Anterior cingulate cortex dysfunction underlies social deficits in Shank3 mutant mice


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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Fig. 1: Morphological changes in the ACC of Shank3 KO mice.
Fig. 2: Excitatory synaptic dysfunction in the ACC pyramidal neurons of Shank3 KO mice.
Fig. 3: ACC pyramidal neurons show weaker responses to initial social contact in Shank3 KO mice.
Fig. 4: Conditional Shank3 deletion in the ACC recapitulates synaptic impairments and social dysfunction.
Fig. 5: Optogenetic activation of ACC pyramidal neurons rescues social interaction and anxiety behaviors in KO mice.
Fig. 6: Adult restoration of Shank3 expression in the ACC partially rescues synaptic impairments and social dysfunction.
Fig. 7: Systemic administration of an AMPA receptor-positive modulator improves social behaviors in KO mice.

Data availability

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).

Author information




B.G., G.F., W.W. and S.W. designed the experiments. B.G. performed in vitro patch-clamp recording. J.C. and J.Y. performed the fluorescence in situ hybridization and immunohistochemistry. B.G. and J.C. conducted the fiber photometry and behavior test. Q.C. designed the Cas9 gRNA. B.G. and Q.C. performed in vivo optrode recording. B.G., K.R., H.Y. and C.Q. performed the viral injection and behavioral test. B.G., Q.C., H.L. and T.L.-J. conducted the pharmacological rescue experiments. B.G. and D.F. performed the western blot. B.G., Q.C. and F.J. performed sparse labeling and morphological characterization analyses. Y.L. conducted the electron microscopy. H.M. performed statistical analyses. G.F., W.W. and S.W. wrote the paper with the assistance of B.G., J.C., Q.C., H.H. and Z.F.

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Correspondence to Guoping Feng or Wenting Wang or Shengxi Wu.

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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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Supplementary information

Supplementary Figs. 1–25

Reporting Summary

Supplementary Table 1

Statistical methods summary

Supplementary Table 2

Statistical detail information for figures and supplementary figures

Supplementary Video 1

Fiber photometry recording social interaction of a WT mouse in the home cage

Supplementary Video 2

Optogenetic activation of ACC in a Shank3 KO mouse improved the social interaction

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Guo, B., Chen, J., Chen, Q. et al. Anterior cingulate cortex dysfunction underlies social deficits in Shank3 mutant mice. Nat Neurosci 22, 1223–1234 (2019).

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