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Open AccessJournal ArticleDOI

Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3

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TLDR
It is concluded 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.
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.

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Citations
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Journal ArticleDOI

Enhanced Glutamatergic Currents at Birth in Shank3 KO Mice.

TL;DR: In CA3 pyramidal neurons of Shank3-mutant mice, glutamatergic but not GABAergic activity is affected at early developmental stages, hence reflecting the heterogeneity of mechanisms underlying the pathogenesis of ASD.
Book ChapterDOI

SHANK Mutations in Intellectual Disability and Autism Spectrum Disorder

TL;DR: An overview of SHANK function and SHANK mutations is presented from the perspective of both in vitro and in-vivo studies pointing to future directions where research on SHANK will likely go.
Dissertation

Diverse effects of anti-GluN1 antibodies in hippocampal excitatory synapses

Angela Wu
TL;DR: This paper aims to provide a history of the field and some of the techniques used in its development, as well as some of its subsequent publications, to help clarify its aims and aims.
Posted ContentDOI

Gene discovery and functional assessment of rare copy-number variants in neurodevelopmental disorders

TL;DR: It is clear that phenotypic assessment and complete genetic evaluation of large cohorts of individuals carrying specific CNVs and functional evaluation using multiple animal models are necessary to understand the molecular genetic basis of neurodevelopmental disorders.
References
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Journal ArticleDOI

Diagnostic and Statistical Manual of Mental Disorders

TL;DR: An issue concerning the criteria for tic disorders is highlighted, and how this might affect classification of dyskinesias in psychotic spectrum disorders.
Journal ArticleDOI

Optimized survival of hippocampal neurons in B27-supplemented Neurobasal, a new serum-free medium combination

TL;DR: High survival was achieved with osmolarity lower than found in Dulbecco's Modified Eagle's Medium (DMEM), and by reducing cysteine and glutamine concentrations and by the elimination of toxic ferrnous sulphate found in DME/F12, and Neurobasal is a new medium that incorporates modifications to DMEM.
Journal ArticleDOI

Functional impact of global rare copy number variation in autism spectrum disorders

Dalila Pinto, +181 more
- 15 Jul 2010 - 
TL;DR: The genome-wide characteristics of rare (<1% frequency) copy number variation in ASD are analysed using dense genotyping arrays to reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
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