Dogs

Neural mechanisms underlying reduced nocifensive sensitivity in autism-associated Shank3 mutant dogs

Abstract

Autistic individuals carrying mutations in SHANK3 (encoding a synaptic scaffolding protein) have been consistently reported to exhibit reduced pain sensitivity. However, the neural mechanisms underlying impaired pain processing remain unclear. To investigate the role of SHANK3 in pain processing, we conducted behavioral, electrophysiological, and pharmacological tests upon nociceptive stimulation in a Shank3 mutant dog model. Behaviorally, Shank3 mutant dogs showed reduced nocifensive sensitivity compared to wild-type (WT) dogs. Electrophysiologically, Shank3 mutant dogs exhibited reduced neural responses elicited by the activations of both Aδ- and C-fiber nociceptors. Additionally, Shank3 mutants showed a lower level of aperiodic exponents, which serve as a marker for the excitatory-inhibitory balance of neural activity. The aperiodic exponents mediated the relationship between genotype and nocifensive sensitivity as well as between genotype and neural responses elicited by nociceptive stimuli. Pharmacologically, the reduced nocifensive sensitivity and atypical excitatory-inhibitory balance were rescued by a GABAAR antagonist pentylenetetrazole. These findings highlight the critical role of Shank3 in pain processing and suggest that an impaired excitatory-inhibitory balance may be responsible for the reduced nocifensive reactivity in autism.

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Fig. 1: Experimental design and behavioral results.
Fig. 2: Reduced cortical responses to nociceptive laser stimuli in Shank3 mutant dogs.
Fig. 3: Reduced oscillatory responses to nociceptive laser stimuli in Shank3 mutant dogs.
Fig. 4: Reduced spectral powers of resting-state brain oscillations in Shank3 mutant dogs.
Fig. 5: The aperiodic exponent mediated the relationship between genotype and nocifensive sensitivity or neural responses evoked by nociceptive stimuli.
Fig. 6: PTZ improved nocifensive sensitivity and aperiodic exponent in Shank3 mutants.

Data availability

The data and analysis code that support the findings of this study are available from the corresponding authors upon reasonable request.

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Acknowledgements

We thank Professor K. Guo and members of the Zhang laboratory for discussion. This work was supported in part by grants from the National Key Research and Development Program (2021ZD0203901 to Y.Z.), the National Science Foundation of China (32394030 to Y.Z., 32071061 to L.H.), the Beijing Natural Science Foundation (JQ22018 to L.H.), Wuhan Municipal S&T Project (Grant No. 2024020702030125 to Y.Z.), and sample storage by the Canine Biobank, Chinese Academy of Sciences (KFJ-BRP-004 to Y.Z.).

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Authors and Affiliations

  1. State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China

    Qi Shi, Baolong Ren, Liang Wu & Yong Q. Zhang

  2. University of Chinese Academy of Sciences, Beijing, 100101, China

    Qi Shi & Baolong Ren

  3. State Key Laboratory of Cognitive Science and Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, 100101, China

    Xuejing Lu, Libo Zhang & Li Hu

  4. Department of Psychology, University of Chinese Academy of Sciences, Beijing, 100049, China

    Xuejing Lu, Libo Zhang & Li Hu

  5. School of Life Sciences, Hubei University, Wuhan, 430415, China

    Yong Q. Zhang

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Contributions

Conceptualization: QS, LH, YZ; Methodology: QS, LH; Software: QS, LH; Validation: QS; Formal analysis: QS; Investigation: QS, BR, LW; Resources: LH, YZ; Data curation: QS; Writing – original draft preparation: QS, LH, YZ; Writing – review & editing: XL, LZ, YZ, LH; Visualisation: QS; Supervision: LH, YZ; Project administration: LH, YZ; Funding acquisition: LH, YZ.

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Li Hu or Yong Q. Zhang.

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Shi, Q., Ren, B., Lu, X. et al. Neural mechanisms underlying reduced nocifensive sensitivity in autism-associated Shank3 mutant dogs.
Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-02952-y

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  • DOI: https://doi.org/10.1038/s41380-025-02952-y

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