper
“Cellular, electrophysiological and biochemical analyses uncovered defects at striatal synapses and cortico-striatal circuits in Shank3 mutant mice.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Abstract
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“Biochemical, morphological and electrophysiological studies revealed synaptic dysfunction at cortico-striatal synapses, part of the neural circuits strongly implicated as dysfunctional in ASDs.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Introduction
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“In the rotarod motor test, Shank3B−/− and control animals performed at similar levels (Supplementary Fig. 2).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Shank3B−/− mice display repetitive grooming
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“However, the other two isoforms were not affected (here named Shank3β and Shank3γ).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Shank3B−/− mice display repetitive grooming
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“Wildtype mice displayed a preference for the novel animal, as shown by the increase in time spent in the compartment containing “Stranger 2”.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Social interaction deficits in Shank3B−/− mice
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“Shank3B−/− mice did not display any gross anatomical or histological brain abnormality, but on rare occasion exhibited seizures during handling in routine husbandry procedures.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Shank3B−/− mice display repetitive grooming
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“In this test, the Shank3B−/− mice displayed dysfunctional social interaction behaviour, as measured by observing both time spent in the compartment containing the social partner (Fig. 2a, b) or in close interaction (Fig. 2d).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Social interaction deficits in Shank3B−/− mice
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“Notably, Shank3B−/− mice exhibited a clear preference for interacting with the empty cage rather than with the social partner (Fig. 2a, d).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Social interaction deficits in Shank3B−/− mice
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“This led to the complete elimination of both Shank3α and Shank3β isoforms and a significant reduction of the putative Shank3γ isoform at the PSD (−42.12% ± 9.27% of control, n=3, p<0.05) (Fig. 1b).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Shank3B−/− mice display repetitive grooming
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“This led to the complete elimination of both Shank3α and Shank3β isoforms and a significant reduction of the putative Shank3γ isoform at the PSD (−42.12% ± 9.27% of control, n=3, p<0.05) (Fig. 1b).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Shank3B−/− mice display repetitive grooming
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“In the elevated zero maze, the Shank3B−/− mice spent less time exploring the open arms of the maze versus the closed arms (Fig. 1f).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Shank3B−/− mice display repetitive grooming
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“However, rearing, which is a form of vertical exploration considered to be anxiogenic for mice, was significantly reduced in the mutants (Fig. 1e).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Shank3B−/− mice display repetitive grooming
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“This resulted in a complete elimination of Shank3α, the longest Shank3 isoform (Fig. 1b).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Shank3B−/− mice display repetitive grooming
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“Furthermore, 24 h videotaping in pre-lesion animals revealed that Shank3B−/−mice showed an increase in time spent grooming when compared to wildtype controls (Fig. 1d).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Shank3B−/− mice display repetitive grooming
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“The Shank3B−/−mutants markedly spent more time in the center chamber (Fig. 2c) and a reduced amount of time closely interacting with either social partner (Fig. 2e).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Social interaction deficits in Shank3B−/− mice
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In the paper
“The Shank3B−/−mutants markedly spent more time in the center chamber (Fig. 2c) and a reduced amount of time closely interacting with either social partner (Fig. 2e).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Social interaction deficits in Shank3B−/− mice
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“We found that field population spikes were significantly reduced in Shank3B−/− mice when compared with controls (Fig. 5a).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Perturbation of striatal postsynaptic function
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“In an identical test, the Shank3A−/− mice displayed normal initiation of social interaction, but perturbed recognition of social novelty (Supplementary Fig 4).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Social interaction deficits in Shank3B−/− mice
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“Shank3B−/− mice displayed a significant reduction in spine density (Fig 4d, e).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Morphological defects of medium spiny neurons
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“We did not observe significant changes in spine length or head diameter, however, the neck width of Shank3B−/− MSN spines was slightly larger than that of controls (Supplementary Fig. 8).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Morphological defects of medium spiny neurons
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“We did not observe significant changes in spine length or head diameter, however, the neck width of Shank3B−/− MSN spines was slightly larger than that of controls (Supplementary Fig. 8).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Morphological defects of medium spiny neurons
