Recurrent mutations in the SHANK3 gene have been identified in multiple individuals with ASD as described below. SHANK3 lies within a multi-genic region on chromosome 22 that is deleted in Phelan-McDermid syndrome, a disorder which is frequently accompanied by ASD. De novo and inherited point mutations and copy number variants involving SHANK3 have been identified in individuals with ASD in multiple reports (PMIDs 17173049, 17999366, 18615476, 20186804, 20385823, 21378602, 21624971, 22558107, 22892527, 23758760), including de novo SHANK3 variants in PMIDs 17173049, 17999366 and 18615476 that were predicted to be loss-of-function variants or shown experimentally to disrupt SHANK3 function. An additional seven de novo loss-of-function variants in SHANK3 were identified in simplex ASD cases in Leblond et al., 2014 (PMID 25188300); in contrast, no truncating variants in SHANK3 were observed in 1,031 controls. Individuals with truncating SHANK3 variants were found to display ASD with moderate to severe/profound intellectual disability (mean IQ of 31 8) in this report. Furthermore, in a screen and meta-analysis of SHANK copy number variants in ASD, SHANK3 deletions were shown to be statistically enriched in ASD cases compared to controls [10/5,657 cases (0.18%) vs. 2/19,163 controls (0.01); P=0.019, OR=4.05 (1.26-13.01)] (PMID 25188300). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Multiple inconsistent associations have been reported with idiopathic ASD in other studies (PMIDs 19384346, 19566951, 22892527, 24398551, 27876814). A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified SHANK3 as a gene reaching exome-wide significance (P < 2.5E-06). De novo SHANK3 mutations in individuals with schizophrenia have also been reported in Gauthier et al., 2010 (PMID 20385823), and association of SHANK3 with schizophrenia has been reported as well (PMID 28371232).
Molecular Function
Shank proteins are multidomain scaffold proteins of the postsynaptic density that connect neurotransmitter receptors, ion channels, and other membrane proteins to the actin cytoskeleton and G-protein-coupled signaling pathways. Shank proteins also play a role in synapse formation and dendritic spine maturation.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders.
Targeted next-generation sequencing identifies the disruption of the SHANK3 and RYR2 genes in a patient carrying a de novo t(1;22)(q43;q13.3) associated with signs of Phelan-McDermid syndrome
A 29 Mainland Chinese cohort of patients with Phelan-McDermid syndrome: genotype-phenotype correlations and the role of SHANK3 haploinsufficiency in the important phenotypes
Discovery: 500 German schizophrenia cases (273 males, 227 females, mean age at inclusion=34.4 11 years), 4300 European controls from the Exome Variant Server
Discovery: 500 German schizophrenia cases (273 males, 227 females, mean age at inclusion=34.4 11 years), 503 European controls from the 1000 Genomes Project, and 4300 European controls from the Exome Variant Server
Discovery: 500 German schizophrenia cases (273 males, 227 females, mean age at inclusion=34.4 11 years), 4300 European controls from the Exome Variant Server
Discovery: 500 German schizophrenia cases (273 males, 227 females, mean age at inclusion=34.4 11 years), 503 European controls from the 1000 Genomes Project, and 4300 European controls from the Exome Variant Server
Discovery: 500 German schizophrenia cases (273 males, 227 females, mean age at inclusion=34.4 11 years), 503 European controls from the 1000 Genomes Project, and 4300 European controls from the Exome Variant Server
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Targeted Cre/loxP mediated deletion of exon 4 to exon 9 of Shank3 gene.
Allele Type: Partial knockout
Strain of Origin: Not Specified
Genetic Background: Not Specified
ES Cell Line: Bruce4 C57BL/6
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Targeted Cre/loxP mediated deletion of exon 4 to exon 9 of Shank3 gene.
Allele Type: Partial knockout
Strain of Origin: Not Specified
Genetic Background: Not Specified
ES Cell Line: Bruce4 C57BL/6
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Targeted deletion of exon 13 to 16 of Shank3 containing the PDZ domain, the positive selection marker neo cassette is retained.
Allele Type: Partial knockout
Strain of Origin: Not Specified
Genetic Background: C57Bl6*129svJ
ES Cell Line: R1
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Targeted deletion of exons 4 - 7 containing the ankyrin repeat domains of Shank3 gene, the positive selection marker neo cassette is retained.
Allele Type: Partial knockout
Strain of Origin: Not Specified
Genetic Background: Not Specified
ES Cell Line: R1
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Targeted deletion of exons 4-9 of Shank3 gene which includes the ankyrin repeat domains.
Allele Type: Partial knockout
Strain of Origin: Not Specified
Genetic Background: Not Specified
ES Cell Line: 129SvEv
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Deletion of exon 21 of Shank3 resulting in lack of entire C-termain portion of Shank3 (the article reporting this model was retracted, however phenotypic data for the model has been retained following the retraction notification and MGI).
Allele Type: Knockout
Strain of Origin: 129S6/SvEvTac
Genetic Background: Not Specified
ES Cell Line: Not Specified
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Targeted deletion of exon 11 within the SH3 domain of Shank3 gene. A loxP site was inserted upstream of exon 11 and an FRT flanked neo cassette and loxP site were inserted downstream of exon 11 via homologous recombination. Recombinase-mediated recombination deleted exon 11 and the neo cassette. Deletion allele also known as Shank3^alphabeta- or Shank3delta11-.
Allele Type: Knockout
Strain of Origin: Not specified
Genetic Background: C57BL/6
ES Cell Line: Not specified
Mutant ES Cell Line: Not specified
Model Source: Tobias Boeckers lab, Genoway
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Targeted deletion of exon 21 of the Shank3 gene using cre/loxP and frt flanked neo cassette. After removal of the neo cassette, mice containing the floxed gene were mated to actin-Cre mice for deleting the exon. Wild type Shank3 protein is not detected in these mice. Lower molecular weight isoforms of Shank3 are however detectable.
Allele Type: Knockout
Strain of Origin: 129S6/SvEvTac
Genetic Background: C57BL/6
ES Cell Line: Mutant ES Cell Line: Model Source: Paul F. Worley Lab (PMID 21565394)
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Targeted deletion of exon 21 (previously described in PMID 24259569); Deletion of exon 21 removes the majority of the Shank3 C-terminus; major isoforms absent but fast migrating truncated fragments present.
Allele Type: Knockout
Strain of Origin: 129S6/SvEvTac
Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source: PMID 24259569
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Autism-associated guanine nucleotide insertion mutation (Shank3G) present in exon 21 was inserted into the Shank 3 gene, with the construct containing the mutation within exon21 sequence knocked into intron 20 .The additional G results in a frameshift mutation and a premature stop codon downstream of exon 21. Mice containing the Shank3G mutation were crossed for 4 generations with C57BL6J. Het and homozygous mice were generated as littermates.
Allele Type: ASD LOF mutation
Strain of Origin: 129Sv/Evs6
Genetic Background: C57BL/6J*129Sv/Evs6
ES Cell Line: SM-1
Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Autism-associated guanine nucleotide insertion mutation (Shank3G) present in exon 21 was inserted into the Shank 3 gene, with the construct containing the mutation within exon21 sequence knocked into intron 20 .The additional G results in a frameshift mutation and a premature stop codon downstream of exon 21. Mice containing the Shank3G mutation were crossed for 4 generations with C57BL6J. Het and homozygous mice were generated as littermates.
Allele Type: ASD LOF mutation
Strain of Origin: 129Sv/Evs6
Genetic Background: C57BL/6J*129Sv/Evs6
ES Cell Line: SM-1
Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Targeted Cre-LoxP mediated excision of exons 4-9 of Shank3 gene containing the ankyrin repeats. After germline transmission in C57BL6J, knock in mice were mated with mice expressing Flp1 recombinase to excise the Neo cassette used for positive selection. The resulting conditional Shank3 mice were crossed with mice expressing ZP3-Cre to excise exon4-9 in oocytes of female pups, then further crossed with C57BL6J, to homozygosity (Authors do not note that the construct used or the final mice are the same as that reported used in Bozdagi et al Mol Autism (2010) or Yang et al J Neurosci (2012), even if exon 4-9 are targeted in all these studies, therefore they are presumed to be different here).
Allele Type: Knockout
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: 129s6SvEvTac
Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Targeted Cre-LoxP mediated excision of exons 4-9 of Shank3 gene containing the ankyrin repeats. After germline transmission in C57BL6J, knock in mice were mated with mice expressing Flp1 recombinase to excise the Neo cassette used for positive selection. The resulting conditional Shank3 mice were crossed with mice expressing ZP3-Cre to excise exon4-9 in oocytes of female pups, then further crossed with C57BL6J, to homozygosity (Authors do not note that the construct used or the final mice are the same as that reported used in Bozdagi et al Mol Autism (2010) or Yang et al J Neurosci (2012), even if exon 4-9 are targeted in all these studies, therefore they are presumed to be different here).
Allele Type: Knockout
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: 129s6SvEvTac
Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Autism-associated guanine nucleotide insertion mutation (Shank3InsG) was placed at position 3680 in exon 21, this insertion causes a frameshift and a stop codon immediately after the G insertion. The mice were maintained in C57B6/S129Sv background. Mice were bred to homozygosity normally.
Allele Type: ASD LOF mutation
Strain of Origin: Genetic Background: C57BL/6J*S129Sv
ES Cell Line: R1
Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Autism-associated guanine nucleotide insertion mutation (Shank3InsG) was placed at position 3680 in exon 21, this insertion causes a frameshift and a stop codon immediately after the G insertion. The mice were maintained in C57B6/S129Sv background. Mice were bred to homozygosity.
Allele Type: ASD LOF mutation
Strain of Origin: Genetic Background: C57BL/6J*S129Sv
ES Cell Line: R1
Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Schizophrenia associated non-sense mutation changing arginine to a stop codon (R1117X) was introduced by changing the codon for R 'CGG' to stop codon TGA in position 1117. Mice were maintained in C57Bl6*129Sv background and bred to homozygosity.
Allele Type: NDD LOF mutation
Strain of Origin: Genetic Background: C57BL/6J*S129Sv
ES Cell Line: R1
Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Schizophrenia associated non-sense mutation changing arginine to a stop codon (R1117X) was introduced by changing the codon for R 'CGG' to stop codon TGA in position 1117. Mice were maintained in C57Bl6*129Sv background.
Allele Type: NDD LOF mutation
Strain of Origin: Genetic Background: C57BL/6J*S129Sv
ES Cell Line: R1
Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Targeted knockin inversion of exons 13 to 16, that include the coding region of the PDZ domain, generated using the FLEx genetic switch strategy. The inverted insert is flanked by FRT and loxP sites. The knockin floxed mouse is called a functional knockout by authors.
Allele Type: LOF knockin
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source: Jackson Laboratories
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Mice with inverted exons 13-16 and the transgene CAGGS-CreER used as controls or parent models. Genotype of these mice is: Shank3fx/fx;CreER+/-.Mice received corn oil treatment (vehicle) at 2-4.5 months.
Allele Type: LOF knockin
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source: Jackson Laboratories
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Disruption of all murine Shank3 isoforms by cre/loxP mediated excision of exons 4-22 of the Shank3 gene, spanning 58 kb to include the coding sequences for all known Shank3 isoforms. The floxed mice were bred with CMV-cre mice to generate mice with deletions and bred till homozygosity. Authors report loss of all known Shank3 mRNA and protein.
