Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3
Open accessAbstract
SHANK3 is a synaptic scaffolding protein enriched in the postsynaptic density (PSD) of excitatory synapses. Small microdeletions and point mutations in SHANK3 have been identified in a small subgroup of individuals with autism spectrum disorder (ASD) and intellectual disability. SHANK3 also plays a key role in the chromosome 22q13.3 microdeletion syndrome (Phelan-McDermid syndrome), which includes ASD and cognitive dysfunction as major clinical features. To evaluate the role of Shank3 in vivo, we disrupted major isoforms of the gene in mice by deleting exons 4-9. Isoform-specific Shank3(e4-9) homozygous mutant mice display abnormal social behaviors, communication patterns, repetitive behaviors and learning and memory. Shank3(e4-9) male mice display more severe impairments than females in motor coordination. Shank3(e4-9) mice have reduced levels of Homer1b/c, GKAP and GluA1 at the PSD, and show attenuated activity-dependent redistribution of GluA1-containing AMPA receptors. Subtle morphological alterations in dendritic spines are also observed. Although synaptic transmission is normal in CA1 hippocampus, long-term potentiation is deficient in Shank3(e4-9) mice. We conclude that loss of major Shank3 species produces biochemical, cellular and morphological changes, leading to behavioral abnormalities in mice that bear similarities to human ASD patients with SHANK3 mutations.
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Deletion of Shank3 has been reported to inhibit LTP.
“Deletion of Shank3 has been reported to inhibit LTP (164–166).”
From Synaptic memory and CaMKII (2023) · cites this paper as [166]
Selected mRNA isoforms analyzed in silico indicate that each Shank3 isoform (Shank3a-f) has a unique combination of protein domains.
“The exact number of protein isoforms has not been determined, but selected mRNA isoforms analyzed in silico indicate that each Shank3 isoform (Shank3a-f) has a unique combination of different protein domains as illustrated in Figure 2B (Wang et al., 2011).”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Wang et al., 2011
Available evidence indicates that the overall transcriptional structure of SHANK family genes is conserved in mice.
“Together, the available evidence indicates that the overall transcriptional structure of SHANK family genes is conserved in mice (Wang et al., 2011).”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Wang et al., 2011
Spine density is decreased in striatum of Δex13-16−/− mice and in CA1 hippocampus of Δex4-9J−/− mice.
“spine density was decreased in the striatum and CA1 hippocampus of Δex13-16−/− and Δex4-9J−/− mice, respectively.”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Wang et al., 2011
Δex4-9J deletion disrupts mRNA transcripts from promoters 1 and 2 (Shank3a and Shank3b) but not Shank3c-f.
“The Δex4-9J deletion disrupted mRNA transcripts from promoters 1 and 2 (Shank3a and Shank3b) but not Shank3c-f as confirmed by isoform-specific RT-PCR analysis (Wang et al., 2011).”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Wang et al., 2011
Each of these Shank3 mutant lines is expected to disrupt different Shank3 isoforms.
“Based on current knowledge of Shank3 promoters and alternative splicing, each of these mice is expected to have disruption of different Shank3 isoforms (Wang et al., 2011)”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Wang et al., 2011
Spine length is increased in CA1 hippocampus of Δex4-9J−/− mice.
“Spine length was increased in CA1 hippocampus of Δex4-9J−/− mice (Wang et al., 2011)”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Wang et al., 2011
PSD thickness and length are not decreased in hippocampal CA1 synapses of ex4-9J−/− mice or Δex11−/− mice.
“but not in the hippocampal CA1 synapses in ex4-9J−/− mice (Wang et al., 2011) or Δex11−/− mice (Schmeisser et al., 2012).”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Wang et al., 2011
GluN2A is reduced in hippocampus of Δex4-9J−/− mice.
“In the case of NMDA receptors, GluN2A subunit was reduced in the hippocampus of Δex4-9J−/− mice (Wang et al., 2011).”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Wang et al., 2011
Δex4-9J mice show an unexpected mRNA splice isoform from exon 2 to exon 10, in addition to the expected exon 3 to 10.
