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

Xiaoming Wang, Alexandra L. Bey, Brittany M. Katz, Alexandra Badea, Namsoo Kim, Lisa K. David, Lara J. Duffney, Sunil Kumar, Stephen D. Mague, Samuel W. Hulbert, Nisha Dutta, Volodya Hayrapetyan, Chunxiu Yu, Erin Gaidis, Shengli Zhao, Jin-Dong Ding, Qiong Xu, Leeyup Chung, Ramona M. Rodriguiz, Fan Wang, Richard J. Weinberg, William C. Wetsel, Kafui Dzirasa, Henry Yin and Yong-hui Jiang ()
Additional contact information
Xiaoming Wang: Duke University
Alexandra L. Bey: Duke University
Brittany M. Katz: Duke University
Alexandra Badea: Duke University
Namsoo Kim: Duke University
Lisa K. David: Duke University
Lara J. Duffney: Duke University
Sunil Kumar: Duke University
Stephen D. Mague: Duke University
Samuel W. Hulbert: Duke University
Nisha Dutta: Duke University
Volodya Hayrapetyan: Duke University
Chunxiu Yu: Duke University
Erin Gaidis: Duke University
Shengli Zhao: Duke University
Jin-Dong Ding: Duke University
Qiong Xu: Duke University
Leeyup Chung: Duke University
Ramona M. Rodriguiz: Duke University
Fan Wang: Duke University
Richard J. Weinberg: The University of North Carolina at Chapel Hill
William C. Wetsel: Duke University
Kafui Dzirasa: Duke University
Henry Yin: Duke University
Yong-hui Jiang: Duke University

Nature Communications, 2016, vol. 7, issue 1, 1-18

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11459

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