Abstract
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.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Data availability
All supporting datasets generated or analyzed during the present study are available from the corresponding author upon reasonable request.
References
Apps, M. A., Rushworth, M. F. & Chang, S. W. The anterior cingulate gyrus and social cognition: tracking the motivation of others. Neuron 90, 692–707 (2016).
Dolen, G., Darvishzadeh, A., Huang, K. W. & Malenka, R. C. Social reward requires coordinated activity of nucleus accumbens oxytocin and serotonin. Nature 501, 179–184 (2013).
Gunaydin, L. A. et al. Natural neural projection dynamics underlying social behavior. Cell 157, 1535–1551 (2014).
Holroyd, C. B. & Yeung, N. Motivation of extended behaviors by anterior cingulate cortex. Trends Cogn. Sci. 16, 122–128 (2012).
Chang, S. W., Gariépy, J. F. & Platt, M. L. Neuronal reference frames for social decisions in primate frontal cortex. Nat. Neurosci. 16, 243–250 (2012).
Willsey, A. J. & State, M. W. Autism spectrum disorders: from genes to neurobiology. Curr. Opin. Neurobiol. 30, 92–99 (2015).
Bourgeron, T. Current knowledge on the genetics of autism and propositions for future research. C. R. Biol. 339, 300–307 (2016).
Durand, C. et al. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat. Genet. 39, 25–27 (2007).
Moessner, R. et al. Contribution of SHANK3 mutations to autism spectrum disorder. Am. J. Hum. Genet. 81, 1289–1297 (2007).
Gauthier, J. et al. Novel de novo SHANK3 mutation in autistic patients. Am. J. Med. Genet. B 150B, 421–424 (2009).
Naisbitt, S. et al. Shank, a novel family of postsynaptic density proteins that binds to the NMDA receptor/PSD-95/GKAP complex and cortactin. Neuron 23, 569–582 (1999).
Sala, C. et al. Regulation of dendritic spine morphology and synaptic function by Shank and Homer. Neuron 31, 115–130 (2001).
Monteiro, P. & Feng, G. SHANK proteins: roles at the synapse and in autism spectrum disorder. Nat. Rev. Neurosci. 18, 147–157 (2017).
Bozdagi, O. et al. Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication. Mol. Autism 1, 15 (2010).
Peça, J. et al. Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature 472, 437–442 (2011).
Wang, X. et al. Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3. Hum. Mol. Genet 20, 3093–3108 (2011).
Kouser, M. et al. Loss of predominant Shank3 isoforms results in hippocampus-dependent impairments in behavior and synaptic transmission. J. Neurosci. 33, 18448–18468 (2013).
Lee, J. et al. Shank3-mutant mice lacking exon 9 show altered excitation/inhibition balance, enhanced rearing, and spatial memory deficit. Front. Cell Neurosci. 9, 94 (2015).
Speed, H. E. et al. Autism-associated insertion mutation (InsG) of Shank3 Exon 21 causes impaired synaptic transmission and behavioral deficits. J. Neurosci. 35, 9648–9665 (2015).
Jaramillo, T. C. et al. Altered striatal synaptic function and abnormal behaviour in Shank3 Exon4-9 deletion mouse model of autism. Autism Res. 9, 350–375 (2016).
Mei, Y. et al. Adult restoration of Shank3 expression rescues selective autistic-like phenotypes. Nature 530, 481–484 (2016).
Wang, X. et al. Altered mGluR5-Homer scaffolds and corticostriatal connectivity in a Shank3 complete knockout model of autism. Nat. Commun. 7, 11459 (2016).
Zhou, Y. et al. Mice with Shank3 mutations associated with ASD and schizophrenia display both shared and distinct defects. Neuron 89, 147–162 (2016).
Wang, W. et al. Striatopallidal dysfunction underlies repetitive behavior in Shank3-deficient model of autism. J. Clin. Investig. 127, 1978–1990 (2017).
Rudebeck, P. H., Buckley, M. J., Walton, M. E. & Rushworth, M. F. A role for the macaque anterior cingulate gyrus in social valuation. Science 313, 1310–1312 (2006).
Behrens, T. E., Hunt, L. T., Woolrich, M. W. & Rushworth, M. F. Associative learning of social value. Nature 456, 245–249 (2008).
Murugan, M. et al. Combined social and spatial coding in a descending projection from the prefrontal cortex. Cell 171, 1663–1677.e1616 (2017).
Zhou, T. et al. History of winning remodels thalamo-PFC circuit to reinforce social dominance. Science 357, 162–168 (2017).
Ferguson, B. R. & Gao, W. J. Thalamic control of cognition and social behavior via regulation of gamma-aminobutyric acidergic signaling and excitation/inhibition balance in the medial prefrontal cortex. Biol. Psychiatry 83, 657–669 (2018).
Benekareddy, M. et al. Identification of a corticohabenular circuit regulating socially directed behavior. Biol. Psychiatry 83, 607–617 (2017).
Bourgeron, T. A synaptic trek to autism. Curr. Opin. Neurobiol. 19, 231–234 (2009).
Zhang, Q. et al. Impaired dendritic development and memory in sorbs2 knock-out mice. J. Neurosci. 36, 2247–2260 (2016).
Jia, F., Miao, H., Zhu, X. & Xu, F. Pseudo-typed Semliki Forest virus delivers EGFP into neurons. J. Neurovirol. 23, 205–215 (2017).
Toyoda, H. et al. Roles of the AMPA receptor subunit GluA1 but not GluA2 in synaptic potentiation and activation of ERK in the anterior cingulate cortex. Mol. Pain. 5, 46 (2009).