“One unexpected finding from RNA expression analysis of Δex4-9J mice was the presence of an mRNA splice isoform from exon 2 to exon 10, in addition to the expected splicing isoform from exon 3 to exon 10 due to the deletion of exons 4-9 (Wang et al., 2011).”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Wang et al., 2011
Homer1b/c and GKAP1/SAPAP1 are reduced in PSD fraction but not cytosolic fraction of Δex4-9J−/− hippocampus.
“Homer1b/c and GKAP1/SAPAP1 were reduced in the PSD fraction but not in the cytosolic fraction of Δex4-9J−/− hippocampus (Wang et al., 2011).”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Wang et al., 2011
Isoform-specific disruption of Shank3 was evident in Δex4-7, Δex4-9J, Δex11, and Δex13-16 mice.
“Isoform-specific disruption of Shank3 was evident in Δex4-7, Δex4-9J, Δex11, and Δex13-16 mice (Peca et al., 2011; Schmeisser et al., 2012; Wang et al., 2011).”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Wang et al., 2011
Cryptic splicing from exon 2 to 10 in Δex4-9J−/− mice occurs in brain but not kidney.
“Intriguingly, this cryptic splicing from exon 2 to 10 occurred only in brain but not in kidney of Δex4-9J−/− mice.”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Wang et al., 2011
GluA1 is reduced in hippocampal neurons in culture and hippocampal tissues from Δex4-9J−/− and Δex4-9B+/− mice.
“The AMPA receptor subunit GluA1 was reduced in hippocampal neurons examined in culture and hippocampal tissues from Δex4-9J−/− (Wang et al., 2011) and Δex4-9B+/− mice (Bozdagi et al., 2010)”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Wang et al., 2011
Reduction of spine density in Δex4-9J−/− mice is developmental stage-specific, with significant loss at 4 weeks but not 10 weeks.
“The reduction of spine density visualized by Golgi impregnation was developmental stage-specific in Δex4-9J−/− mice, with significant spine loss observed at 4 weeks but not at 10 weeks of age (Wang et al., 2011).”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Wang et al., 2011
Impaired performance in Morris water maze is seen in Δex4-9J−/− mice but not in Δex13-16−/− and Δex4-9B−/− animals.
“Impaired performance in the Morris water maze task was seen in Δex4-9J−/− mice (Wang et al., 2011) but not in Δex13-16−/− (Peca et al., 2011) and Δex4-9B−/− animals (Yang et al., 2012).”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Wang et al., 2011
A naturally occurring Disc1 mutation in the 129 strain was segregated from the Δex4-9J−/− deletion but was not reported in other Shank3 mutant mice using 129 ES cells.
“A naturally occurring Disc1 (Disrupted in schizophrenia) mutation in the 129 strain of ES cells (Clapcote et al., 2007; Clapcote and Roder, 2006) was segregated from the Δex4-9J−/− deletion (Wang et al., 2011) but was not reported in other Shank3 mutant mice using mouse 129 ES cells (Peca et al., 2011; Schmeisser et al., 2012).”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Wang et al., 2011
Short-term and long-term memory in a social transmission test are impaired in Δex4-9J−/− mice.
“Short-term and long-term memory in a social transmission test were impaired in Δex4-9J−/− mice (Wang et al., 2011).”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Wang et al., 2011
Repetitive behaviors measured by increased self-grooming and behavioral inflexibility in reverse Morris water maze were observed in Δex4-9J−/− and Δex4-9B−/− mice.
“Repetitive behaviors measured by increased self-grooming in the home cage and behavioral inflexibility in the reverse Morris water maze were observed in Δex4-9J−/− (Wang et al., 2011) and Δex4-9B−/− mice”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Wang et al., 2011
Number, frequency, and duration of ultrasonic vocalizations are altered in a sex-specific manner in Δex4-9J−/− mice.
