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

Abstract

Mutations in <i>SHANK3</i> are a leading monogenic cause of autism spectrum disorder (ASD), often associated with profound sensory abnormalities. However, the impact of <i>SHANK3</i> 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 <i>SHANK3</i> mutations and in <i>Shank3</i> mutant mice. Patients carrying <i>SHANK3</i> mutations exhibited impaired valence-oriented sniffing and electroencephalography (EEG) responses, whereas <i>Shank3B</i>^-/- 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 <i>SHANK3</i> in encoding olfactory valence and identify CoA dysfunction as a circuit mechanism in mice.