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“Sholl analysis revealed neuronal hypertrophy as measured by an increase in complexity of dendritic arbors (Fig. 4a), total dendritic length (Fig. 4b) and also an increase in surface area (Fig. 4c) in Shank3B−/− MSNs.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Morphological defects of medium spiny neurons
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“At the PSD level, we observed reduced levels of SAPAP3, Homer-1b/c and PSD93 (Fig. 3b) as well as a reduction in the glutamate receptor subunits GluR2, NR2A and NR2B (Fig. 3c).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Altered PSD composition in the striatum
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“At the PSD level, we observed reduced levels of SAPAP3, Homer-1b/c and PSD93 (Fig. 3b) as well as a reduction in the glutamate receptor subunits GluR2, NR2A and NR2B (Fig. 3c).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Altered PSD composition in the striatum
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“We found a significant reduction in mean thickness (Fig. 4g) of PSDs from Shank3B−/− mice relative to controls.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Morphological defects of medium spiny neurons
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“Presynaptic function was not altered, as indicated by the relationship of stimulation intensity to the amplitude of the action potential component of the response termed negative peak 1 (NP1) and the paired-pulse ratio (PPR; Supplementary Fig. 10).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Perturbation of striatal postsynaptic function
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“In an identical test, the Shank3A−/− mice displayed normal initiation of social interaction, but perturbed recognition of social novelty (Supplementary Fig 4).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Social interaction deficits in Shank3B−/− mice
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“Cross-fostering of Shank3B−/− neonatal pups with wildtype dams (KOcf) revealed qualitatively equivalent social defects in the mutant mice as compared to those observed in mutant mice from homozygous x homozygous matings.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Social interaction deficits in Shank3B−/− mice
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“Additionally, rearing wildtype neonatal pups by Shank3B−/− dams (WTcf) did not perturb normal sociability in wildtype animals (Supplementary Fig. 6).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Social interaction deficits in Shank3B−/− mice
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“However, measurement of caudate volume in the same animals revealed a small but significant volumetric enlargement of this structure in Shank3B−/− mice (Supplementary Fig. 9).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Striatal hypertrophy in Shank3B−/− mice
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“Sholl analysis revealed neuronal hypertrophy as measured by an increase in complexity of dendritic arbors (Fig. 4a), total dendritic length (Fig. 4b) and also an increase in surface area (Fig. 4c) in Shank3B−/− MSNs.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Morphological defects of medium spiny neurons
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“Additionally, PSD length was also significantly reduced in the Shank3B−/− mice (Fig. 4h).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Morphological defects of medium spiny neurons
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In the paper
“Sholl analysis revealed neuronal hypertrophy as measured by an increase in complexity of dendritic arbors (Fig. 4a), total dendritic length (Fig. 4b) and also an increase in surface area (Fig. 4c) in Shank3B−/− MSNs.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Morphological defects of medium spiny neurons
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“Consistent with their mild behavioural phenotypes Shank3A−/− mice displayed minimal disruption at cortico-striatal synapses (Supplementary Fig. 11).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Perturbation of striatal postsynaptic function
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“Furthermore, Shank3, but not Shank1 or Shank2, is highly expressed in the striatum (Fig. 3a) (Supplementary Fig. 7 and Supplementary Table 1).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Altered PSD composition in the striatum
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“We found that there was no significant difference in overall brain size between the genotypes.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Striatal hypertrophy in Shank3B−/− mice
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“Reversal learning and probe trials, again demonstrated similar levels of performance between Shank3B−/− mice and controls (Supplementary Fig. 14d–f).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Perturbation of striatal postsynaptic function
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“We also found a significant reduction of peak mEPSC amplitude in Shank3B−/− MSNs (Fig. 5b, d), indicating a reduction in the postsynaptic response from the available synapses.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Perturbation of striatal postsynaptic function
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In the paper
“We found that Shank3B−/− mice performed at the same levels as controls in both learning and probe trials (Supplementary Fig. 14a–c).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Perturbation of striatal postsynaptic function
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In the paper
“Finally, similar defects in mEPSC frequency and amplitude were observed in Shank3B−/− and wildtype littermate mice obtained from heterozygous matings (Supplementary Fig. 13).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Perturbation of striatal postsynaptic function
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“These two lines of mice displayed different levels of severity in synaptic defects and phenotypes.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Discussion
plaincorrelationaln = 2- Asserted: passes — The authors put it forward as true.