Allele Type: Knockout
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Shank3 exon 4-22 floxed mice were bred to CMV-cre mice to generate heterozygous Shank3 knockouts.
Allele Type: Knockout
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional deletion of exons 4-22 of the Shank3 gene in 10-12 week old female mice by injecting AAV10- Cre virus, bilaterally, in the nucleus accumbens (NAc) to selectively knockdown Shank3 in the Nac
Allele Type: Conditional loss-of-function
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Targeted deletion of exon 13 to 16 of Shank3 containing the PDZ domain, the positive selection marker neo cassette is retained.
Allele Type: Partial knockout
Strain of Origin: C57BL/6J
Genetic Background: C57BL/6J*129Sv/Ev
ES Cell Line: R1
Mutant ES Cell Line: Model Source: PMID 21423165
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
KI of neo-STOP cassette inserted in intron 12, between exon 12 and exon 13, resulting in loss of higher mol weight Shank3 isoforms, bred to homozygosity. All Shank3 protein expressed in these mutants lacks the PDX domain.
Allele Type: Partial knockout
Strain of Origin: Not Specified
Genetic Background: C57BL/6J
ES Cell Line: 129s6SvEvTac
Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Neo-STOP cassette was inserted in intron 12, between exon 12 and exon 13, of the Shank3 gene and results in the loss of two higher molecular weight isoforms of Shank3, and results in a protein lacking the PDZ domain.
Allele Type: Partial knockout
Strain of Origin: Not Specified
Genetic Background: C57BL/6J
ES Cell Line: 129s6SvEvTac
Mutant ES Cell Line: Model Source:
Model Type:
RESCUE-Dietary
Model Genotype:
Homozygous
Mutation:
Adult shank3 knockout mice were treated for three weeks between ages 8-11 weeks, with L. reuteri. Mice were gavaged with 10^9 bacteria of L. reuteri reconstituted in PBS, twice a week for three weeks. Behavioral experimentation was carried out between ages 11-13 weeks, and then mice were immediately sacrificed for downstream molecular and biochemical analysis. L. reuteri used for this study was obtained from ATCC (Lactobacillus reuteri MM4-1A; ATCC-PTA-6475).
Allele Type: Knockout
Strain of Origin: Not Specified
Genetic Background: Not Specified
ES Cell Line: Mutant ES Cell Line: Model Source: PMID 21423165
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Mice with autism-linked human missense mutation S685I knocked in using CRISPR-CAS9. A FLAG-tagged Shank3 construct is used.
Allele Type: ASD LOF mutation
Strain of Origin: FVB/N
Genetic Background: FVB
ES Cell Line: FVB/N
Mutant ES Cell Line: Model Source: PMID 30610205
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Heterozygous mice with autism-linked human missennse mutation S685I knocked in using CRISPR-CAS9. FLAG-tagged Shank3 construct is used.
Allele Type: ASD LOF mutation
Strain of Origin: FVB/N
Genetic Background: FVB
ES Cell Line: FVB/N
Mutant ES Cell Line: Model Source: PMID 30610205
Model Type:
Genetic
Model Genotype:
Wildtype
Mutation:
Seven-week-old wildtype C57BL/6 male mice were injected with Shank3-siRNA (1424750, NM_021423.2), bilaterally in the dorsal striatum, using a stereotaxic apparatus, resulting in a reduction of Shank3 transcript levels to 0.4 fold compared with control siRNA injected mice.
Allele Type: Knockdown
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: NA
Mutant ES Cell Line: NA
Model Source: Daehan BioLink (Eumsung, Chungbuk, Republic of Korea)
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Model with exons 13 to 16 (containing the PDZ domain) of the Shank3 gene replaced with a NEO cassette. This model is identical to the construct of M_SHANK3_4_KO_HM but on a different genetic background; M_SHANK3_4_KO_HM
Allele Type: Knockout
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Mice with selective knockout of Shank3 in the anterior cingulate cortex were generated CRISPR/Cas9 mediated genome editing by administering an AAV2/9 vector harboring Staphylococcus aureus Cas9 (SaCas9) and a single-guide RNA (sgRNA) to adult WT mice. This eliminated Shank3 alpha, beta and gamma isoforms in the anterior cingulate cortex.
Allele Type: Conditional loss-of-function
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Mice with selective ablation of Shank3 below cervical level 2 were generated by crossing Shank3f mice with loxp sites flanking exons 13 and 16 with mice expressing Cre recombinase below cervical level 2 (Cdx2-Cre; Shank3f/+)
Allele Type: Conditional loss-of-function
Strain of Origin: Genetic Background: C57BL/6J*129/SvEv*CD1
ES Cell Line: Mutant ES Cell Line: Model Source: PMID 31398341; Akyol et al., 2008; Eric Fearon; RRID:IMSR_JAX:009350
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Mice with selective ablation of Shank3 in all DRG, trigeminal, and sympathetic ganglia somatosensory neurons were generated by crossing Shank3f mice with loxp sites flanking exons 13 and 16 with mice expressing Advillin-Cre recombinase (Advillin-Cre; Shank3f/+).
Allele Type: Conditional loss-of-function
Strain of Origin: Genetic Background: C57BL/6J*129/SvEv*CD1
ES Cell Line: Mutant ES Cell Line: Model Source: PMID 31398341; Hasegawa et al, 2007; Fan Wang; RRID:IMSR_JAX:032536
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Mice with selective ablation of Shank3 in all DRG, trigeminal, and sympathetic ganglia somatosensory neurons were generated by crossing Shank3f mice with loxp sites flanking exons 13 and 16 with mice expressing Advillin-Cre recombinase (Advillin-Cre; Shank3f/f).
Allele Type: Conditional loss-of-function
Strain of Origin: Genetic Background: C57BL/6J*129/SvEv*CD1
ES Cell Line: Mutant ES Cell Line: Model Source: PMID 31398341; Hasegawa et al, 2007; Fan Wang; RRID:IMSR_JAX:032536
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Targeted deletion of exon 13 to 16 of Shank3 containing the PDZ domain, the positive selection marker neo cassette is retained; M_SHANK3_4_KO_HT
Allele Type: Knockout
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source: Jackson Laboratories; RRID:IMSR_JAX:017688
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Mice with cre-dependent FLEx switch allele containing an inverted Shank3 PDZ domain (exons 13-16) that functions as a knockout allele in the absence of Cre recombinase; M_SHANK3_21_KI_HM.
Allele Type: LOF knockin
Strain of Origin: Genetic Background: C57BL/6J*129/SvEv*CD1
ES Cell Line: Mutant ES Cell Line: Model Source: Jackson Laboratories; Guoping Feng; RRID:IMSR_JAX:028800; Mei et al., 2016
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Mice with cre-dependent FLEx switch allele containing an inverted Shank3 PDZ domain (exons 13-16) that functions as a knockout allele in the absence of Cre recombinase, Shank3^FX/FX; M_SHANK3_21_KI_HM.
Allele Type: LOF knockin
Strain of Origin: Genetic Background: C57BL/6J*129/SvEv*CD1
ES Cell Line: Mutant ES Cell Line: Model Source: Jackson Laboratories; Guoping Feng; RRID:IMSR_JAX:028800; Mei et al., 2016
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Targeted deletion of exon 13 to 16 of Shank3 containing the PDZ domain, the positive selection marker neo cassette is retained; M_SHANK3_4_KO_HT
Allele Type: Knockout
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source: Jackson Laboratories; RRID:IMSR_JAX:017688
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Mutant mice with sensory neuron specific inducible deletion of Shank3 (Advillin-CreERT2; Shank3^f/+) in the early postnatal period (P5) were generated by crossing Shank3f mice with loxp sites flanking exons 13 and 16 and transgenic Advillin-CreERT2 driver mice that expresse a tamoxifen-inducible iCre recombinase directed by endogenous Avil (advillin) promoter elements in the dorsal root ganglia and sensory neurons.
Allele Type: Conditional loss-of-function
Strain of Origin: Genetic Background: C57BL/6J*129/SvEv*CD1
ES Cell Line: Mutant ES Cell Line: Model Source: Jackson Laboratory; John Wood; RRID:IMSR_JAX:032027 (Lau et al, 2011)
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Mutant mice with sensory neuron specific inducible deletion of Shank3 (Advillin-CreERT2; Shank3^f/+) in the early postnatal period (P10) were generated by crossing Shank3f mice with loxp sites flanking exons 13 and 16 and transgenic Advillin-CreERT2 driver mice that expresse a tamoxifen-inducible iCre recombinase directed by endogenous Avil (advillin) promoter elements in the dorsal root ganglia and sensory neurons.
Allele Type: Conditional loss-of-function
Strain of Origin: Genetic Background: C57BL/6J*129/SvEv*CD1
ES Cell Line: Mutant ES Cell Line: Model Source: Jackson Laboratory; John Wood; RRID:IMSR_JAX:032027 (Lau et al, 2011)
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Mutant mice with sensory neuron specific inducible deletion of Shank3 (Advillin-CreERT2; Shank3^f/+) in the early postnatal period (P28) were generated by crossing Shank3f mice with loxp sites flanking exons 13 and 16 and transgenic Advillin-CreERT2 driver mice that expresse a tamoxifen-inducible iCre recombinase directed by endogenous Avil (advillin) promoter elements in the dorsal root ganglia and sensory neurons.
Allele Type: Conditional loss-of-function
Strain of Origin: Genetic Background: C57BL/6J*129/SvEv*CD1
ES Cell Line: Mutant ES Cell Line: Model Source: Jackson Laboratory; John Wood; RRID:IMSR_JAX:032027 (Lau et al, 2011)
Model Type:
Genetic LOF
Model Genotype:
Chimeric
Mutation:
Human neuronal-chimeric mouse generated by transplanting gfp labelled control cells and human npc labelled with mcherry from an asd patient with a heterozygous truncated shank3 mutation into the motorcortex or the lateral ventricles of immune-deficient newborn mice at p1-2. transplanted mice were tested at at 30 days post-transplantation. the asd patient carried a de novo frameshift mutation which leads to a premature stop codon.
Allele Type: Wildtype
Strain of Origin: NA
Genetic Background: NOD/SCID
ES Cell Line: NA
Mutant ES Cell Line: NA
Model Source: Charles Rivers
Model Type:
Genetic
Model Genotype:
Wildtype
Mutation:
AAV-shShank3-luczsGreen were injected into nucleus accumbens of WT mice, D1R:Cre (MMRRC Stock No: 37156-JAX), and Drd1a-tdTomato reporter mice during early postnatal development (P6).
Allele Type: knockdown
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
RESCUE-Pharmacological
Model Genotype:
Homozygous
Mutation:
Shank3 knockout (MGI:6162240) mice were treated with neuronal nitric oxide synthase (nNOS) inhibitor, 7-nitroindazole (7-NI), for 10 consecutive days. The pharmacological interventions were performed by daily intraperitoneal (IP) injection at a dose of 80 mg/kg.
