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

Wang, Xiaoming

Bey, Alexandra L

Katz, Brittany M

Badea, Alexandra

Kim, Namsoo

David, Lisa K

Duffney, Lara J

Kumar, Sunil

Mague, Stephen D

Hulbert, Samuel W

Dutta, Nisha

Hayrapetyan, Volodya

Yu, Chunxiu

Gaidis, Erin

Zhao, Shengli

Ding, Jin-Dong

Xu, Qiong

Chung, Leeyup

Rodriguiz, Ramona M

Wang, Fan

Weinberg, Richard J

Wetsel, William C

Dzirasa, Kafui

Yin, Henry

Jiang, Yong-Hui

England

2016-11-10T18:06:40Z

2016-05-10

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.

http://www.ncbi.nlm.nih.gov/pubmed/27161151

ncomms11459

2041-1723

https://hdl.handle.net/10161/13004

eng

Springer Science and Business Media LLC

Nat Commun

10.1038/ncomms11459

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

Journal article

Badea, Alexandra|0000-0001-6621-4560

Kim, Namsoo|0000-0003-3083-8835

Hulbert, Samuel W|0000-0003-0369-0150

Wang, Fan|0000-0003-2988-0614

http://www.ncbi.nlm.nih.gov/pubmed/27161151

11459

Basic Science Departments

Biomedical Engineering

Cell Biology

Clinical Science Departments

Duke

Duke Institute for Brain Sciences

Institutes and Provost's Academic Units

Neurobiology

Neurosurgery

Pediatrics

Pediatrics, Medical Genetics

Pratt School of Engineering

Psychiatry & Behavioral Sciences

Psychiatry & Behavioral Sciences, Brain Stimulation and Neurophysiology

Radiology

School of Medicine

University Institutes and Centers

Published online

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