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In the paper
“We did not observe significant differences in NMDA/AMPA ratio in Shank3B−/− neurons (Supplementary Fig. 12).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Perturbation of striatal postsynaptic function
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Concomitantly, we performed electrophysiological recordings from the hippocampal CA1 subregion and found no obvious difference in field recording of population spikes or PPR between genotypes (Supplementary Fig 15a–c).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Perturbation of striatal postsynaptic function
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found that the frequency of mEPSCs was significantly reduced in Shank3B−/− MSNs (Fig. 5b, c), suggesting a reduction in the number of functional synapses in Shank3B−/− MSNs since we did not observe defects on presynaptic function by measuring PPR (Fig. 5e).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Perturbation of striatal postsynaptic function
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In addition, we found no significant differences in mEPSC frequency, or mEPSC amplitude (Supplementary Fig 15d–f).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Perturbation of striatal postsynaptic function
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Abstract
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: Shank3 is a key postsynaptic density protein at glutamatergic synapses.
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 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.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Abstract
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: The repetitive grooming and social interaction deficits observed in Shank3 mutant mice correspond to autistic-like behaviours in humans.
None of the sources cited for this claim have been checked yet.
In the paper
“Disruption of Shank3 is thought to be the cause of core neurodevelopmental and neurobehavioural deficits in the 22q13 deletion syndrome (Phelan-McDermid syndrome), an autism spectrum disorder9–11.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Introduction
What the sources say
- Not checked yetcites [9] Durand, C. M. et al. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nature Genet. 39, 25–27 (2006) source
- Not checked yetcites [10] Prasad, C. et al. Genetic evaluation of pervasive developmental disorders: the terminal 22q13 deletion syndrome may represent a recognizable phenotype. Clin. Genet. 57, 103–109 (2000) source
- Not checked yetcites [11] Wilson, H. L. et al. Molecular characterisation of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms. J. Med. Genet. 40, 575–584 (2003) source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Furthermore, recent genetic screens have identified several mutations/rare variants of the Shank3 gene in ASD patients outside of diagnosed 22q13 deletion syndrome12,13.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Introduction
What the sources say
- Not checked yetcites [12] Moessner, R. et al. Contribution of SHANK3 mutations to autism spectrum disorder. Am. J. Hum. Genet. 81, 1289–1297 (2007) source
- Not checked yetcites [13] Gauthier, J. et al. Novel de novo SHANK3 mutation in autistic patients. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 150B, 421–424 (2009) source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“F5 Shank3A and F5 Shank3B knockouts from these matings are reared to weaning age with body weights similar to those from F5 control animals.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Shank3B−/− mice display repetitive grooming
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Our studies provide a synaptic and circuitry mechanism underlying Shank3 disruption and ASD-like behaviours.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Introduction
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data further suggest a genetic origin of the abnormal social behaviors in the Shank3 mutant mice.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Social interaction deficits in Shank3B−/− mice
hedgedconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taken together, these results highlight a critical in vivo role for Shank3 in the normal development of medium spiny neurons and striatal glutamatergic synapses.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Morphological defects of medium spiny neurons
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: Shank3 is a key postsynaptic density protein at glutamatergic synapses.
None of the sources cited for this claim have been checked yet.
In the paper
“These data suggest a correlation between neuronal hypertrophy and brain volume, consistent with studies from other mouse models of ASD22,23.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Striatal hypertrophy in Shank3B−/− mice
What the sources say
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, the dysfunction of Neurexin/Neuroligin/PSD95/SAPAP/Shank complex could underlie a common synaptic mechanism for a subset of autistic spectrum disorders.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Neuroimaging studies provide evidence that caudate and frontal-striatal circuitries are dysfunctional areas in ASD28–30.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Discussion
What the sources say
- Not checked yetcites [28] Silk, T. J. et al. Visuospatial processing and the function of prefrontal-parietal networks in autism spectrum disorders: a functional MRI study. Am. J. Psychiatry 163, 1440–1443 (2006) source
- Not checked yetcites [29] Horwitz, B., Rumsey, J. M., Grady, C. L. & Rapoport, S. I. The cerebral metabolic landscape in autism. Intercorrelations of regional glucose utilization. Arch. Neurol. 45, 749–755 (1988) source
- Not checked yetcites [30] Sears, L. L. et al. An MRI study of the basal ganglia in autism. Prog. Neuropsychopharmacol. Biol. Psychiatry 23, 613–624 (1999) source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our present study with Shank3 mutant mice not only sheds light on a critical in vivo role for Shank3 in striatal glutamatergic synaptic structure and function, but also demonstrates causality between a disruption in this gene and the development of autistic-like behaviours in mice.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Discussion
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The repetitive grooming and social interaction deficits observed in Shank3 mutant mice correspond to autistic-like behaviours in humans.