Allele Type: Knockout
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source: 37212048
Description: Abnormal synaptic potentiation and spine expansion in ca1 neurons
Exp Paradigm: Simultaneous monitoring of spine size and synaptic response in ca1 neurons before and after tbp
Miniature post synaptic current amplitude: excitatory1
Decreased
Description: Abnormal synaptic transmission demonstrated by decreased amplitude of miniature excitatory postsynaptic currents (mepscs) with increased frequency of mepscs in hippocampal ca1 pyramidal neurons
Exp Paradigm: Whole cell patch-clamp recordings of spontaneous mepscs in the presence of tetrodotoxin in hippocampal ca1 pyramidal neurons
Description: Decreased paired-pulse ratio in hippocampal ca1 pyramidal neurons
Exp Paradigm: Whole cell patch-clamp recordingsin the presence of tetrodotoxin in hippocampal ca1 pyramidal neurons
Description: Reduced synaptic transmission mediated by ampa receptor is indicated using antagonist for ampa/kainate receptors or nmda receptor, where the i/o curve is reduced in the schaffer collateral- ca1 synapses only in the presence of the latter
Exp Paradigm: Extracellular recordings of schaffer collateral-ca1 synapses in hippocampal slices
Description: Decreased glutamate ampa receptor component of neuronal sigaling indicated by mean slope of i/o function
Exp Paradigm: Whole cell recordings of hippocampal slices
Description: Decreased maintenance of long-term potentiation at schaffer collateral/ca1 synapses in response to either high-frequency stimulus or tbs
Exp Paradigm: Extracellular fepsp recordings at schaffer collateral/ca1 synapses after induction of ltp by tetanic stimulation or tbs
Description: Decreased male-female social interaction demonstrated by shorter duration of total social sniffing by male
Exp Paradigm: Direct-contacts between male-female mice
Description: In assessments made in neurocube, shank3(exon13-16) ko mutants have reductions in variability of paw position, compared to controls and this was one of the important phenotypes that led to differences from controls
Exp Paradigm: NA
Description: In the assessments made by smartcube, the discrimination index for shank3(exon13-16) ko mutants (differentiating them from controls), was strongly affected by decreased locomotor activity
Exp Paradigm: NA
Description: Shank3(exon13-16) ko mutant males exposed to the urine of an estrus female, in the of arena, mutant males exposed to the urine of an estrus female, in the of arena, have shorter distance travelled compared to controls
Exp Paradigm: NA
Description: Increased dendritic complexity indicative of neuronal hypertrophy due to increased complexity of dendritic arborization, total dendritic length, and surface area
Exp Paradigm: Sholl analysis of golgi stained striatal medium spiny neurons (msns)
Description: Shank3 mutants show decreased expression of gaba receptors gabra1, gabra2, and gabrb1 in the hippocampus, compared to controls. pearson corelation analysis showed the abundance of l. reuteri, but not l. brevis, or l. ruminis, correlated with expression of each of the three gaba receptor subunits.
Exp Paradigm: NA
Description: z-scored peak amplitude of SPW-R events was significantly lower in Shank3-KO mice compared to that in wild-type mice; this difference was ascribed to the decrease in larger SPW-R events
Description: Decreased synaptic transmission indicated by reduced field population spikes
Exp Paradigm: Extracellular recordings of cortico-striatal synaptic circuitry in acute brain slices
Decay kinetics of miniature post synaptic currents4
Decreased
Description: Mutants show slowed decay kinetics compared with controls, measured by an increased in the weighted decay tau.
Exp Paradigm: Whole-cell patch-clamp recordings were obtained from medial spiny neurons in coronal cortico-striatal brain slices.
Description: Mutants show decrease in ampar/nmdar ratio in response to social interaction, in the vta compared with controls, indicating a decrease in ltp in the vta.
Exp Paradigm: Direct social interaction-evoked long-term potentiation (ltp) in vta da neurons was recorded.
Description: Decreased rate of drop in mean firing rates following monocular deprivation in v1m neurons; absence of recovery in firing rates over the ensuing period; in v1b neurons total drive from two eyes after 6 days monocular deprivation is restored to nondeprived levels in wildtypes
Exp Paradigm: NA
Miniature post synaptic current frequency: excitatory4
Increased
Description: Mutants show increased frequency of evoked epsc frequencies compared with controls.
Exp Paradigm: Whole-cell patch-clamp recordings were obtained from medial spiny neurons in coronal cortico-striatal brain slices.
Description: Absence of increase in ipsilateral eye compensation after 3 days and 8 days monocular deprivation; no change in odi shift toward the open eye; no change in loss of responsiveness of the closed contralateral eye after 3-days md;
Exp Paradigm: NA
Description: SPW-Rs with higher MUAs in the vCA1 did not give rise to more correlated neuronal activities in Shank3 KO mice compared to that in WT; correlation between online and offline sequential ordering was disrupted in Shank3-KO mice; compared to SPW-Rs accompanying higher MUAs in the dCA1 gave rise to more correlated neuronal activity both in the wild-type mice and Shank3 KO mice andsignificant positive correlation of mean rank order differences between online theta cycles and offline ripples was preserved in Shank3 KO mice
Description: Abnormal postsynaptic function demonstrated by decreased frequency and amplitude of ampar-mepscs of msns
Exp Paradigm: Whole-cell voltage clamp recordings of ampar-mespcs in dorsolateral striatal medium spiny neurons (msns)
Miniature post synaptic current amplitude: excitatory4
Decreased
Description: Mutants show decreased amplitude of evoked ampar mediated epsc amplitudes but no change in nmdar mediated epsc amplitudes compared with controls.
Exp Paradigm: Whole-cell patch-clamp recordings were obtained from medial spiny neurons in coronal cortico-striatal brain slices.
Description: In the assessments made by smartcube, the discrimination index for shank3(exon13-16) ko mutants (differentiating them from controls), was strongly affected by increase in grooming
Exp Paradigm: NA
Description: Male shank3 mutants spent less time investigating the compartment with the unfamiliar mouse and more time in the empty chamber compared to controls. female shank3 mutants show no preference between the empty and occupied compartments, compared to controls.
Exp Paradigm: NA
Description: Abnormal social novelty demonstrated by decreased time interacting with novel mouse
Exp Paradigm: Modified three-chambered social arena task with introduction of a novel social partner
Description: Decreased social interaction behavior demonstrated by clear preference for interacting with empty cage
Exp Paradigm: Modified three-chambered social arena task
Description: Male shank3 null mice show decreased interaction with an estrus b6 female compared with controls as measured by a decrease in nose-to-nose interaction bouts. male shank3 null mice show no change in nose to nose interaction duration, nose to anogenital interaction bouts or duration, following bouts or duration or approaches with an estrus b6 female compared with controls.
Exp Paradigm: NA
Description: duration of approach of Shank3 KO mouse was similar for the familiar mouse and the novel mouse, discrimination score was not significantly different from zero
Description: Female shank3 mutants show decreases in two species of veillonella compared to controls.
Exp Paradigm: Microbial dna was extracted from stool samples, and from stool sample from the colon.
Description: Mutants show significant differences in the phylogenetic profile of the microbial communities compared with controls, irrespective of cage of origin.
Exp Paradigm: NA
16s rrna gene sequence analysis for identification of bacteria
Description: Decrease in overall bacterial composition compared to controls; no change in the top principle components of the gut microbiota; decreased richness of bacterial species (alpha diversity) in the gut, particularly in females; decreases in relative abundance of members of the class bacilli, order lactobacillales, family lactobacillaceae, and genus lactobacillus; decreases in coprococcus, bacteroides, acetobacter, turicibacter, and prevotella, at the genus level; increases in family veillonellaceae and genus veillonella
Exp Paradigm: NA
16s rrna gene sequence analysis for identification of bacteria
Description: Shank3 mutants show decreases in both lactobacillus and prevotella, at the genus level, compared to controls. shank3 mutants show decreases in levels of several species of lactobacillus including l. reuteri, l. brevis, and l. ruminis compared to controls.
Exp Paradigm: Microbial dna was extracted from stool samples, and from stool sample from the colon.
Description: Male shank3 mutants show increases in one species of veillonella compared to controls.
Exp Paradigm: Microbial dna was extracted from stool samples, and from stool sample from the colon.
Description: Shank3 mutants show a decrease in overall bacterial composition compared to controls. shank3 mutants show no change in the top principle components of the gut microbiota, compared to controls.
Exp Paradigm: Microbial dna was extracted from stool samples, and from stool sample from the colon.
16s rrna gene sequence analysis for identification of bacteria
Ultrasonic vocalization: interaction induced: opposite sex stimulus2
Decreased
Description: Shank3(exon13-16) ko mutant males exposed to the urine of an estrus female, in the of arena, emitted fewer vocalizations compared to controls
Exp Paradigm: NA
Ultrasonic vocalization: interaction induced: opposite sex stimulus7
Decreased
Description: Male shank3 null mice show decrease in the number of ultrasonic vocalizations emitted compared with controls (4j,k). male shank3 null mice show no change in the number of ultrasonic vocalizations emitted compared with controls (s13h).
Exp Paradigm: NA
Description: Increased anxiety demonstrated by: reduced rearing activity which is a form of vertical exploration, less time exploring open arms of maze, increased latency to cross brightly lit area
Exp Paradigm: Open field test measurement of rearing; elevated zero maze; light-dark emergence test-open field test
Description: Mutants spent less time in the light chamber, show increased latency to enter the light chamber, and show decrease in the number of alterations between the light and dark chambers, compared with controls.
Exp Paradigm: NA
Description: Increased anxiety demonstrated by: reduced rearing activity which is a form of vertical exploration, less time exploring open arms of maze, increased latency to cross brightly lit area
Exp Paradigm: Open field test measurement of rearing; elevated zero maze; light-dark emergence test- light-dark exploration test
Description: Increased anxiety demonstrated by: reduced rearing activity which is a form of vertical exploration, less time exploring open arms of maze, increased latency to cross brightly lit area
Exp Paradigm: Open field test measurement of rearing; elevated zero maze; light-dark emergence test- elevated zero maze test
Description: Shank3(exon13-16) ko mutants' latency of approach stimulus, rearing etc was one of the top features contributing to the difference between mutant and wild type mice in smartcube analysis
Exp Paradigm: NA
Description: Shank3(exon13-16) ko mutant males exposed to the urine of estrus female display increased anxiety as they spend less time in the center of the open field arena
Exp Paradigm: NA
Description: Shank3 null mice spent more time in the target quadrant and crossed the platform zone more number of times, 5 hours but not 24 hours after the last training session, during the probe trial session.
Exp Paradigm: NA
Description: Abnormal social novelty demonstrated by decreased time interacting with novel mouse
Exp Paradigm: Modified three-chambered social arena task with introduction of a novel social partner
Description: Shank3 (exon 4-9) ko mutant males exposed to the urine of an estrus female, in the of arena, mutant males exposed to the urine of an estrus female, in the of arena, have shorter distance travelled compared to controls
Exp Paradigm: NA
Description: In assessments made in neurocube, shank3(exon4-9) ko mutants have differences from controls in variability of paw position at p60
Exp Paradigm: Neurocube
Description: Decreased social interactions with tendency to participate in non-social self focused behaviors
Exp Paradigm: Dyadic test for social behavior
Ultrasonic vocalization: interaction induced: opposite sex stimulus2
Decreased
Description: Shank3 (exon 4-9) ko mutant males exposed to the urine of an estrus female, in the of arena, emitted fewer vocalizations compared to controls
Exp Paradigm: NA
Description: Abnormal ultrasonic vocalization: increased number of calls, decreased call pattern complexity, no change in call frequency across duration
Exp Paradigm: Male mice:
Description: Abnormal ultrasonic vocalization: decreased number of calls, decreased call pattern complexity, increased high frequency calls for shorter durations
Exp Paradigm: Female mice:
Description: Shank3 (exon 4-9) ko mutants displayed less exploration of the two chambers in the three chamber social approach test during the habituation phase
Exp Paradigm: NA
Description: Shank3 (exon 4-9) ko mutant males exposed to the urine of estrus female display increased anxiety as they spend less time in the center of the open field arena
Exp Paradigm: NA
Description: In the pfc of shank3 mutant mice with ablation of exons 4-9, -catenin at the synaptic membrane fraction was significantly reduced, compared to controls.
