Sex-Dependent Alterations in Behavioral Development of Mice Lacking α5-Nicotinic Acetylcholine Receptors

Complex neurodevelopmental disorders such as autism spectrum disorders (ASD) and schizophrenia are characterized by impaired social interactions, cognitive deficits, and repetitive behaviors. Genome-wide association studies (GWAS) have identified the α5 nicotinic acetylcholine receptor (α5-nAChR) subunit as a significant risk factor for these neuropsychiatric conditions. The α5 subunit is a critical modulator of neural circuit dynamics, specifically through its functional involvement within vasoactive intestinal peptide (VIP)-positive interneurons; however, its role in the sex-dependent maturation of behavioral phenotypes remains poorly understood. We characterized α5-nAChR knockout (ACNA5) mice to investigate the neurodevelopmental consequences of α5 subunit loss. ACNA5 mice displayed sexually dimorphic and age-dependent core symptoms relevant to ASD and schizophrenia. Regarding anxiety-like behavior, there was an opposite sex pattern between genotypes, evident only in adulthood. Cognitive assessment using the novel object location task revealed early-onset spatial memory deficits in ACNA5 females, whereas males exhibited a progressive decline from adolescence to adulthood. In the social domain, adult ACNA5 mice failed to exhibit social novelty preference; females displayed complete social indifference, while males displayed a pronounced familiarity bias. In addition, ACNA5 mice of both sexes displayed amplified repetitive behavior, emerging earlier in males, and poor nest-building scores across developmental stages. Together, these findings identify the α5-nAChR subunit as a crucial modulator of the maturation of neural circuits underlying social motivation, cognition, and emotional regulation. Our results implicate α5-containing nicotinic receptors in the pathogenesis of neurodevelopmental disorders and establish the ACNA5 mouse as a valuable model for investigating sex-specific developmental trajectories and therapeutic windows.