Role of androgen receptors in sexually dimorphic phenotypes in UBE3A-dependent autism spectrum disorder

Autism spectrum disorders (ASDs) involve social, communication, and behavioral challenges. ASDs display a remarkable sex difference with a 4:1 male to female prevalence ratio; however, the underlying mechanism remains largely unknown. Using the UBE3A-overexpressing mouse model for ASD, we studied sexually dimorphic changes at behavioral, genetic, and molecular levels. We found that male mice with extra copies of <i>Ube3A</i> exhibited greater impairments in social communication, long-term memory, and pain sensitivity compared to females. UBE3A-mediated degradation reduced androgen receptor (AR) levels in both sexes but only male mice showed significant dysregulation in the expression of AR target genes. Importantly, restoring AR levels in the brain normalized levels of AR target genes, and rescued the deficits in social preference, grooming, and memory in male UBE3A-overexpressing mice, without affecting females. These findings reveal the critical role of AR signaling in sex-specific changes linked to UBE3A-dependent ASD.