Exp Paradigm: NA
Description: In the pfc of shank3 mutant mice with ablation of exons 4-9, the level of -catenin in the nucleus was increased compared to controls.
Exp Paradigm: NA
Description: Actin signaling is significantly downregulated in the prefrontal cortex of shank3 het mice (ankyrin repeats deleted) determined by significant changes in expression profile from the cortical protein synaptic density (psd) fractions , in two dimensional fluorescence difference gel electrophoresis. significant reduction in p-cofilin (inactive cofilin) and limk1 were observed.
Exp Paradigm: Males only
Two-dimensional flourescence difference gel electrophoresis (2-dige)
Description: Mutants show reduced expression of cell surface glun1 compared to controls, in the striatum and thalamus. mutants show no change in the total expression of analyzed receptors.
Exp Paradigm: NA
Description: Myelin basic protein (MBP) was significantly upregulated at 1 week of age in Shank3 knockout mice in the corpus callosum and cortex, and there is a trend to increase (p=0.1) in the striatum at the same age.
Exp Paradigm: Myelin basic protein (MBP)
Description: Sciatic nerve tissue of Shank3 knockout mice stained with FluoroMyelin dye showed significantly increased staining intensity at 1 and 20 weeks of age, and a trend to increase (p=0.09) at 3 weeks of age.
Exp Paradigm: FluoroMyelin
Description: There was elongation of paranode and node length in the corpus callosum and cervical spinal cord at 3 and 20 weeks in Shank3 knockout mice (corpus callosum nodal length at 20 weeks p=0.10), but no significant difference was found in nodal and paranodal length in the sciatic nerve at those ages. Paranodal length was also increased in the cortex at 3 and 20 weeks, while nodal length was increased in the cortex at 20 weeks, but not 3 weeks. In the striatum, elongation was observed at 20 weeks in paranodal and nodal length, and no changes were observed at 3 weeks. Juxtaposition of potassium channel Kv1.2 and CASPR are required for proper node function. At 20-weeks the percent of Kv1.2 adjacent to CASPR was decreased in cortex, striatum, cervical spinal cord and
Exp Paradigm: CASPR, Kv1.2
Description: Mutants show reduced expression of cell surface glua2 compared to controls, in the striatum and thalamus. mutants show reduced expression of cell surface glua1 compared to controls, in the hippocampus and striatum. mutants show no change in the total expr
Exp Paradigm: NA
Description: Myelin basic protein (MBP) was significantly downregulated in the corpus callosum at 20 weeks of age in Shank3 knockout mice, with a trend of decrease (p=0.05) at 3 weeks of age. No change in MBP intensity was seen in the cortex or striatum at 3 or 20 weeks of age. MBP expression in the cervical spinal cord of 20-week old Shank3 knockout mice was significantly reduced.
Exp Paradigm: Myelin basic protein (MBP)
Description: Myelin protein zero (MPZ) was significantly downregulated at 1, 3 and 20 weeks of age in Shank3 knockout mice in the sciatic nerve.
Exp Paradigm: Myelin protein zero (MPZ)
Description: Ultrastructural analysis shows there is a significant increase of the g-ratio in the ventral cervical spinal cord of 20-week old Shank3 knockout mice, indicating a decrease in myelination since axon diameter is unchanged.
G-ratio measurement (axon diameters/fiber diameters of myelinated axons)
Description: Decreased bungarotoxin positive area in muscles indicating a decreased in acetylcholine receptor clusters at the neuromuscular junction
Exp Paradigm: Bungarotoxin
Description: There was a significant decrease in the volume of corpus callosum in both hemispheres in Shank3 knockout mice compared to wildtype mice. This decrease is driven by female mice at 4 weeks of age, and significant in both females and males at 9 weeks of age.
Description: Myelin basic protein (MBP) was significantly downregulated at 3 and 20 weeks in Shank3 KO knockout mice in the corpus callosum and cortex but not changed in the striatum. Immunostainings revealed an MBP reduction in the cervical spinal cord of 1 week and 20 weeks in Shank3 knockout mice but not at 3 weeks.
Exp Paradigm: Myelin basic protein (MBP)
Description: Myelin basic protein (MBP) was significantly upregulated in the sciatic nerve of 20-week old Shank3 knockout mice.
Exp Paradigm: Myelin basic protein (MBP)
Description: The number of CC1-positive cells in the corpus callosum, a marker for oligodendrocytes, was significantly reduced in at 3 and 20 weeks in Shank3 knockout mice, and there is a trend for decrease (p=0.10) at 1 week of age. Also, analysis of 2â?²,3â?²-cyclic-nucleotide 3â?²-phosphodiesterase (CNP) expression, a marker for immature and mature oligodendrocytes, showed a decrease in expression at 3 weeks but not at 20 weeks in the corpus callosum, cortex and striatum, suggesting maturation-dependent alterations.
Exp Paradigm: CC1, CNP
Description: Myelin basic protein (MBP) was significantly upregulated in the corpus callosum, cortex and striatum of 1-week old Shank3 knockout mice.
Exp Paradigm: Myelin basic protein (MBP)
Description: Ultrastructural analysis shows was a significant decrease of the g-ratio in the sciatic nerve of 20-week old Shank3 knockout mice, indicating an increase in myelination since axon diameter is unchanged.
G-ratio measurement (axon diameters/fiber diameters of myelinated axons)
Description: There was a reduction of the white matter observed from immunostaining brain slices against myelin basic protein (MBP) by measuring the thickness of the corpus callosum.
Exp Paradigm: Myelin basic protein (MBP); Measurements were taken from discrete mediolateral positions starting from the mid-line and moving laterally in intervals of 200 μm
Description: Brain tissue of Shank3 knockout mice stained with FluoroMyelin dye showed significantly reduced staining intensity in the cortex, and did not show a difference in staining intensity in the striatum. The ventral white matter of the cervical spinal cord of 20-week old Shank3 knockout mice was found to have decreased FluoroMyelin intensity.
Exp Paradigm: FluoroMyelin
Description: Myelin basic protein (MBP) was significantly upregulated at 1, 3 and 20 weeks of age in Shank3 knockout mice in the sciatic nerve.
Exp Paradigm: Myelin basic protein (MBP)
Description: There is a decrease in SHANK3 expression in the cervical spinal cord and sciatic nerve at 1, 3 and 20 weeks of age. In the spinal cord, there is a decrease SHANK3 protein colocalized with myelin basic protein (MBP) and neurofilament heavy chain (NFH), and in the sciatic nerve there is a decrease of SHANK3 protein colocalized with MBP, but not NFH.
Exp Paradigm: SHANK3, Myelin basic protein (MBP), Neurofilament Heavy Chain (NFH)
Description: Protein lysates of the corpus callosum of Shank3 knockout mice showed that Shank3 isoform e expression was increased at 1 week of age. Full-length (300 kDa) Shank3 showed a trend to increase (p=0.06) at 1 week of age.
Description: Protein lysates of the corpus callosum of Shank3 knockout mice showed that Shank3 isoform a and c/d expression was reduced at 1, 3 and 20 weeks of age. Full-length (300 kDa) Shank3 and isoform e expression was reduced at 20 weeks only. At 20 weeks of age, Shank3 knockout mice show decreased Shank3 isoform f expression in the cervical spinal cord, and decreased Shank3 300kDa, isoform a and e1 expression in the sciatic nerve.
Description: Decrease in somatic shank3 levels in motorneurons of the ventral horn of the spinal cord, in muscles, and neuromuscular junctions in newborns and adults
Exp Paradigm: Shank3
Description: Mutants sleep less and spend more time awake during the dark period compared with controls. mutants also show decrease in total time spent in nrem and rem sleep during the light and dark hours compared with controls.
Exp Paradigm: NA
Description: Mutants show decrease in bout number of rem sleep between 19 and 24 hours of the dark cycle compared with controls but no change in the bout number for nrem sleep.
Exp Paradigm: NA
Description: Mutants spent more time in wakefulness and less time in nrem and rem sleep near the end of the dark period after sleep deprivation compared with controls. mutants show no change in reduced wakefulness, increased time spent in nrem and rem sleep, and increase in sleep consolidation during the total recovery phase following sleep deprivation compared with controls. mutants show no change in nrem eeg delta power compared with controls, indicating that mutant mice accumulate similar sleep pressure post sleep deprivation. mutants show increase of nrem eeg spectral power compared with controls in the first 2hours post sleep deprivation in the higher frequencies (3.9-19.5 hz) compared with controls, indicating abnormal homeostatic response to sleep deprivation.
Exp Paradigm: Mutant and wt mice were sleep deprived for 5 hours.
Description: Mutants took longer to enter nrem sleep after sleep deprivation compared with controls.
Exp Paradigm: Mutant and wt mice were sleep deprived for 5 hours.
Description: Mutants show decrease in nrem and rem bout duration at the end of the dark cycle compared with controls at 19 to 24 hours.
Exp Paradigm: NA
Circadian rhythms: timing/phases of locomotor activity1
Decreased
Description: Mutants show decreased wheel turning activity in constant darkness compared with controls measured by the number of wheel revolutions, indicating abnormality in circadian rhythms. mutants show no change in length of the active phase or the time between the start of one active phase to the start of the subsequent active phase in constant darkness compared with controls. mutants show increase in wheel turning activity under 5 weeks of continuous light-dark cycles, compared with controls.
Exp Paradigm: Wheel-running was measured for 2 weeks under might-dark followed by 3 weeks in constant darkness; or 5 weeks of continuous light-dark cycles.
Description: Abnormal swing time, stance time, stride frequency, left pair gap and area, width and length of steps; male abnormality is greater than female
Description: Context re-exposure after 24 h was associated with reduced rearing time in Shank3 mutant mice, specifically in the presence of novel items with which to potentially engage.
Description: Shank3 mutant mice have increased levels of mglur5 in the synaptosomal and postsynaptic density fraction in the hippcampal lysates.
Exp Paradigm: NA
Event related oscillations (eros) in electroencephalography (eeg)1
Abnormal
Description: Mutants show decrease in delta frequencies (0.5-4 hz) and increase in alpha frequencies (10-15 hz) during nrem sleep compared with controls, resulting in significant change in spectral frequencies at 95% confidence interval.
Exp Paradigm: Nrem delta power is a measure of synchrony of the neural network and can be a measure of sleep intensity or depth.
Synaptic neuroreceptor ratio (nmdar/ampar) dependent transmission2
Decreased
Description: Synaptic transmission dependent on the nmdar/ampar ratio is reduced in shank3 mutants. it is determined using amplitude/frequency of miniature epscs that nmdar mediated currents are reduced
Exp Paradigm: Males only
Description: Approach-and retreat-related dopamine transients in tail-of-striatum were greatly elevated in Shank3 mutant mice compared with wildtype mice. Dopamine transients in tail-of-striatum in mutant mice exhibited pronounced approach-related variability and did not habituate as they did in wildtype mice upon repeated approaches of the object.
