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J Clin Invest DOI:10.1172/JCI87997

Striatopallidal dysfunction underlies repetitive behavior in Shank3-deficient model of autism.

Publication TypeJournal Article
Year of Publication2017
AuthorsWang, W, Li, C, Chen, Q, van der Goes, M-S, Hawrot, J, Yao, AY, Gao, X, Lu, C, Zang, Y, Zhang, Q, Lyman, K, Wang, D, Guo, B, Wu, S, Gerfen, CR, Fu, Z, Feng, G
JournalJ Clin Invest
Volume127
Issue5
Pages1978-1990
Date Published2017 May 01
ISSN1558-8238
KeywordsAnimals, Autistic Disorder, Corpus Striatum, Disease Models, Animal, Humans, Mice, Mice, Knockout, Nerve Tissue Proteins, Neuronal Plasticity, Substantia Nigra, Synaptic Transmission
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.

DOI10.1172/JCI87997
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/28414301?dopt=Abstract

Alternate JournalJ. Clin. Invest.
PubMed ID28414301
PubMed Central IDPMC5409790
Grant ListR01 MH097104 / MH / NIMH NIH HHS / United States