Striatopallidal dysfunction underlies repetitive behavior in Shank3-deficient model of autism
Wenting Wang, … , Zhanyan Fu, Guoping Feng
Wenting Wang, … , Zhanyan Fu, Guoping Feng
Published May 1, 2017; First published April 17, 2017
Citation Information: J Clin Invest. 2017;127(5):1978-1990. https://doi.org/10.1172/JCI87997.
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Categories: Research Article Neuroscience

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

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.

Authors

Wenting Wang, Chenchen Li, Qian Chen, Marie-Sophie van der Goes, James Hawrot, Annie Y. Yao, Xian Gao, Congyi Lu, Ying Zang, Qiangge Zhang, Katherine Lyman, Dongqing Wang, Baolin Guo, Shengxi Wu, Charles R. Gerfen, Zhanyan Fu, Guoping Feng

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Figure 5

Enhancing D2 MSN activity using DREADD-hM3Dq reduced repetitive grooming behavior in Shank3B-KO mice.

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Enhancing D2 MSN activity using DREADD-hM3Dq reduced repetitive grooming...
(A) The injecting site of AAV-DIO-hM3Dq-mCherry virus and behavior paradigm. (B) Representative traces of CNO-induced neuronal membrane depolarization of a hM3Dq-mCherry-expressing D1 (upper panel) or D2 MSN (lower panel). (C and E) A reduction in grooming time between pre- and post-CNO treatment only was found in KO/A2a-Cre mice. (C, D1: WT-mCherry, N = 7, P = 0.78; KO-mCherry, N = 6, P = 0.88; WT-hM3Dq, N = 7, P = 0.54; KO-hM3Dq, N = 7, P = 0.87; E, D2: WT-mCherry, N = 6, P = 0.75; KO-mCherry, N = 6, P = 0.75; WT-hM3Dq, N = 7, P = 0.18; KO-hM3Dq, N = 7, P = 0.0031). (D and F) DREADD significantly decreased grooming changes in KO/A2a-Cre mice (F, WT and KO, P = 0.43. mCherry and DREADD, P = 0.03; interaction, P = 0.29, 2-way ANOVA), but not D1-Cre mice (D, WT and KO, P = 0.9. mCherry and DREADD, P = 0.78; interaction, P = 0.78). (G and I) Summary data showing no changes in locomotor activity between pre- and post-CNO treatment in WT/D1-Cre or KO/D1-Cre mice (G, WT-mCherry, N = 6, P = 0.33; KO-mCherry, N = 6, P = 0.89; WT-hM3Dq, N = 6, P = 0.18; KO-hM3Dq, N = 6, P = 0.08.) and WT/A2a-Cre or KO/A2a-Cre mice (I, WT-mCherry, N = 7, P = 0.10; KO-mCherry, N = 6, P = 0.07; WT-hM3Dq, N = 7, P = 0.41; KO-hM3Dq, N = 9, P = 0.29). (H and J) DREADD did not change locomotor activities in both D1-Cre mice (H, WT and KO, P = 0.18. mCherry and DREADD, P = 0.66; interaction, P = 0.05) and A2a-Cre mice (J, WT and KO, P = 0.64. mCherry and DREADD, P = 0.81; interaction, P = 0.57). A paired t test was used for C, E, G, and I and 2-way ANOVA was used for D, F, H, and J. *P < 0.05; **P < 0.01. N, animal number.