Exp Paradigm: Context re-exposure with novel object; optogenetic reporter construct in AAV vector injected into tail of striatum
Description: The input/output relationship of stimulus intensity to slope of fepsp is decreased in shank3 mutant mice, which may indicate a reduction in the number of functional ca3-ca1 synapses
Exp Paradigm: Males only
Miniature post synaptic current frequency: excitatory2
Decreased
Description: The frequencey of mepscs in hippocampal synapses in the shank3 mutant mice was signficantly reduced, indicatinga possible decrease in the number of ca3-ca1 synapses
Exp Paradigm: Males only
Description: Context re-exposure after 24 h was associated with protracted bouts of self-centered repetitive behaviors in Shank3 mutant mice, specifically in the presence of novel items with which to potentially engage.
Exp Paradigm: Context re-exposure
Description: Increased injurious self-grooming in approx. 20% of stock animals from the age of 3 months and in almost 70% of all breeding animals after the second litter was observed. Injured animals were excluded from all experiments.
Description: Shank3 mutant mice have a significantly reduced number of marbles buried in the marble burying test, compared to wild type controls
Exp Paradigm: Males and females
Description: Older shank3 mutant mice have increased levels of grooming in the number of bouts and time spent, in a novel environment (new cage)
Exp Paradigm: Males and females
Description: Excessive self-grooming in shank3 ko but not shank3 ht mice
Exp Paradigm: To monitor spontaneous self-grooming, mice were placed in a clean cage (identical to the home cage), with minimal bedding to discourage digging, which was then placed in a sound-proof box for video monitoring; animals were habituated in the new cage for 10 minutes before self-grooming was monitored during another 10 minutes; cumulative grooming time was reported for this second 10 minute period;
Description: Shank3 mutant mice show increased pain perception as the latency to lick their paw after a foot shock has been delivered is lower in these mice compared to wild type controls
Exp Paradigm: Males and females
Description: Shank3 mutant mice show significantly reduced nest building behavior, showing no change in their nestlets, whereas wild type controls readily made nests from the material.
Exp Paradigm: Males and females
Description: Social investigation reduced in shank3 ko but not shank3 ht mice
Exp Paradigm: Mice were tested for social motivation and social novelty in a three-chamber arena over three phases; in phase 1, identical inanimate objects (inverted ceramic cups with blue stripe) were placed in both side chambers; in phase 2, social interaction with a novel intruder is measured relative to a previously encountered object from phase 1; phase 3 tests for social novelty with a second intruder;
Description: Social approach of Shank3 mutant mice was greatly impaired at context re-exposure on the next day. Failure to interact upon context re-exposure in Shank3 mutant mice was observed to be context specific and long lasting with undiminished strength up to at least 1 month after initial exposure.
Exp Paradigm: Context re-exposure
Description: Shank3 mutant mice have reduced memory of a familiar stimulus mouse as they spend a similar amount of time interacting with the familiar and novel stimulus mice in the three chamber social approach test
Exp Paradigm: Males and females
Description: Increased avoidance behavior or decreased exploratory behavior present in both shank3 ko and ht mice
Exp Paradigm: Decreased marble-burying in both shank3 ko and ht mice
Description: Shank3 mutant mice showed increased time spent in open arms and increased number of entries into open arms compared to wildtype littermates on the first day, but exhibited decreased time spent in open arms and decreased entries into open arms on the second day of elevated plus maze exposure.
Description: Shank3 mutants show reduced response to novelty, unlike wild type controls, as they have reduced locomotor activity in the novel environment of the open field test
Exp Paradigm: Males and females
Description: Shank3 mutant mice show increased anxiety-like behavior in the light/dark box test as they have a very high latency to explore the dark box and spend very little tim in the dark box. authors have noted that this may be attributable to increase in avoidance behavior, rather in increase in anxiety.
Exp Paradigm: Males and females
Description: Novel object explorative behavior was reduced in Shank3 mutant mice in a familiar context after 24-hour context re-exposure.
Exp Paradigm: Context re-exposure
Description: Shank3 mutant mice show reduced spatial learning measured by latency to reach the hidden platform, in the morris water maze test. they take longer times to reach the platform compared to wild type controls
Exp Paradigm: Males and females
Description: Shank3 mutant mice show significantly reduced memory of the position of the platform, despite spending increased amount of time in the correct quadrant compared to other quadrants. number of crossings at the are significantly lower in shank3 mutants compared to wild type controls in both the probe trial and the probe trial of the reversal phase of morris water maze
Exp Paradigm: Males and females
Description: Mutants show upregulation of genes involved in cholesterol metabolism (hmgcr, insig1) and transcription (jun, fosl2, nfil3, stat4) under normal home cage conditions and upregulation of genes involved in potassium ion transport (kcnv1, kcnk1, kcnk2), dephosphorylation (dusp10, dusp3, and ptprj) and neuron projection development (cntn1, ntrk2, reln, and sema3a) under conditions of sleep deprivation, indicating sleep deprivation exacerbates baseline differences in gene expression.
Exp Paradigm: Mice were subjected to 5 hours of sleep deprivation. gene expression was quantified in the prefrontal cortex.
Description: Shank3 full length isoforms show a reduction of 85% in the synaptosomal and total fractions of frontal cortical lysates from homozygous knockout mice, compared to wild type
Exp Paradigm: NA
Description: Mutants show downregulation of genes involved in mapk signaling (mapk3, elk1), circadian rhythms (per3, tef, hlf) and transcription (tef, hlf) under normal homecage conditions and downregulation of genes involved in gnrh signaling (mapk1, elk1, mapk11), circadian rhythms (per3, nr1d1, tef, hlf, prkab2, bhlhe41) and sodium ion transport (slc6a15, slc22a4 and slc24a4) under sleep deprived condition, indicating sleep deprivation exacerbates baseline differences in gene expression.
Exp Paradigm: Mice were subjected to 5 hours of sleep deprivation. gene expression was quantified in the prefrontal cortex.
Description: Inreased clk2 protein in knockout mice neurons
Exp Paradigm: Primary cortical neurons were stimulated with bdnf (to elicit synaptic-plasticity dependent changes) on the 16th day in vitro and harvested in ripa buffer for sds-page and western blotting;
Description: Levesl of nr1 and nr2a are significantly reduced in the synaptosomal fraction of the frontal cortex from shank3 het mice
Exp Paradigm: Males only
Description: There is a reduction in spine density from purkinje cell dendrites in shank3 het mice, measured as number of spines per 10 micro meter on distal dendrites
Exp Paradigm: Males only
Synaptic neuroreceptor ratio (nmdar/ampar) dependent transmission1
Decreased
Description: Nmdar to ampar -epsc ratio is significantly reduced in layer v pyramidal neurons of shank3 het mice compared to wild type controls
Exp Paradigm: Males only
Description: Nmdar dependent excitatory synaptic transmission in layer v pyramidal neurons is significantly reduced in the prefrontal cortex (pfc) of shank3 het mice, compared to wild type.
Exp Paradigm: Males only
Description: Saline injected shank3-ex21-del mutant mice show reduced amplitudes of nmdar-epscs induced by a series of stimulus intensities compared to saline-injected wt mice.
Exp Paradigm: NA
Synaptic neuroreceptor ratio (nmdar/ampar) dependent transmission4
Decreased
Description: Saline injected shank3-ex21-del mutant mice show decreased nmdar- to ampar-epsc ratio compared to saline-injected wt mice.
Exp Paradigm: NA
Description: Increased avoidance behavior or decreased exploratory behavior present in both shank3 ko and ht mice
Exp Paradigm: Decreased marble-burying in both shank3 ko and ht mice
Description: Shank3 hets have significantly reduced learning of the conditioned response in eyeblink conditioning, compared to controls. the response amplitude of the eye-blink is also reduced
Exp Paradigm: Males only
Description: Shank3 hets have a reduced reponse amplitude as well in the conditioned response, the authors state that this magnitude reflects the neural representation of the learned response
Exp Paradigm: NA
Description: Similar to the decrease in f-actin in the pfc there is a reduction or loss of f actin in the hippocampus seen using phalloidin immunostaining
Exp Paradigm: Males only
Description: Shank3 mutants with ablated exon21 show increased protein levels of hdac2 in the nuclear fraction of the prefrontal cortex, compared to controls.
Exp Paradigm: NA
Description: Shank3 mutants with ablated exon21 show increased beta-catenin enrichment on the hdac2 promoter in the pfc, implicating beta-catenin in the upregulated transcription of hdac2.
Exp Paradigm: NA
Chromatin modification: histone modification: open chromatin4
Decreased
Description: Shank3 mutants with ablated exon21 show decreased global level of h3 acetylation in the frontal cortex than wild-type mice.
Exp Paradigm: 45 d post injection
Description: In the pfc of shank3 mutant mice with ablation of exon 21, the level of -catenin in the nucleus was increased compared to controls.
Exp Paradigm: NA
Description: Shank3 mutants with ablated exon21 show decrease of f-actin expression in pfc slices, indicating a loss of integrity of actin cytoskeleton at synapses.
Exp Paradigm: NA
Description: There is a significant reduction in protein phosphrylation levels, specifically for proteins involved in the rac1 signaling pathway, including pak1/2/3, limk and cofilin.
Exp Paradigm: Males only
Description: In the pfc of shank3 mutant mice with ablation of exon 21, the level of active (nonphosphorylated) -catenin in the cytosol were significantly elevated, compared to controls.
Exp Paradigm: NA
Description: Decrease in the inactive form of cofilin leads to decreased levels or loss of f actin determined by levels of f-actin in the synapse, even when total levels of actin in the synaptic cytosol were similar between shank3 hets and wild type controls (pfc lysate). this was confirmed using phalloidin immunostaining in pfc slices
Exp Paradigm: Males only-western blot: actin and f-actin levels
Description: In the pfc of shank3 mutant mice with ablation of exon 21, -catenin at the synaptic membrane fraction was significantly reduced, compared to controls.
Exp Paradigm: NA
Description: The activity of cofilin is increased following the reduction in phosphorylated (inactive) levels of cofilin as the rac1 signaling pathway is reduced
Exp Paradigm: Males only
Description: Shank3-ex21-del mutant mice show decreased protein levels of actin regulators beta-pix (arhgef7) and limk1 compared to controls.
Exp Paradigm: NA
Description: The rac1 signaling pathway is significantly downregulated in the prefrontal cortex of shank3 het mice determined by the reduced levels of activated (phosphorylated) downstream effectors and increased levels of inactivated (phosphorylated) target protein cofilin.
Exp Paradigm: Males only
Description: Decrease in the inactive form of cofilin leads to decreased levels or loss of f actin determined by levels of f-actin in the synapse, even when total levels of actin in the synaptic cytosol were similar between shank3 hets and wild type controls (pfc lysate). this was confirmed using phalloidin immunostaining in pfc slices
Exp Paradigm: Males only- immunostaining: phalloidin in pfc slices
Description: Saline-treated shank3 mutant mice with ablated exon 21 shows a change in expression in 365 genes with values of at least 1.2-fold (213 downregulated, 152 upregulated) compared to controls.
