SHANK3 mutations disrupt olfactory valence coding across species, with cortical amygdala mechanisms identified in mice.

Mutations in SHANK3 are a leading monogenic cause of autism spectrum disorder (ASD), often associated with profound sensory abnormalities. However, the impact of SHANK3 deficiency on olfactory processing and the underlying neural mechanisms remains unclear. Here, we identify a cross-species disruption of olfactory valence perception in individuals with SHANK3 mutations and in Shank3 mutant mice. Patients carrying SHANK3 mutations exhibited impaired valence-oriented sniffing and electroencephalography (EEG) responses, whereas Shank3B-/- mice displayed blunted behavioral responses to both attractive and aversive odors. In mice, these behavioral deficits were associated with attenuated odor-evoked calcium signals and reduced excitatory synaptic transmission in the cortical amygdala (CoA), a key node for olfactory valence processing. Acute CoA-specific Shank3 deletion recapitulated these deficits, whereas targeted restoration of CoA Shank3 expression rescued odor-induced appetitive and aversive behaviors. Our findings reveal a conserved function for SHANK3 in encoding olfactory valence and identify CoA dysfunction as a circuit mechanism in mice.