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
“We also found a significant reduction of peak mEPSC amplitude in Shank3B−/− MSNs (Fig. 5b, d), indicating a reduction in the postsynaptic response from the available synapses.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Perturbation of striatal postsynaptic function
hedgeddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our data indicate that disruptions of different locations of the Shank3 gene can lead to varying degrees of functional defects, which may in part contribute to phenotypic heterogeneity in Shank3-related ASDs.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Discussion
hedgedconditionaln = 2- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together, these data demonstrate a critical role for Shank3 in postsynaptic function in cortico-striatal circuitry.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Perturbation of striatal postsynaptic function
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Shank3 is a key postsynaptic density protein at glutamatergic synapses.
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
“We found that the frequency of mEPSCs was significantly reduced in Shank3B−/− MSNs (Fig. 5b, c), suggesting a reduction in the number of functional synapses in Shank3B−/− MSNs since we did not observe defects on presynaptic function by measuring PPR (Fig. 5e).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Perturbation of striatal postsynaptic function
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The robust social interaction deficits in Shank3B mutant mice demonstrate a casual role for the disruption of this gene in the genesis of social dysfunction and provide a valuable experimental system for future genetic dissection of the neuronal basis of social behaviour.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Discussion
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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None of the sources cited for this claim have been checked yet.
In the paper
“Cortico-striatal circuitry dysfunction has also been strongly implicated in repetitive/compulsive behaviours in OCD31–33.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Discussion
What the sources say
- Not checked yetcites [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 yetcites [32] Shmelkov, S. V. et al. Slitrk5 deficiency impairs corticostriatal circuitry and leads to obsessive-compulsive-like behaviors in mice. Nature Med. 16, 598–602 (2010) source
- Not checked yetcites [33] Graybiel, A. M. Habits, rituals, and the evaluative brain. Annu. Rev. Neurosci. 31, 359–387 (2008) source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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 data support the hypothesis that repetitive behaviours in OCD and ASD may share a common circuitry mechanism.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Discussion
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“stimulation of the corpus callosum predominantly results in activation of cortical axons41,42”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Full Methods > Cortico-striatal electrophysiology
What the sources say
- Not checked yetcites [41] Yin, H. H., Davis, M. I., Ronesi, J. A. & Lovinger, D. M. The role of protein synthesis in striatal long-term depression. J. Neurosci. 26, 11811–11820 (2006) source
- Not checked yetcites [42] Malenka, R. C. & Kocsis, J. D. Presynaptic actions of carbachol and adenosine on corticostriatal synaptic transmission studied in vitro . J. Neurosci. 8, 3750–3756 (1988) source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 29
- Probably not a substantial claim. 36
- The quote only partly states this claim. 2
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here we 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.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Introduction
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The repetitive grooming and social interaction deficits observed in Shank3 mutant mice correspond to autistic-like behaviours in humans.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here we show that mice with Shank3 gene deletions exhibit self-injurious repetitive grooming and deficits in social interaction.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The repetitive grooming and social interaction deficits observed in Shank3 mutant mice correspond to autistic-like behaviours in humans.
