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Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3
Xiaoming Wang1, Portia A McCoy, Ramona M Rodriguiz
1Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA.
Human Molecular Genetics
|May 12, 2011
Summary
SHANK3 protein loss in mice causes autism-like behaviors and learning deficits. These findings link SHANK3 gene mutations to neurodevelopmental disorders like autism spectrum disorder (ASD).
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- SHANK3 is a crucial synaptic scaffolding protein.
- SHANK3 mutations are linked to autism spectrum disorder (ASD) and Phelan-McDermid syndrome.
Purpose of the Study:
- To investigate the in vivo function of SHANK3 by creating and analyzing mutant mice.
- To understand the molecular and cellular consequences of SHANK3 disruption.
Main Methods:
- Generation of isoform-specific Shank3(e4-9) homozygous mutant mice.
- Behavioral testing for social interaction, communication, repetitive behaviors, learning, and memory.
- Biochemical analysis of postsynaptic density (PSD) protein levels and receptor trafficking.
- Electrophysiological assessment of synaptic plasticity (long-term potentiation).
Main Results:
- Shank3 mutant mice exhibit deficits in social behavior, communication, learning, and memory.
- Male mutant mice show more severe motor coordination impairments.
- Reduced levels of key PSD proteins (Homer1b/c, GKAP, GluA1) and impaired AMPA receptor trafficking were observed.
- Dendritic spine morphology was subtly altered, and long-term potentiation was deficient.
Conclusions:
- Loss of major SHANK3 isoforms leads to biochemical, cellular, and morphological synaptic changes.
- These changes result in behavioral abnormalities in mice that model human conditions associated with SHANK3 mutations, such as ASD.