Exp Paradigm: NA
Description: Based on comaprison between synaptosomal and total lysate fractions from the frontal cortex, there is reduced targeting of nr1 and nr2a nmdar receptor subunits to the synapses in shank3 het mice frontal cortices
Exp Paradigm: Males only
Miniature post synaptic current frequency: excitatory1
Decreased
Description: The frequencey of mepscs in hippocampal synapses in the shank3 mutant mice was signficantly reduced, indicatinga possible decrease in the number ofca1 pyramidal neurons in the presence of tetradotoxin
Exp Paradigm: NA
Description: There is a decrease in the magnitude to post-tetanic potentiation in the first five minutes following the conditioning stimulus in the hippocampal slices from shank3g homozygous mice
Exp Paradigm: NA
Synaptic neuroreceptor ratio (nmdar/ampar) dependent transmission1
Decreased
Description: The ratio of nmdar to ampar mediated epscs is reduced in shank3g homozygous mice, authors indicated a reduction in nmda mediated component of epsc
Exp Paradigm: NA
Description: Shank3g homozygous mice show reduced marble-burying and the authors attribute this to increased novelty avoidance phenotype
Exp Paradigm: NA
Description: Shank3g homozygous mice show reduced nest building from nesting material and the authors characterize this as an increase in avoidance phenotype or response to novelty
Exp Paradigm: NA
Description: Shank3g mice show reduced response, determined by locomotor activity, compared to littermate wildtype controls in several tests when first introduced in the new environment of testing, like open field, elevated plus maze and light-dark exploration test
Exp Paradigm: Open field test
Description: Shank3g mice show reduced response, determined by locomotor activity, compared to littermate wildtype controls in several tests when first introduced in the new environment of testing, like open field, elevated plus maze and light-dark exploration test
Exp Paradigm: Light-dark exploration test
Description: Shank3g mice show reduced response, determined by locomotor activity, compared to littermate wildtype controls in several tests when first introduced in the new environment of testing, like open field, elevated plus maze and light-dark exploration test
Exp Paradigm: Elevated plus maze test
Description: Shank3g homozygous mice have reduced spatial learning in the morris water maze hidden platform task determined by distance travelled
Exp Paradigm: NA
Description: Shank3g het mice show reduced nest building from nesting material and the authors characterize this as an increase in avoidance phenotype or response to novelty
Exp Paradigm: NA
Synaptic neuroreceptor ratio (nmdar/ampar) dependent transmission1
Decreased
Description: Nmdar/ampar mediated synaptic transmission is reduced in the medium spiny neurons of the striatum in shank3 e4-9 hm mutants
Exp Paradigm: Males only
Description: Shank3 e4-9 hm mutants spend significantly increased time grooming compared to wt controls, authors note that the number of bouts was not different but the time spent in each bout was more
Exp Paradigm: NA
Description: Shank3 e4-9 hm mutants show reduced amount of time and number of instances of interaction in the reciprocal social interaction test requiring direct interaction with stimulus adult mouse
Exp Paradigm: NA
Description: Shank 3 e4-9 hm mutants show a significantly higher tendency for swimming close ot the walls in the morris water maze test compared to hets or wt controls
Exp Paradigm: NA
Description: Shank3 e4-9 hm mutants show a complete loss of the highest mol wt. band of shank3 protein in the striatal lysate, detected by both c and n terminal antibodies, loss of c-3, c7 and n-3 bands are also noted, hm mutants showing a loss of several isoforms of shank3
Exp Paradigm: NA
Description: Shank3 e4-9 hm mutants have decreased levels of glua2, glua3, homer 1b/c and psd95 in the synaptosomal fraction from the striatum
Exp Paradigm: NA
Synaptic neuroreceptor ratio (nmdar/ampar) dependent transmission1
Decreased
Description: Nmdar/ampar mediated synaptic transmission is reduced in the medium spiny neurons of the striatum in shank3 e4-9 het mutants
Exp Paradigm: Males only
Description: Shank3 e4-9 het mutants spend significantly increased time grooming compared to wt controls, authors note that the number of bouts was not different but the time spent in each bout was more
Exp Paradigm: NA
Description: Shank3 e4-9 het mutants have no preference for a familiar object moved to a new location, unlike wt controls indicating reduced reference memory in the object-place recognition test
Exp Paradigm: NA
Description: Shank3 e4-9 het mutants have reduced levels of highest molecular weight bands of shank 3 protein as expected in heterozygotes
Exp Paradigm: NA
Description: Shank3 insg hm mutants had reduced dendritic spine density in layer 2/3 pyramidal neurons in the 'frontal association area', compared to wt
Exp Paradigm: NA
Miniature post synaptic current amplitude: excitatory1
Increased
Description: At p14, shank3 insg hm mutants have increased amplitude of ampa mediated mepscs in the dorsolateral striatal msns from wt
Exp Paradigm: NA
Description: Shank3 insg have significantly impaired acoustic startle reflex and authors note that this complicated interpretation of ppi data
Exp Paradigm: NA
Description: Shank3 insg hm mutants show reduction in juvenile play with reduced nose-anogenital sniffing and following behavior compared to wt
Exp Paradigm: NA
Description: Shank3 insg hm mutants have decreased exploratory activity in an environment determined by the amount of distance traveled
Exp Paradigm: NA
Description: Shank3 insg hm mutants have increased anxiety-like behavior as they spend reduced time in center in the open field and in the open arms of the elevated zero maze
Exp Paradigm: Open field test
Description: Shank3 insg hm mutants have increased anxiety-like behavior as they spend reduced time in center in the open field and in the open arms of the elevated zero maze
Exp Paradigm: Elevated zero maze test
Description: Shank3 insg hm mice have decreased levels of homer 1b-c, psd 95 and 93 in the cortial synaptic membrane prep from adult mice
Exp Paradigm: NA
Description: Shank3 insg hm mutation results in loss of wt shank3 and even the expected 135 kda band of the truncated protein is also not detected in western blots, shank3 mrna levels are also severely reduced indicating possible degradation via the nonsense mediated decay
Exp Paradigm: Western blot: striatal lysate
Description: Shank3 insg hm mutation results in loss of wt shank3 and even the expected 135 kda band of the truncated protein is also not detected in western blots, shank3 mrna levels are also severely reduced indicating possible degradation via the nonsense mediated decay
Exp Paradigm: Quantitative pcr (qrt-pcr)
Description: Shank3 insg mutants have decreased levels of homer 1b-c and syngap1, sapap3 in the striatal synaptosomal plasma membrane prep
Exp Paradigm: NA
Description: Shank3 insg ht mutants have significantly reduced distance traveled compared to wt in the open field test indicating decrease in exploratory activity
Exp Paradigm: NA
Description: Shank3 r-x hm mutants had reduced dendritic spine density in layer 2/3 pyramidal neurons in the 'frontal association area', compared to wt
Exp Paradigm: NA
Miniature post synaptic current amplitude: excitatory1
Decreased
Description: Miniature epsc frequency and amplitude are both reduced shank3 r-x hm mutants (this mutation is reported in schizophrenia patients) in the pyramidal neurons of the prefrontal cortex
Exp Paradigm: NA
Miniature post synaptic current frequency: excitatory1
Decreased
Description: Miniature epsc frequency and amplitude are both reduced shank3 r-x hm mutants (this mutation isreported in schizophrenia patients) in the pyramidal neurons of the prefrontal cortex
Exp Paradigm: NA
Description: Shank3 r-x have significantly impaired acoustic startle reflex and authors note that this complicated interpretation of ppi data
Exp Paradigm: NA
Description: Shank3 r-x hm mutants have decreased exploratory activity in an environment determined by the amount of distance traveled
Exp Paradigm: NA
Description: Shank3 r-x hm mutants have increased anxiety-like behavior as they spend reduced time in center in the open field and in the open arms of the elevated zero maze
Exp Paradigm: Open field test
Description: Shank3 r-x hm mutants have increased anxiety-like behavior as they spend reduced time in center in the open field and in the open arms of the elevated zero maze
Exp Paradigm: Elevated zero maze test
Description: Shank3 r-x hm mutation results in the production of the 122kda truncated protein that is expected following the mutation, detected using a n term antibody, while the shank3 mrna is detected at a higher levels than in insg mutants
Exp Paradigm: Quantitative pcr (qrt-pcr)
Description: Shank3 r-x hm mutants have slight but significant decrease in homer protein in the cortical synaptic membrane preparation at p14
Exp Paradigm: NA
Description: Shank3 r-x hm mutants have decreased levels of homer 1b-c and syngap1, sapap3 in the striatal synaptosomal plasma membrane prep
Exp Paradigm: NA
Description: Shank3 r-x hm mutation results in the production of the 122kda truncated protein that is expected following the mutation, detected using a n term antibody, while the shank3 mrna is detected at a higher levels than in insg mutants
Exp Paradigm: Western blot: striatal lysate
Description: Shank3 r-x hm mice have decreased levels of homer 1b-c, psd 95 and 93 in the cortial synaptic membrane prep from adult mice
Exp Paradigm: NA
Miniature post synaptic current amplitude: excitatory1
Decreased
Description: Shank3 r-x ht mutants have small but significant decrease in the amplitude of ampar mediated mepscs in the dorsostriatal msns
Exp Paradigm: NA
Description: Shank3 r-x ht mutants show increased dominant behavior and propensity of winning in social confrontation in the tube test than wt
Exp Paradigm: NA
Description: Shank3 r-x ht mutants show decreased sociability and preference for social target compared to an object in the three chamber test
Exp Paradigm: NA
Description: Mutants show decrease in evoked epsc amplitudes on different levels of stimulation intensity in acc pyramidal neurons.
Exp Paradigm: Anterior cingulate cortex; pyramidal neurons
Description: Mutants show decrease in time spent investigating novel object and in the number of zone crossings in the four chambered task where one chamber had a familiar object and the other three had novel objects.
Exp Paradigm: NA
Description: Mutants show no expression of shank3 in the anterior cingulate cortex and the motor cortex.
Exp Paradigm: Anterior cingulate cortex; pyramidal neurons
Description: Mutants show decreased spine density in the medium spiny neurons of the striatum compared to controls.
Exp Paradigm: Used systemic viral injection to sparsely label neurons with green fluorescent protein.
Description: Mutants showed no difference in time spent with the stranger mouse or the novel object, in contrast to wildtype mice that spent more time with the stranger mouse than with the novel object.
Exp Paradigm: S129 males were used as stranger mice.
Description: Mutants show decreased expression of postsynaptic density proteins, sapap3, homer1b/c, nr2a, nr2b and glua2 in the striatum, compared to controls. mutants show decreased expression of glua1 in the cerebellum compared to controls.
Exp Paradigm: Western blots of striatal synaptosomal fractions of the striatum were performed.
Description: Mutants show decreased expression of shank3 in the striatum, cortex and cerebellum compared to controls.
Exp Paradigm: Western blots of striatal synaptosomal fractions of the striatum, cortex and cerebellum were performed.
Description: Increased grooming is observed after splashing in shank3 nulls (tested in shank3 null mice that did not develop lesions)
Exp Paradigm: Splashing test conducted in mice that did not show excessive self grooming behavior in home cage
Description: Shank3 mutant mice exhibited decreased expression of NR1, Synaptophysin, GAD1, VGAT, Homer, and PSD95 in the cortex and striatum compared to wildtype control mice.