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 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).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Shank3B−/− mice display repetitive grooming
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Shank3B−/− mice display repetitive grooming
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the open field test, when compared to controls, Shank3B−/− mice showed similar levels of activity and thigmotaxis (Supplementary Fig. 2).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Shank3B−/− mice display repetitive grooming
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The 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.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Shank3B−/− mice display repetitive grooming
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Shank3B−/− mice display repetitive grooming
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, Shank3A−/−mice displayed no lesions or anxiety-like behaviour (Supplementary Fig. 3).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Shank3B−/− mice display repetitive grooming
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, spontaneous seizures were never observed.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Shank3B−/− mice display repetitive grooming
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one. The quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Additionally, 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).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Social interaction deficits in Shank3B−/− mice
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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
“Shank3 is the most abundant Shank family member expressed in the striatum and Shank3B−/−mice exhibit excessive/repetitive grooming leading to skin lesions.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Shank family proteins (Shank1–3) directly bind SAPAP to form the PSD95/SAPAP/Shank complex14,15.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Introduction
What the sources say
- Not checked yetcites [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 yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper 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
“This core of proteins is thought to function as a scaffold, orchestrating the assembly of the macromolecular postsynaptic signaling complex at glutamatergic synapses.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Introduction
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Thus, the Shank3B−/− mice display an anxiety-like behaviour and excessive, self-injurious grooming.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Shank3B−/− mice display repetitive grooming
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In the paper
“These observations indicate that Shank3B−/− mice display excessive grooming and self-injurious behaviour.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Shank3B−/− mice display repetitive grooming
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In the paper
“Shank family members have been proposed as key regulators of the PSD at glutamatergic synapses18.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Altered PSD composition in the striatum
What the sources say
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Thus, data from both social interaction tests indicate that Shank3B−/− mice display abnormal social interaction as well as deficits in discriminating social novelty.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Social interaction deficits in Shank3B−/− mice
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In the paper
“These results suggest an altered molecular composition of postsynaptic machinery in the striatum and a possible disruption of glutamatergic signalling.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Altered PSD composition in the striatum
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In the paper
“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.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Perturbation of striatal postsynaptic function
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In the paper
“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.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Discussion
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In the paper
“PSD95-SAPAP-Shank proteins form a key postsynaptic scaffold at glutamatergic synapses which interacts with many synaptic proteins including the Neurexin-Neuroligin complex25.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Discussion
What the sources say
- Not checked yetcites [25] Irie, M. et al. Binding of neuroligins to PSD-95. Science 277, 1511–1515 (1997) source
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In the paper
“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.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Perturbation of striatal postsynaptic function
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In the paper
“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.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Discussion
What the sources say
- Not checked yetcites [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 yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Repetitive behaviours are also often seen in autistic patients and in some mouse models of ASDs34–36.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Discussion
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Full Methods > Mice
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In the paper
“The release of the animals and relative position of social and inanimate targets was counterbalanced.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Full Methods > Social Interaction Paradigm
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In the paper
“Unless otherwise noted, all tests were conducted with naive cohorts of mice.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Full Methods > Mice
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“The observer was blinded to genotype.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Full Methods > Motor and Anxiety-like behaviours31
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In the paper
“All experiments were done blind to genotypes.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Methods Summary > Behavioural analysis
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Discussion
What the sources say
- Not checked yetcites [31] Welch, J. M. et al. Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice. Nature 448, 894–900 (2007) source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Similarly, genetic makeup is thought to play a key role in the phenotypical manifestation of social behaviours38.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Discussion
What the sources say
- Not checked yetcites [38] Ebstein, R. P., Israel, S., Chew, S. H., Zhong, S. & Knafo, A. Genetics of human social behavior. Neuron 65, 831–844 (2010) source
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In the paper
“Quantification of social behaviors was performed using Noldus Observer software (Leesburg, VA) by a researcher blinded to the genotype of the target animals.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Full Methods > Social Interaction Paradigm
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Probably not a substantial claim.
In the paper
“The regulation of social behaviours and social interaction is thought to be controlled by several brain regions and circuits37.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Discussion
What the sources say
- Not checked yetcites [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
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“The observer was blinded to genotype during the scoring of the videotapes.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Full Methods > Grooming behaviour31
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In the paper
“As with striatal volumes, brain volumes were computed in Osirix from the average of two segmentations.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Full Methods > Magnetic Resonance Image Acquisition
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“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.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Full Methods > Cortico-striatal electrophysiology
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Mice 5–6 week old were used for all whole-cell electrophysiology procedures by an experimentalist blinded to genotype.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Full Methods > Cortico-striatal electrophysiology
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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In the paper
“Two separate striatal segmentations were obtained for each animal, with the average volume then taken.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Full Methods > Magnetic Resonance Image Acquisition
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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In the paper
“Mice were assigned a code previous to dissection, as to maintain a blinded genotype across all procedures, including dissection, cell filling, imaging and quantification.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Full Methods > Cell Filling
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“All analysis of spine metrics were performed by observers that were blinded to the genotypes of the animals.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Full Methods > Cell Filling
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“PSD measurements were performed using ImageJ (NIH, Bethesda, Maryland) by an observer that was blinded to the genotype of the samples.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Full Methods > Electron microscopy
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Mice were assigned a code previous to dissection, as to maintain a blinded genotype across all procedures, including dissection, sample processing, imaging and quantification.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Full Methods > Electron microscopy
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“Animals were assigned a blinding code, which was maintained during magnetic resonance (MR) data acquisition and analysis.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Full Methods > Magnetic Resonance Image Acquisition
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“Intrarater reliability (kappa value) was > 0.99.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Full Methods > Magnetic Resonance Image Acquisition
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. The quote only partly states this claim.
