title: Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3.
abstract: 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.
authors.affiliation: Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Wang
authors.forename: Portia A
authors.initials: PA
authors.lastname: McCoy
authors.forename: Ramona M
authors.initials: RM
authors.lastname: Rodriguiz
authors.forename: Yanzhen
authors.initials: Y
authors.lastname: Pan
authors.forename: H Shawn
authors.initials: HS
authors.lastname: Je
authors.forename: Adam C
authors.initials: AC
authors.lastname: Roberts
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Kim
authors.forename: Janet
authors.initials: J
authors.lastname: Berrios
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Colvin
authors.forename: Danielle
authors.initials: D
authors.lastname: Bousquet-Moore
authors.forename: Isabel
authors.initials: I
authors.lastname: Lorenzo
authors.forename: Gangyi
authors.initials: G
authors.lastname: Wu
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Weinberg
authors.forename: Michael D
authors.initials: MD
authors.lastname: Ehlers
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Philpot
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Beaudet
authors.forename: William C
authors.initials: WC
authors.lastname: Wetsel
authors.forename: Yong-Hui
authors.initials: YH
authors.lastname: Jiang
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D000072233:Homer Scaffolding Proteins; D007858:Learning / Q000502:physiology; D008297:Male; D008568:Memory / Q000502:physiology; D051379:Mice; D008840:Microfilament Proteins; D009043:Motor Activity / Q000235:genetics / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D000074407:SAP90-PSD95 Associated Proteins; D013569:Synapses / Q000378:metabolism* / Q000502:physiology*; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; C000614187:DLGAP1 protein, human; C000614190:Dlgap1 protein, mouse; D000072233:Homer Scaffolding Proteins; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D000074407:SAP90-PSD95 Associated Proteins; C492356:Shank3 protein, mouse