Autism-like atypical face processing in Shank3 mutant dogs

Atypical face processing is a neurocognitive basis of social deficits in autism spectrum disorder (ASD) and a candidate cognitive marker for the disease. Although hundreds of risk genes have been identified in ASD, it remains unclear whether mutations in a specific gene may cause ASD-like atypical face processing. Dogs have acquired exquisite face processing abilities during domestication and may serve as an effective animal model for studying genetic associations of ASD-like atypical face processing. Here, we showed that dogs with Shank3 mutations exhibited behavioral and attentional avoidance of faces, contrasting with wild-type controls. Moreover, neural responses specific to faces (versus objects) recorded from the electrodes over the temporal cortex were significantly decreased and delayed in Shank3 mutants compared to wild-type controls. Cortical responses in the frontal/parietal region underlying categorization of faces by species/breeds were reduced in Shank3 mutants. Our findings of atypical face processing in dogs with Shank3 mutations provide a useful animal model for studying ASD mechanisms and treatments.

Methods
Subjects

Twenty-three WT (beagles) from Sinogene Ltd (Beijing, China) and fifteen Shank3 mutant dogs (beagles) were tested in this study. The mean age did not differ significantly between WT controls and Shank3 mutants (WT, 19.3 ± 1.33 months of age (mean ± SEM); Mutants, 24.5 ± 2.75 months of age, U = 125.5, P = 0.164, see Tables S1 and S2 for detailed information about the subjects in each experiment). Four WT controls (80, 201138, 210755, 201115) and three Shank3 mutants (201111, 201112, 201141) were tested in a previous behavioral study of dog-human interactions (20). Two Shank3 mutants (190203, 190604) were tested in an ECoG study which required the subjects to passively listen to pure sinusoidal tones (27). None of these studies involved any training with food or employed stimuli of animal/human faces or houses. Three dogs tested in this work were littermates (i.e., WT(201115) and Shank3 mutants (201111 and 201112)). WT(201115) participated in Experiment 1. Shank3 mutants 201111 participated in Experiments 1 and 4. Shank3 mutants 201112 participated in Experiment 4. The Shank3 mutations generate frameshifts and truncated proteins disrupting the ANK domain and proline-rich domain of Shank3 in mutant dogs (20). All mutant dogs showed a similarly reduced level of Shank3 protein and similar autism-like social deficits, including social withdrawal and reduced social interactions with humans (20). Each dog was housed in a single cage and maintained on a 12-hour light/12-hour dark cycle with lights on at 7:00 am. All subjects were submitted to ophthalmological and behavior evaluation to verify their health conditions before the study. No animal was sacrificed in these studies. All experimental procedures were approved by the Ethical Committee of the Institute of Genetics and Developmental Biology of the Chinese Academy of Sciences (AP2022033).