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Nat Commun. 2016 May 10;7:11459. doi: 10.1038/ncomms11459.

Altered mGluR5-Homer scaffolds and corticostriatal connectivity in a Shank3 complete knockout model of autism.

Author information

1
Department of Pediatrics, Duke University, Durham, North Carolina 27710, USA.
2
Department of Neurobiology, Duke University, Durham, North Carolina 27710, USA.
3
Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina 27710, USA.
4
Department of Radiology, Duke University, Durham, North Carolina 27710, USA.
5
Department of Psychology and Neuroscience, Duke University, Durham, North Carolina 27710, USA.
6
Department of Cell Biology, Duke University, Durham, North Carolina 27710, USA.
7
Department of Ophthalmology, Duke University, Durham, North Carolina 27710, USA.
8
Department of Child Health Care, The Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai 201102, China.
9
Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, North Carolina 27599, USA.
10
Duke Institute for Brain Sciences, Duke University, Durham, North Carolina 27710, USA.
11
University Program in Genetics and Genomics, Duke University, Durham, North Carolina 27710, USA.

Abstract

Human neuroimaging studies suggest that aberrant neural connectivity underlies behavioural deficits in autism spectrum disorders (ASDs), but the molecular and neural circuit mechanisms underlying ASDs remain elusive. Here, we describe a complete knockout mouse model of the autism-associated Shank3 gene, with a deletion of exons 4-22 (Δe4-22). Both mGluR5-Homer scaffolds and mGluR5-mediated signalling are selectively altered in striatal neurons. These changes are associated with perturbed function at striatal synapses, abnormal brain morphology, aberrant structural connectivity and ASD-like behaviour. In vivo recording reveals that the cortico-striatal-thalamic circuit is tonically hyperactive in mutants, but becomes hypoactive during social behaviour. Manipulation of mGluR5 activity attenuates excessive grooming and instrumental learning differentially, and rescues impaired striatal synaptic plasticity in Δe4-22(-/-) mice. These findings show that deficiency of Shank3 can impair mGluR5-Homer scaffolding, resulting in cortico-striatal circuit abnormalities that underlie deficits in learning and ASD-like behaviours. These data suggest causal links between genetic, molecular, and circuit mechanisms underlying the pathophysiology of ASDs.

PMID:
27161151
PMCID:
PMC4866051
DOI:
10.1038/ncomms11459
[Indexed for MEDLINE]
Free PMC Article

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