Striatopallidal dysfunction underlies repetitive behavior in Shank3-deficient model of autism
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JCI87997.pdf
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Author(s)
Zang, Ying
Lyman, Katherine
Guo, Baolin
Wu, Shengxi
Gerfen, Charles R.
Wang, Wenting
Li, Chenchen
Chen, Qian
Van der Goes, Marie-Sophie
Hawrot, James
Date Issued
February 2017
Journal
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Citation
Wang, Wenting et al. “Striatopallidal Dysfunction Underlies Repetitive Behavior in Shank3-Deficient Model of Autism.” Journal of Clinical Investigation 127, 5 (April 2017): 1978–1990 © 2017 American Society for Clinical Investigation
Version
Final published version
Abstract
The postsynaptic scaffolding protein SH3 and multiple ankyrin repeat domains 3 (SHANK3) is critical for the development and function of glutamatergic synapses. Disruption of the SHANK3-encoding gene has been strongly implicated as a monogenic cause of autism, and Shank3 mutant mice show repetitive grooming and social interaction deficits. Although basal ganglia dysfunction has been proposed to underlie repetitive behaviors, few studies have provided direct evidence to support this notion and the exact cellular mechanisms remain largely unknown. Here, we utilized the Shank3B mutant mouse model of autism to investigate how Shank3 mutation may differentially affect striatonigral (direct pathway) and striatopallidal (indirect pathway) medium spiny neurons (MSNs) and its relevance to repetitive grooming behavior in Shank3B mutant mice. We found that Shank3 deletion preferentially affects synapses onto striatopallidal MSNs. Striatopallidal MSNs showed profound defects, including alterations in synaptic transmission, synaptic plasticity, and spine density. Importantly, the repetitive grooming behavior was rescued by selectively enhancing the striatopallidal MSN activity via a Gq-coupled human M3 muscarinic receptor (hM3Dq), a type of designer receptors exclusively activated by designer drugs (DREADD). Our findings directly demonstrate the existence of distinct changes between 2 striatal pathways in a mouse model of autism and indicate that the indirect striatal pathway disruption might play a causative role in repetitive behavior of Shank3B mutant mice.
MIT Department
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
McGovern Institute for Brain Research at MIT
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DOI of Published Version
https://doi.org/10.1172/JCI87997