“The number, frequency, and duration of ultrasonic vocalizations were altered in a sex-specific manner in Δex4-9J−/− mice (Wang et al., 2011).”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Wang et al., 2011
Reduced social interaction and affiliation behaviors are the most notable and consistent observation in Shank3 mutant mice.
“The most notable and consistent observation was reduced social interaction and affiliation behaviors using different testing methods”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Wang et al., 2011
Synaptic transmission is reduced at hippocampal CA1 synapses of Δex4-9B+/− and Δex4-9B−/− mice, but not in Δex4-9J−/− or Δex13-16−/− mice.
“synaptic transmission is reduced at hippocampal CA1 synapses of Δex4-9B+/− (Bozdagi et al., 2010) and Δex4-9B−/− (Yang et al., 2012), but not in Δex4-9J−/− (Wang et al., 2011) or Δex13-16−/− mice (Peca et al., 2011)”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Wang et al., 2011
Prepulse inhibition is not affected in Δex4-9J−/− and Δex4-9B−/− mice.
“Prepulse inhibition (PPI) is not affected in Δex4-9J−/− (Wang et al., 2011) and Δex4-9B−/− (Yang et al., 2012) mice”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Wang et al., 2011
Hippocampal LTP is reduced at CA1 synapses of Δex4-9J−/− and Δex4-9B mice.
“Hippocampal LTP was reduced at CA1 synapses of Δex4-9J−/− and Δex4-9B but not examined in Δex11−/− and Δex13-16−/− animals”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Wang et al., 2011
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References 61 · Cited by 537
- Authors
- Wang, X., McCoy, P. A., Rodriguiz, R. M., Pan, Y., Je, H. S., Roberts, A. C., Kim, C. J., Berrios, J., Colvin, J. S., Bousquet-Moore, D., Lorenzo, I., Wu, G., Weinberg, R. J., Ehlers, M. D., Philpot, B. D., Beaudet, A. L., Wetsel, W. C., & Jiang, Y.-H.
- Affiliations
- Duke University (US)
- Baylor College of Medicine (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Jiang, Yong-hui
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-05-10
- Volume
- 20
- Issue
- 15
- Pages
- 3093-3108
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC3131048
- OpenAlex
- W2119535735
- Semantic Scholar
- c6eea75d576121a03f5002ca4a226b43b2fe6aa0
- Cited by
- 537
- References
- 61
- Citations by year
- 2026: 14 · 2025: 25 · 2024: 28 · 2023: 36 · 2022: 35 · 2021: 39 · 2020: 42 · 2019: 35 · 2018: 40 · 2017: 36 · 2016: 47 · 2015: 47 · 2014: 37 · 2013: 32 · 2012: 37
- FWCI
- 22.35
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Human Molecular Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- National University of Singapore (submittedVersion)
- UNC Libraries
- Funders
- Autism Speaks
- Simons Foundation
- Angelman Syndrome Foundation
- North Carolina Biotechnology Center
- National Institutes of Health
- National Institute of Mental Health (U19MH082441, T32MH019109, MH019109, MH082441, R01MH098114)
- National Eye Institute (R01EY018323)
- National Institute of Neurological Disorders and Stroke (R01NS039444, NS039444)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32-HD-40127, 5K12-HD0043494-08, K12HD043494, T32HD040127)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- SHANK3, autism spectrum disorder, Phelan-McDermid syndrome, synaptic scaffolding proteins, postsynaptic density, social behavior, repetitive behavior, learning and memory, GKAP, GluR1, AMPA receptor trafficking, dendritic spines, long-term potentiation, sex differences, mouse model
- MeSH terms
- Homer Scaffolding Proteins, SAP90-PSD95 Associated Proteins, Animals, Behavior, Animal, Carrier Proteins, Female, Learning, Male, Memory, Microfilament Proteins, Motor Activity, Nerve Tissue Proteins, Synaptic Transmission, RNA, Messenger, Synapses, Protein Isoforms, Mice
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