Exp Paradigm: cortex, striatum
Description: Striatal msns have reduced spine density in shank3 null mice, combined with reduced frequency of sepscs, authors suggest a loss in excitatory synapses
Exp Paradigm: NA
Dti: fractional anisotropy or relative anisotropy in brain regions2
Decreased
Description: Areas exhibiting reduced fa include genu of the corpus callosum, vingulum, anterior commissure, fimbria, optic tract, nigrostriatal bundles, cerebral peduncles, cerebellum and brainstem
Exp Paradigm: NA
Description: Mglur5 levels are increased in the striatum in shank3 null mice including in the postsynaptic density
Exp Paradigm: Western blot: striatum
Description: Striatal msns have increased spikes in response to depolarizing steps of current in shank3 null mice indicating a tendency for hyper-excitability
Exp Paradigm: NA
Description: Shank3 mutant mice exhibited increased 3-Nitrotyrosine protein expression in the cortex and striatum compared to wildtype controls.
Exp Paradigm: cortex, striatum
Event related oscillations (eros) in electroencephalography (eeg)2
Decreased
Description: Reduced oscillatory power is noted in the nucleus accumbens in the 7-11 hz band of shank3 null mice both before and after being exposed ot a social stimulus
Exp Paradigm: NA
Description: After a hfs probability of presynaptic release did not increase significantly in shank3 null mice, unlike controls where hfs causes an increase in the probability of release
Exp Paradigm: NA
Description: Shank3 mutant male mice displayed decreased sociability, showing no preference for either the stranger mouse or empty cage, while wildtype male mice spent significantly more time interacting with the stranger mouse than with the empty cage. Shank3 mutant female mice displayed no preference for either the stranger mouse or the empty cage, similar to wildtype female controls.
Exp Paradigm: First session: mice encounter a stranger mouse (S) and an empty cage (E).
Description: No preference towards own home nest versus a similar one is observed in shank3 nulls, even if shank3 null pups perform similar to controls when only one nest sample is provided
Exp Paradigm: NA
Description: Shank3 mutant male mice displayed decreased social memory, showing no preference for either the novel or familiar mouse, while wildtype male mice spent significantly more time interacting with the novel mouse. Shank3 mutant female mice displayed no preference for either the novel mouse or the familiar mouse, similar to wildtype female controls.
Exp Paradigm: Second session: mice encounter the first intruder (S1) and a novel intruder (S2).
Description: Dominance was not maintained across days in triads containing 3 unfamiliar shank3 null adults, unlike in wild type triads where dominance ranking was established in a day and maintained till day 6
Exp Paradigm: NA
Description: Shank3 mutant male mice spent significantly less time in the open arms and more time in the closed arms compared to wildtype male controls. Female mice spent similar amounts of time in the open arms to wildtype female controls.
Description: Shank3 null mice have a high tendency to escape from any new environment and do not show normal exploratory activity
Exp Paradigm: Novel cage test
Description: Shank3 null mice have a high tendency to escape from any new environment and do not show normal exploratory activity
Exp Paradigm: Home cage behavior
Description: Shank3 null mice have increased latency to enter the lighted chamber than littermate and also try to escape from all new environments
Exp Paradigm: NA
Description: Shank3 null mice do not learn the task in which food pellet is 'earned' after lever-press in the 7 days of continuous reinforcement training, a striatal dependent task
Exp Paradigm: NA
Description: Wildtype male mice spent significantly more time exploring the novel object than the familiar object, whereas Shank3 mutant male mice did not exhibit any significant preference for the novel object over the familiar one.
Description: Homer2, homer 1b/c are reduced in the striatal and hippocampal synapses while sapap and sapap3 are reduced in the synapses only in the striatal synapses of shank3 null mice
Exp Paradigm: NA
Description: assessed Trpv4-mediated whole-cell currents from D1RMSNs and observed an increase only in LPS-challenged Shank3+/- mice
Exp Paradigm: crossed Shank3+/- with Drd1a-tdTomato mice
Description: increased density of cFos positive neurons in the nucleus accumbens 24h after LPS injection
Exp Paradigm: crossed Shank3+/- with Drd1a-tdTomato mice; cFos staining
Description: LPS challenge in Shank3+/- mice caused hyperexcitability in D1R-MSNs and not in putative D2R-MSNs
Exp Paradigm: crossed Shank3+/- with Drd1a-tdTomato mice
Description: Shank3 het mice spent a comparable amount of time around the juvenile and object stimulus when injectd with LPS 24 hrs prior to task.
Exp Paradigm: LPS was injected 24h prior to test
Description: LPS did not affect the activity of Shank3+/+ neurons in the nucleus accumbens; Shank3+/- mice did not show the peak of normalized Î?F/F upon entering in juvenile proximity and, indeed, presented a similar mean z-score Î?F/F between juvenile and object stimuli
Exp Paradigm: unilaterally injected a GCamp7sexpressing virus (ssAAV5/2-hSyn1-chl-jGCamp7s-WPRE-SV40p(A)) into the nucleus accumbens; record somatic Ca2+ transients; 24hrs after LPS injection
Description: LPS injections increased the inflammatory markers IL-1b and TNF-alpha expression 24h after LPS injection in both Shank3 WT and Shank3 het mice, the observed increase in Trpv4 was only seen in Shank3 het mice and not detectable 7 days after LPS challenge
Exp Paradigm: 24hrs after LPS injection
Description: Striatal msns have significantly reduced spiking frequency in mutants with shank3 knocked out in the nac, compared to controls, indicating that the loss of shank3 locally and specifically in the nac causes the reduction in spiking, similar to what is observed in the complete ko
Exp Paradigm: NA
Description: Shank3 hets have reduced discrimination and memory for objects differing in texture (rough or smooth) and do not preferentially interact with a novel textured-object over a familiar one
Exp Paradigm: NA
Description: Tactile prepulse inhibition responses are enhanced in shank3 het mice, as opposed to control littermates that display reduced magnitude of acoustic startle response when they receive an air puff prepulse
Exp Paradigm: NA
Description: Shank3 het mice have reduced preference for novel object when the retention period (or interval) is extended to 1 hr from 5 min, whereas wt mice still prefer the novel object
Exp Paradigm: NA
Description: Shank3 ko's have reduced social recognition memory as do not show a decrease in interaction time with a familiar juvenile mouse
Exp Paradigm: NA
Description: Shank3 hets have reduced social recognition memory as do not show a decrease in interaction time with a familiar juvenile mouse
Exp Paradigm: NA
Description: Shank3 het females show decreased rearing behavior in their home cage, authors note this as a sign of exploratory behavior
Exp Paradigm: NA
Description: Male shank3 mutant mice treated with l. reuteri show a robust increase in the hippocampal expression of gabra2 and gabrb1, and a modest decrease in hippocampal gabra1, compared to untreated mutants. male shank3 mutant mice treated with l. reuteri show increase in gabra2, gabrb1, and gabra1, compared to untreated mutants, in the prefrontal cortex. female shank3 mutant mice treated with l. reuteri show an increase in gabra1, gabra2, and gabrb1 gene expression in the hippocampus, and an in increase in gabra1 and gabra2 expression in the prefrontal cortex compared to untreated mutants. wildtype male mice treated with l. reuteri show no changes in gaba receptor gene expression levels in the hippocampus compared to untreated controls.
Exp Paradigm: NA
Description: Shank3 mutants treated with l. reuteri show increased in gabra1 protein levels in the frontal cortex in males and females, and an increase in the hippocampus in female mutants, compared to untreated controls.
Exp Paradigm: NA
Description: Shank3 mutants treated with l. reuteri buried fewer marbles than untreated mutants. wildtype mice treated with l.reuteri show no change in marble burying.
Exp Paradigm: NA
Description: Male shank3 mutants treated with l. reuteri showed no preference for the empty or occupied chamber compared to untreated mutants that showed preference for the empty chamber. male shank3 mutants treated with l. reuteri spent more time investigating the compartment with the unfamiliar mouse compared to untreated mutants. l.reuteri treatment on wildtype mice showed no change in social behaviors.
Exp Paradigm: NA
Description: Female shank3 mutant mice treated with l. reuteri showed no change in preference for empty and occupied compartments compared to untreated mutants. l.reuteri treatment on wildtype mice showed no change in social behaviors.
Exp Paradigm: NA
Description: Shank3 mutants treated with l. reuteri spent more time in the open arms of the elevated plus maze compared to untreated mutants. wildtype mice treated with l. reuteri show no change in anxiety.
Exp Paradigm: NA
Description: Shank3 mutants treated with l. reuteri spent more time in the center of the open field compared to untreated mutants. wildtype mice treated with l. reuteri show no change in anxiety.
Exp Paradigm: NA
Description: Shank3 mutant mice treated with l. reuteri show normal levels of il-1b, tnf-alpha, ifn-gamma and il-6, compared to untreated mutants.
Exp Paradigm: NA
Description: Male shank3 mutants treated with l. reuteri show increased expression of oxytocin gene in the hypothalamus compared to untreated controls.
Exp Paradigm: NA
Description: Female shank3 mutants treated with l. reuteri show decreased expression of oxytocin gene in the hypothalamus compared to untreated controls.
Exp Paradigm: NA
Description: Mutants show decrease in dendritic spine densities of medium spiny neurons in the dorsal striatum compared with controls.
Exp Paradigm: NA
Description: Mutants show decrease in abi1 and wave protein abundance in the striatal post synaptic density fraction compared with controls.
Exp Paradigm: NA
Description: Shank3-sirna injected mice show decrease in time spent with an unfamiliar object over a familiar object compared with controls.
Exp Paradigm: NA
Description: Shank3-sirna injected mice show decrease in shank3 transcript in the dorsal striatum, 2 days after injection.
Exp Paradigm: Striatal tissue was used for qrt pcr.
Description: Mutants show decrease in mushroom shaped spines in the anterior cingulate cortex.
Exp Paradigm: Anterior cingulate cortex; pyramidal neurons; adeno-associated virus (aav) 9-hsyn-egfp-p2a-egfpf (enhanced green fluorescent protein farnesylated) or local injections of semliki forest virus (sfv) was injected retro-orbitally to sparsely label neurons with green fluorescent protein (gfp)
Description: Mutants show decrease in total, apical and basal dendritic spines in anterior cingulate cortex pyramidal neurons.
Exp Paradigm: Anterior cingulate cortex; pyramidal neurons; adeno-associated virus (aav) 9-hsyn-egfp-p2a-egfpf (enhanced green fluorescent protein farnesylated) or local injections of semliki forest virus (sfv) was injected retro-orbitally to sparsely label neurons with green fluorescent protein (gfp)
Description: Mutants show decrease in the lengths and depths of postsynaptic densities in pyramidal neurons of the anterior cingulate cortex.
Exp Paradigm: Anterior cingulate cortex; pyramidal neurons
Dendritic architecture: dendritic tree complexity1
Decreased
Description: Mutants show decrease in dendritic branching in basal dendrites in the pyramidal neurons of the anterior cingulate cortex.
Exp Paradigm: Anterior cingulate cortex; pyramidal neurons; adeno-associated virus (aav) 9-hsyn-egfp-p2a-egfpf (enhanced green fluorescent protein farnesylated) or local injections of semliki forest virus (sfv) was injected retro-orbitally to sparsely label neurons with green fluorescent protein (gfp)
Description: Mutants require higher presynaptic stimulation intensity to generate a spike from epsps in acc pyramidal neurons, resulting in their hypoactivity.
Exp Paradigm: Anterior cingulate cortex; pyramidal neurons
Description: Mutants show no ltp following paired training paradigm in pyramidal neurons of anterior cingulate cortex.
Exp Paradigm: Anterior cingulate cortex; pyramidal neurons
Neuronal activation: non-familiar social interaction1
Decreased
Description: Mutants show decrease in neuronal activity in pyramidal neurons of the anterior cingulate cortex when they approach unfamiliar mice.
