Social deficit is a core clinical feature of autism spectrum disorder (ASD) but the underlying neural mechanisms remain largely unclear. We demonstrate that structural and functional impairments occur in glutamatergic synapses in the pyramidal neurons of the anterior cingulate cortex (ACC) in mice with a mutation in Shank3, a high-confidence candidate ASD gene. Conditional knockout of Shank3 in the ACC was sufficient to generate excitatory synaptic dysfunction and social interaction deficits, whereas selective enhancement of ACC activity, restoration of SHANK3 expression in the ACC, or systemic administration of an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor-positive modulator improved social behavior in Shank3 mutant mice. Our findings provide direct evidence for the notion that the ACC has a role in the regulation of social behavior in mice and indicate that ACC dysfunction may be involved in social impairments in ASD.
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All supporting datasets generated or analyzed during the present study are available from the corresponding author upon reasonable request.
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We thank J. Kang, M. Wang, X. Wang, T. Luo, Y. Lu, X. Wei (Fourth Military Medical University), D. Wang, X. Gao, M. Fleishman (McGovern Institute for Brain Research, Massachusetts Institute of Technology), Z. Fan and D. Zheng (Zhejiang University) for technical support and suggestions. We thank H. Dong (University of Southern California) for suggestions on the anatomical specificity test, and X. Zhang (University of Ottawa) for critical reading and discussions. We thank L. Shang (Fourth Military Medical University) for suggestions on data statistics. We thank Y. Wu for supporting us during schematic drawing. This study was supported by the Natural Science Foundation of China (nos. 81730035 to S.W., 81771476 and 81371498 to W.W.), Innovation Teams in Priority Areas Accredited by the Ministry of Science and Technology (no. 2014RA4029, S.W.), the International Science and Technology Cooperation Program of China (no. 2011DFA32560, S.W.) and NIMH grant no. MH097104 and P50MH094271 (G.F.). We also thank the Nature Research Editing Service for English language editing (certificate verification key 8862-92CC-FDBE-B0BA-035P).
The authors declare no competing interests.
Peer review information: Nature Neuroscience thanks Camilla Bellone and the other anonymous reviewer(s) for their contribution to the peer review of this work.
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Statistical methods summary
Statistical detail information for figures and supplementary figures
Fiber photometry recording social interaction of a WT mouse in the home cage
Optogenetic activation of ACC in a Shank3 KO mouse improved the social interaction