The ASD Risk Gene D5Ertd579e Regulates Synaptic Plasticity and Selective Autism-Related Behaviors

Abstract

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition shaped by contributions from hundreds of genes, many of which remain poorly characterized. This largely uncharacterized genomic landscape may therefore hold critical insight into how diverse molecular disruptions converge on shared social phenotypes. Here, we investigated KIAA0232 (mouse orthologue D5Ertd579e), an uncharacterized locus lacking known functional domains, using a global null knockout mouse model. While loss of D5Ertd579e did not overtly disrupt cortical progenitor dynamics, laminar organization, or gross brain morphology, D5Ertd579e null mutants exhibited selective behavioral deficits in vocalization, sociability, and novelty preference, while anxiety- and memory-related behaviors remained preserved. These behavioral phenotypes were accompanied by attenuated long-term plasticity, despite normal basal synaptic transmission. Together, our findings indicate that D5Ertd579e loss selectively alters neurodevelopment, preferentially impacting neural systems involved in social and motivational processing while preserving hippocampal-dependent networks. We propose that D5Ertd579e functions as a regionally specific regulator of neurodevelopment, whose disruption may contribute to ASD through distinct genetic pathways. More broadly, this study underscores the importance of interrogating uncharacterized loci to refine mechanistic models of the social brain in ASD.