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

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 GABA