Exp Paradigm: Anterior cingulate cortex; pyramidal neurons
Description: Mutants spent less time in investigating an object and show fewer zone crossings in the four chamber novel object task where three chambers contain novel objects and one chamber contains a familiar object.
Exp Paradigm: NA
Description: Mutants exhibited hairy skin hypersensitivity, measured by an increase of tactile prepulse inhibition of an acoustic startle response assay.
Exp Paradigm: NA
Description: Mutants show lower percent decrease in startle response to a 125 db noise during a 30-minute tactile ppi session, when comparing the first five startle responses to the last five responses to a 125 db noise for mutant mice and their control littermates, indicating lack of habituation to an acoustic startle noise.
Exp Paradigm: NA
Morphology of the spinal cord: sensory and motor tracts1
Decreased
Description: Mutants show decrease in hcn1 expression at spinal cord dorsal horn lamina iii/iv in vglut1+ presynaptic terminals, in large but not small diameter drg cell bodies.
Exp Paradigm: Spinal cord
Description: Mutants show decrease in number of parvalbumin positive interneurons in primary somatosensory cortex, but not primary visual cortex. mutants show decrease in number of parvalbumin positive interneurons in the basolateral amygdala.
Exp Paradigm: Primary somatosensory cortex, primary visual cortex, basolateral amygdala
Spontaneous post synaptic event frequency: inhibitory currents1
Increased
Description: Mutants show increase in spontaneous inhibitory postsynaptic current (sipsc) frequency in layer 2/3 pyramidal neurons from acute primary somatosensory cortex slices resulting in a decrease in e/i ratio in the primary somatosensory cortex. mutants show no change in spontaneous inhibitory postsynaptic current (sipsc) frequency in the visual cortex.
Exp Paradigm: Primary somatosensory cortex, visual cortex
Spontaneous post synaptic event amplitude: inhibitory currents1
Decreased
Description: Mutants show decrease in spontaneous inhibitory postsynaptic current (sipsc) amplitude in layer 2/3 pyramidal neurons from acute primary somatosensory cortex slices resulting in a decrease in e/i ratio in the primary somatosensory cortex. mutants show no change in spontaneous inhibitory postsynaptic current (sipsc) amplitude in the visual cortex.
Exp Paradigm: Primary somatosensory cortex, visual cortex
Spontaneous post synaptic event amplitude: excitatory currents1
Decreased
Description: Mutants show decrease in spontaneous excitatory postsynaptic current (sepsc) amplitude in layer 2/3 pyramidal neurons from acute primary somatosensory cortex slices resulting in a decrease in e/i ratio in the primary somatosensory cortex. mutants show no change in spontaneous excitatory postsynaptic current (sepsc) amplitude in the visual cortex.
Exp Paradigm: Primary somatosensory cortex, visual cortex
Description: Mutants exhibited hairy skin hypersensitivity, measured by an increase of tactile prepulse inhibition of an acoustic startle response assay.
Exp Paradigm: NA
Description: Mutants show lower percent decrease in startle response to a 125 db noise during a 30-minute tactile ppi session, when comparing the first five startle responses to the last five responses to a 125 db noise for mutant mice and their control littermates, indicating lack of habituation to an acoustic startle noise.
Exp Paradigm: NA
Morphology of the spinal cord: sensory and motor tracts1
Decreased
Description: Mutants show decrease in hcn1 expression at spinal cord dorsal horn lamina iii/iv in vglut1+ presynaptic terminals, in large but not small diameter drg cell bodies.
Exp Paradigm: Spinal cord
Description: Mutants exhibited hairy skin hypersensitivity, measured by an increase of tactile prepulse inhibition of an acoustic startle response assay.
Exp Paradigm: NA
Description: Mutants show lower percent decrease in startle response to a 125 db noise during a 30-minute tactile ppi session, when comparing the first five startle responses to the last five responses to a 125 db noise for mutant mice and their control littermates, indicating lack of habituation to an acoustic startle noise.
Exp Paradigm: NA
Morphology of the spinal cord: sensory and motor tracts1
Decreased
Description: Mutants show decrease in hcn1 expression at spinal cord dorsal horn lamina iii/iv in vglut1+ presynaptic terminals, in large but not small diameter drg cell bodies.
Exp Paradigm: Spinal cord
Description: Mutants show increased input resistance, and increased excitability with no change in capacitance or cell body size of recorded large diameter drg neurons. small diameter neurons showed modest reduction in excitability.
Exp Paradigm: Spinal cord
Description: Mutants show decreased hyperpolarizing currents elicited during a hyperpolarizing voltage step protocol in large diameter drg neurons but not small diameter drg neurons.
Exp Paradigm: Spinal cord
Description: Mutants show decrease in excitatory to inhibitory ratio in primary somatosensory cortex slices.
Exp Paradigm: Primary somatosensory cortex
Description: Mutants exhibited hairy skin hypersensitivity, measured by an increase of tactile prepulse inhibition of an acoustic startle response assay.
Exp Paradigm: NA
Description: Mutants show narrowed or crusted eyes, piloerection and a hunched posture.
Exp Paradigm: A score of 0 indicated a clean shiny coat, clear eyes and normal stance. a score of 1 indicated the appearance of dull eyes, dull/ungroomed coat and somewhat hunched stance. a score of 2 denoted narrowed or crusted eyes, piloerection and a hunched posture. a score of 3 indicated severe eye narrowing, profound piloerection or loss of fur, and severely hunched posture.
Description: Mutants show lower percent decrease in startle response to a 125 db noise during a 30-minute tactile ppi session, when comparing the first five startle responses to the last five responses to a 125 db noise for mutant mice and their control littermates, indicating lack of habituation to an acoustic startle noise.
Exp Paradigm: NA
Description: Mutants show decrease in the number of parvalbumin positive interneurons in the primary somatosensory cortex, primary visual cortex and basolateral amygdala.
Exp Paradigm: Primary somatosensory cortex, primary visual cortex, basolateral amygdala
Description: Mutants exhibited hairy skin hypersensitivity, measured by an increase of tactile prepulse inhibition of an acoustic startle response assay.
Exp Paradigm: NA
Description: Mutants show lower percent decrease in startle response to a 125 db noise during a 30-minute tactile ppi session, when comparing the first five startle responses to the last five responses to a 125 db noise for mutant mice and their control littermates, indicating lack of habituation to an acoustic startle noise.
Exp Paradigm: NA
Description: Mutants show no expression of shank3 in the in glut1 positive neurons in the spinal cord dorsal horn lamina iii/iv.
Exp Paradigm: Spinal cord
Morphology of the spinal cord: sensory and motor tracts1
Decreased
Description: Mutants show decrease in hcn1 expression at spinal cord dorsal horn lamina iii/iv in vglut1+ presynaptic terminals, in large but not small diameter drg cell bodies.
Exp Paradigm: Spinal cord
Description: Mutants show decrease in number of parvalbumin positive interneurons in primary somatosensory cortex, but not primary visual cortex. mutants show decrease in number of parvalbumin positive interneurons in the basolateral amygdala.
Exp Paradigm: NA
Description: Mutants exhibited hairy skin hypersensitivity, measured by an increase of tactile prepulse inhibition of an acoustic startle response assay.
Exp Paradigm: NA
Description: Mutants show lower percent decrease in startle response to a 125 db noise during a 30-minute tactile ppi session, when comparing the first five startle responses to the last five responses to a 125 db noise for mutant mice and their control littermates, indicating lack of habituation to an acoustic startle noise.
Exp Paradigm: NA
Description: Mutants show decrease in number of parvalbumin positive interneurons in primary somatosensory cortex, but not primary visual cortex. mutants show increase in number of parvalbumin positive interneurons in the basolateral amygdala.
Exp Paradigm: NA
Description: Mutants exhibited hairy skin hypersensitivity, measured by an increase of tactile prepulse inhibition of an acoustic startle response assay.
Exp Paradigm: NA
Description: Mutants show lower percent decrease in startle response to a 125 db noise during a 30-minute tactile ppi session, when comparing the first five startle responses to the last five responses to a 125 db noise for mutant mice and their control littermates, indicating lack of habituation to an acoustic startle noise.
Exp Paradigm: NA
Description: Mutants show decrease in number of parvalbumin positive interneurons in primary somatosensory cortex, but not primary visual cortex or in the basolateral amygdala.
Exp Paradigm: NA
Description: Mutants exhibited hairy skin hypersensitivity, measured by an increase of tactile prepulse inhibition of an acoustic startle response assay.
Exp Paradigm: NA
Description: Mutants show lower percent decrease in startle response to a 125 db noise during a 30-minute tactile ppi session, when comparing the first five startle responses to the last five responses to a 125 db noise for mutant mice and their control littermates, indicating lack of habituation to an acoustic startle noise.
Exp Paradigm: NA
Description: Shank3 downregulation increased the excitability of D1R-tom(+) compared to scrShank3::D1R-tom(+) MSNs, no changes were detected in the D1R-tom(-) population
Exp Paradigm: P6 AAV-shShank3-luczsGreen injected to nucleus accumbens of Drd1a-tdTomato mice; recorded in presence of synaptic blockers picrotoxin and kynurenic acid
Description: Shank3 downregulation induced a hyperexcitability of D1R-tom(+) MSNs and hypo-excitability of D1R-tom(-) MSNs
Exp Paradigm: P6 AAV-shShank3-luczsGreen injected to nucleus accumbens of Drd1a-tdTomato mice; absence of synaptic blockers
Description: shShank3 P6-injected mice spent a comparable amount of time around the juvenile and object stimulus, while scrShank3 mice showed preference for a juvenile conspecific
Exp Paradigm: P6 AAV-shShank3-luczsGreen injected to nucleus accumbens of WT mice
Description: shShank3 P6-injected mice spent a comparable amount of time around the juvenile and object stimulus, while scrShank3 mice showed preference for a juvenile conspecific
Exp Paradigm: P6 AAV-shShank3-luczsGreen injected to nucleus accumbens of WT mice
Description: decrease in Shank3 gene and protein expression in the nucleus accumbens
Exp Paradigm: P6 AAV-shShank3-luczsGreen injected to nucleus accumbens of WT mice
Description: 7-NI treated Shank3 mutant mice exhibited increased expression of NR1, Synaptophysin, GAD1, VGAT, Homer, and PSD95 in both the cortex and striatum compared to untreated mutant mice.
Exp Paradigm: cortex, striatum
Description: 7-NI treated Shank3 mutant mice exhibited a decrease of the elevated levels of 3-Nitrotyrosine in both the cortex and the striatum.
Exp Paradigm: cortex, striatum
Description: 7-NI treated Shank3 mutant male mice spent significantly more time interacting with the novel mouse than with the familiar mouse.
Exp Paradigm: Second session: mice encounter the first intruder (S1) and a novel intruder (S2).
Description: 7-NI treated Shank3 mutant male mice spent significantly more time interacting with the stranger mouse than with the empty cage.
Exp Paradigm: First session: mice encounter a stranger mouse (S) and an empty cage (E).
Description: 7-NI treated Shank3 mutant male mice spent significantly more time in the open arms and less time in the closed arms than untreated Shank3 mutant male mice; results were comparable to wildtype male controls.
Description: 7-NI treated Shank3 mutant mice exhibited a decrease of cyclic guanosine monophosphate (cGMP) in the cortex compared to untreated mutant mice.
Exp Paradigm: cortex
