DIFFERENTIAL GENOTYPE-PHENOTYPE CORRELATION ACROSS SOCIAL AND SENSORY DOMAINS IN THE HETEROZYGOUS SHANK3B MOUSE MODEL OF AUTISM SPECTRUM DISORDER

Several Shank3 variants have been associated with Autism Spectrum Disorder (ASD) and related neurodevelopmental syndromes. Although Shank3-associated disorders primarily arise from haploinsufficiency, most preclinical studies have relied on full knockout (KO) mouse models, as phenotypic expression in heterozygous (Het) animals is subtle and variable. Moreover, many studies have focused exclusively on male mice or failed to consider sex as a biological variable, limiting translational relevance. To address these gaps, we investigated the social and somatosensory phenotypes of Shank3Δ13–16 Het and KO mice of both sexes during adolescence, compared with age- and sex-matched wild-type (Wt) littermates. Behavioral analyses were combined with ex vivo electrophysiology to assess neurophysiological alterations in brain regions associated with the observed deficits, focusing on circuits underlying sociability and somatosensory processing. Our results show that Shank3 haploinsufficiency induces an alteration in long-term social memory, affecting social discrimination in both sexes. This alteration correlates with a reduction in local excitatory synaptic drive onto pyramidal neurons in the ventral CA1 hippocampal region. In contrast, the somatosensory domain is largely preserved in heterozygous mice, while more pronounced behavioral deficits emerge in knockout animals. Consistently, electrophysiological recordings from layer V pyramidal neurons of the primary somatosensory cortex reveal alterations in the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) observed only in male KO mice. Overall, these findings demonstrate that Shank3 haploinsufficiency differentially affects social and sensory phenotypes and that genotype–sex interactions shape domain-specific neurophysiological alterations, enhancing the translational validity of the Shank3 mouse model.