Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3
Xiaoming Wang,Portia A. McCoy,Ramona M. Rodriguiz,Yanzhen Pan,H. Shawn Je,Adam C. Roberts,Caroline J. Kim,Janet Berrios,Jennifer S. Colvin,Danielle Bousquet-Moore,Isabel Lorenzo,Gang Yi Wu,Richard J. Weinberg,Michael D. Ehlers,Michael D. Ehlers,Benjamin D. Philpot,Arthur L. Beaudet,William C. Wetsel,Yong-hui Jiang +18 more
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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.read more
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Journal ArticleDOI
Shank synaptic scaffold proteins: keys to understanding the pathogenesis of autism and other synaptic disorders.
TL;DR: The major genetic, molecular, behavior and electrophysiological studies that provide new clues into the function of Shanks are summarized and pave the way for the discovery of new therapeutic drugs targeted to treat patients with SHANK mutations and also patients affected by other neurodevelopmental and neuropsychiatric disorders.
Journal ArticleDOI
Altered Striatal Synaptic Function and Abnormal Behaviour in Shank3 Exon4-9 Deletion Mouse Model of Autism.
TL;DR: Behaviorally, biochemical and physiological changes suggest Shank3 isoforms have region‐specific roles in regulation of AMPAR subunit localization and NMDAR function in the Shank3e4‐9 mutant mouse model of autism.
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Autism-related behavioral abnormalities in synapsin knockout mice
Barbara Greco,Francesca Managò,Valter Tucci,Hung-Teh Kao,Flavia Valtorta,Fabio Benfenati,Fabio Benfenati +6 more
TL;DR: Social deficits in SynI−/− and SynII+/− mice appear before the onset of epilepsy, and these deficits are characterized by increased social dominance.
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Transcriptional and functional complexity of Shank3 provides a molecular framework to understand the phenotypic heterogeneity of SHANK3 causing autism and Shank3 mutant mice
TL;DR: The comprehensive data on Shank3 transcriptional regulation provides an essential molecular framework to understand the phenotypic diversity in SHANK3 causing ASD and Shank3 mutant mice.
Journal ArticleDOI
SHANK3 controls maturation of social reward circuits in the VTA
Sebastiano Bariselli,Stamatina Tzanoulinou,Christelle Glangetas,Christelle Glangetas,Christelle Glangetas,Clément Prévost-Solié,Luca Pucci,Joanna Viguie,Paola Bezzi,Eoin C. O'Connor,François Georges,Christian Lüscher,Christian Lüscher,Camilla Bellone +13 more
TL;DR: D dopamine (DA) and GABA cell-type-specific changes in excitatory synapse transmission that converge to reduce DA neuron activity and generate behavioral deficits, including impaired social preference are identified.
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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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