Ran, F. A. et al. In vivo genome editing using Staphylococcus aureus Cas9. Nature 520, 186–191 (2015).
Allsop, S. A. et al. Corticoamygdala transfer of socially derived information gates observational learning. Cell 173, 1329–1342.e1318 (2018).
Lauterborn, J. C., Lynch, G., Vanderklish, P., Arai, A. & Gall, C. M. Positive modulation of AMPA receptors increases neurotrophin expression by hippocampal and cortical neurons. J. Neurosci. 20, 8–21 (2000).
Lipina, T., Weiss, K. & Roder, J. The ampakine CX546 restores the prepulse inhibition and latent inhibition deficits in mGluR5-deficient mice. Neuropsychopharmacol. 32, 745–756 (2007).
Simms, M. L., Kemper, T. L., Timbie, C. M., Bauman, M. L. & Blatt, G. J. The anterior cingulate cortex in autism: heterogeneity of qualitative and quantitative cytoarchitectonic features suggests possible subgroups. Acta Neuropathol. 118, 673–684 (2009).
Haznedar, M. M. et al. Limbic circuitry in patients with autism spectrum disorders studied with positron emission tomography and magnetic resonance imaging. Am. J. Psychiatry 157, 1994–2001 (2000).
Xu, H. et al. A disinhibitory microcircuit mediates conditioned social fear in the prefrontal cortex. Neuron 102, 668–682.e5 (2019).
Etkin, A., Prater, K. E., Hoeft, F., Menon, V. & Schatzberg, A. F. Failure of anterior cingulate activation and connectivity with the amygdala during implicit regulation of emotional processing in generalized anxiety disorder. Am. J. Psychiatry 167, 545–554 (2010).
White, S. W., Oswald, D., Ollendick, T. & Scahill, L. Anxiety in children and adolescents with autism spectrum disorders. Clin. Psychol. Rev. 29, 216–229 (2009).
Kang, S. J. et al. Bidirectional modulation of hyperalgesia via the specific control of excitatory and inhibitory neuronal activity in the ACC. Mol. Brain 8, 81 (2015).
Wang, X., Xu, Q., Bey, A. L., Lee, Y. & Jiang, Y. H. Transcriptional and functional complexity of Shank3 provides a molecular framework to understand the phenotypic heterogeneity of SHANK3 causing autism and Shank3 mutant mice. Mol. Autism 5, 30 (2014).
Bey, A. L. et al. Brain region-specific disruption of Shank3 in mice reveals a dissociation for cortical and striatal circuits in autism-related behaviors. Transl. Psychiatry 8, 94 (2018).
Bariselli, S. et al. SHANK3 controls maturation of social reward circuits in the VTA. Nat. Neurosci. 19, 926–934 (2016).
Forero, D. A., Guio-Vega, G. P. & Gonzalez-Giraldo, Y. A comprehensive regional analysis of genome-wide expression profiles for major depressive disorder. J. Affect. Disord. 218, 86–92 (2017).
Kim, J. W. et al. Pharmacological modulation of AMPA receptor rescues social impairments in animal models of autism. Neuropsychopharmacol. 44, 314–323 (2018).
Chen, Q. et al. Imaging neural activity using Thy1-GCaMP transgenic mice. Neuron 76, 297–308 (2012).
Guo, B. et al. Chronic inflammatory pain impairs mGluR5-mediated depolarization-induced suppression of excitation in the anterior cingulate cortex. Cereb. Cortex 28, 2118–2130 (2018).
Li, Y. et al. Serotonin neurons in the dorsal raphe nucleus encode reward signals. Nat. Commun. 7, 10503 (2016).
Zhao, M. G. et al. Deficits in trace fear memory and long-term potentiation in a mouse model for fragile X syndrome. J. Neurosci. 25, 7385–7392 (2005).
Jia, F. et al. Rapid and sparse labeling of neurons based on the mutant virus-like particle of Semliki forest virus. Neurosci. Bull. 35, 378–388 (2019).
Ge, S. N. et al. Coexpression of VGLUT1 and VGLUT2 in trigeminothalamic projection neurons in the principal sensory trigeminal nucleus of the rat. J. Comp. Neurol. 518, 3149–3168 (2010).
Matthews, G. A. et al. Dorsal raphe dopamine neurons represent the experience of social isolation. Cell 164, 617–631 (2016).
Walsh, J. J. et al. 5-HT release in nucleus accumbens rescues social deficits in mouse autism model. Nature 560, 589–594 (2018).
Acknowledgements
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
Authors and Affiliations
Contributions
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.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Peer review information: Nature Neuroscience thanks Camilla Bellone and the other anonymous reviewer(s) for their contribution to the peer review of this work.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
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
Rights and permissions
About this article
Cite this article
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). https://doi.org/10.1038/s41593-019-0445-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41593-019-0445-9
This article is cited by
-
Impaired synaptic function and hyperexcitability of the pyramidal neurons in the prefrontal cortex of autism-associated Shank3 mutant dogs
Molecular Autism (2024)
-
Neuron type-specific proteomics reveals distinct Shank3 proteoforms in iPSNs and dSPNs lead to striatal synaptopathy in Shank3B–/– mice
Molecular Psychiatry (2024)
-
Advancing preclinical chronic stress models to promote therapeutic discovery for human stress disorders
Neuropsychopharmacology (2024)
-
Whole-brain in vivo base editing reverses behavioral changes in Mef2c-mutant mice
Nature Neuroscience (2024)
-
Restoration of nNOS Expression Rescues Autistic-Like Phenotypes Through Normalization of AMPA Receptor-Mediated Neurotransmission
Molecular Neurobiology (2024)