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In the paper
“Slices were prepared from one WT and one KO pair each day and the experimenter was blind to the genotype.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Full Methods > Cortico-striatal electrophysiology
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The series-resistance was < 20 MΩ.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Full Methods > Cortico-striatal electrophysiology
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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
“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.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Full Methods > Magnetic Resonance Image Acquisition
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, although we refer to our measurements as primarily reflecting corticostriatal transmission, our measurements are not “pure” corticostriatal responses.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Full Methods > Cortico-striatal electrophysiology
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Data analysis was performed blind of genotype in Clamp fit (Axon Instruments/Molecular Devices).”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Full Methods > Cortico-striatal electrophysiology
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All brains and collected sections were coded in order to blind the experimenter of the genotype until after all data was collected and analyzed.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Full Methods > Golgi Staining and Sholl Analysis
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Full Methods > Cortico-striatal electrophysiology
hedged- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“The data from spine density passed the Lilliefors Normality Test and D’Agostino & Pearson Omnibus Normality Test.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Full Methods > Cell Filling
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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
“Intrarater reliability (kappa value) was = 0.97.”
§ Shank3 mutant mice display autistic-like behaviours and striatal dysfunction > Full Methods > Magnetic Resonance Image Acquisition
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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.”
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
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“The Shank3 knockout mice have deficits in striatal glutamatergic synapse structure and function, including reduced cortico-striatal synaptic transmission47”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [47]
In the citing paper
“These Shank2 and Shank3 knockout mice display alterations in excitatory neurotransmission that correlate with ASD behavioural phenotypes.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [47]
In the citing paper
“Shank3 knockout mice have deficits in social interactions and engage in repetitive behaviours, such as excessive grooming, that lead to self injury47.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [47]
In the citing paper
“References 47–49 report the studies of mouse models of Shank mutations to demonstrate the role of Shanks in regulating excitatory neurotransmission.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [47]
In the citing paper
“Behavioral abnormalities associated with CNVs have been confirmed in animal models (Horev et al., 2011; Nakatani et al., 2009; Peca et al., 2011; Tabuchi et al., 2007; Tamada et al., 2010).”
From CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics (2012) · cites this paper as Peca et al., 2011
In the citing paper
“Mice lacking Shank3 have defects in striatal synapses and cortico-striatal circuits (Peca et al., 2011).”
From CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics (2012) · cites this paper as Peca et al., 2011
In the citing paper
“Shank3 shares a similar protein domain structure but has a different expression pattern and subcellular localization than Shank1 and Shank2 (Bockers et al., 2004; Peca et al., 2011; Tao-Cheng et al., 2010).”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Peca et al., 2011
In the citing paper
“Decreased PSD thickness and length were observed at corticostriatal synapses in Δex13-16−/− mice (Peca et al., 2011)”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Peca et al., 2011
In the citing paper
“while the Δex13-16 mutation (Peca et al., 2011) is predicted to disrupt transcripts from promoter 1 to 4 (Shank3a-d) but not from promoter 5 to 6 (Shank3e-f)”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Peca et al., 2011
In the citing paper
“Homer1, GKAP/SAPAP, and PSD-93 were reduced in PSD fractions isolated from the striatum of Δex13-16−/− mice (Peca et al., 2011)”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Peca et al., 2011
In the citing paper
“Both GluN2A and GluN2B subunits were reduced in the striatum of Δex13-16−/− mice (Peca et al., 2011)”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Peca et al., 2011
In the citing paper
“spine density was decreased in the striatum and CA1 hippocampus of Δex13-16−/− and Δex4-9J−/− mice, respectively.”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Peca et al., 2011
