Shi Qi, Ren Baolong, Lu Xuejing, Zhang Libo, Wu Liang, Hu Li, Zhang Yong Q
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China.
University of Chinese Academy of Sciences, Beijing, 100101, China.
Mol Psychiatry. 2025 Mar 17. doi: 10.1038/s41380-025-02952-y.
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 GABAR 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.
一直以来，有报道称携带SHANK3（编码一种突触支架蛋白）突变的自闭症患者表现出疼痛敏感性降低。然而，疼痛处理受损背后的神经机制仍不清楚。为了研究SHANK3在疼痛处理中的作用，我们在一个Shank3突变犬模型中对伤害性刺激进行了行为学、电生理学和药理学测试。在行为学上，与野生型（WT）犬相比，Shank3突变犬的伤害防御敏感性降低。在电生理学上，Shank3突变犬对Aδ纤维和C纤维伤害感受器激活所引发的神经反应减少。此外，Shank3突变体表现出较低水平的非周期性指数，该指数可作为神经活动兴奋抑制平衡的标志物。非周期性指数介导了基因型与伤害防御敏感性之间以及基因型与伤害性刺激引发的神经反应之间的关系。在药理学上，GABAR拮抗剂戊四氮挽救了降低的伤害防御敏感性和非典型的兴奋抑制平衡。这些发现突出了Shank3在疼痛处理中的关键作用，并表明兴奋抑制平衡受损可能是自闭症中伤害防御反应性降低的原因。
