SHANK2A overexpression in forebrain neurons induces early-life communication deficits in mice

SHANK2 is a postsynaptic scaffolding protein critical for excitatory synapse organization, and alterations in SHANK2 dosage are strongly associated with autism spectrum disorder (ASD). While SHANK2 loss-of-function rodent models have been extensively studied, the impact of increased SHANK2 expression on early-life communication remains unclear. Here, we examined ultrasonic vocalizations (USVs) in forebrain-specific SHANK2A-overexpressing (SH-WT) mice using the pup isolation paradigm at P8 and P12, a sensitive developmental window for assessing early social communication. SH-WT pups exhibited a transient increase in vocal output at P8, characterized by elevated call production and altered temporal organization, while fundamental acoustic features remained largely unchanged. By P12, these quantitative differences were no longer evident, indicating developmental normalization. However, SH-WT pups showed subtle alterations in call structure and composition, along with persistent changes in vocal syntax, reflected by more centralized and less diverse transition networks. Together, these findings indicate that SHANK2A overexpression transiently enhances early vocal output while inducing lasting alterations in the organization and flexibility of vocal behavior, suggesting disrupted maturation of communication-related neural circuits relevant to ASD.