In the citing paper
“Dendritic branching and spine area was increased in medium spiny neurons (MSNs) of the striatum of Δex13-16−/− mice (Peca et al., 2011)”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Peca et al., 2011
In the citing paper
“Phenotypic analyses at the biochemical, synaptic, and behavioral levels were performed extensively on either heterozygotes or homozygotes at different ages for Shank3 Δex4-7, Δex4-9J, Δex4-9B, and Δex13-16 but to a lesser degree in Δex11 mutant mice”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Peca et al., 2011
In the citing paper
“Five lines of Shank3 mutant mice carrying different mutations in Shank3 have been reported (Bozdagi et al., 2010; Peca et al., 2011; Schmeisser et al., 2012; Wang et al., 2011)”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Peca et al., 2011
In the citing paper
“The mutations in these mice include deletions of exons 4-9 by two groups with slightly different design [(Δex4-9Buxbaum(B)) (Bozdagi et al., 2010) and Δex4-9Jiang (J) (Wang et al., 2011)], deletion of exons 4-7(Δex4-7) (Peca et al., 2011) encoding the ANK repeat domain, deletion of exon 11(Δex11) encoding the SH3 domain (Schmeisser et al., 2012), and deletion of exons 13-16 (Δex13-16) encoding the”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Peca et al., 2011
In the citing paper
“Isoform-specific disruption of Shank3 was evident in Δex4-7, Δex4-9J, Δex11, and Δex13-16 mice (Peca et al., 2011; Schmeisser et al., 2012; Wang et al., 2011).”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Peca et al., 2011
In the citing paper
“and GluA2 was reduced in the striatum of Δex13-16−/− mice (Peca et al., 2011).”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Peca et al., 2011
In the citing paper
“A more marked increase in self-grooming and self-injurious behaviors was observed in Δex11−/− and Δex13-16−/− mice”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Peca et al., 2011
In the citing paper
“In striatum, the frequency of mEPSCs and amplitude of population spikes were significantly decreased in Δex13-16−/− mice, but only mildly affected in Δex4-7−/− mice (Peca et al., 2011).”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Peca et al., 2011
In the citing paper
“Presynaptic responses measured by paired pulse ratio and input/output curves were not altered at corticostriatal synapses in Δex13-16−/− or Δex4-7−/− mice (Peca et al., 2011).”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Peca et al., 2011
In the citing paper
“but were not apparent in Δex4-7−/− mice (Peca et al., 2011).”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Peca et al., 2011
In the citing paper
“Impaired performance in the Morris water maze task was seen in Δex4-9J−/− mice (Wang et al., 2011) but not in Δex13-16−/− (Peca et al., 2011) and Δex4-9B−/− animals (Yang et al., 2012).”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Peca et al., 2011
In the citing paper
“Mutations in the SH3 and PDZ domains are missense mutations in humans (Boccuto et al., 2012; Waga et al., 2011), but mouse mutation of Δex11 and Δex13-16 are exon deletion and frame shift mutations (Peca et al., 2011; Schmeisser et al., 2012).”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Peca et al., 2011
In the citing paper
“The most notable and consistent observation was reduced social interaction and affiliation behaviors using different testing methods”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Peca et al., 2011
In the citing paper
“Deletion of the two longer Shank3 isoforms (Shank3α and β) in the Shank3B−/− mice is associated with increased dendritic length and complexity but reduced spine density, PSD length and thickness in striatal medium spiny neurons [277].”
From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [277]
In the citing paper
“high mRNA levels of Shank1 in cortex and hippocampus and of Shank3 in striatum and cortex [36, 77]”
In the citing paper
“In mice, both congenital knockout and haploinsufficiency of Shank3 leads to diminished social interest in others and is associated with the disruption of cortical and subcortical circuits thought to be involved in ASD 22–26 and its ontogenesis 22,25,27,28.”
From Reduced sociability and social agency encoding in adult Shank3-mutant mice are restored through gene re-expression in real time (2021) · cites this paper as [25]
In the citing paper
“While loss of Shank3 expression in the HET animals is largely evident throughout the brain 25”
From Reduced sociability and social agency encoding in adult Shank3-mutant mice are restored through gene re-expression in real time (2021) · cites this paper as [25]
Citations
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Metadata
- 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
- Published
- 2011-03-20
- Volume
- 472
- Issue
- 7344
- Pages
- 437-442
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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
- green
- www.ncbi.nlm.nih.gov
- 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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