Sex-specific cortical networks drive social behavior differences in an autism spectrum disorder model

Social behavior is highly sensitive to brain network dysfunction caused by neuropsychiatric conditions like autism spectrum disorders (ASDs). Some studies suggest that autistic females show fewer social skill impairments than autistic males. However, the relationship between sex differences in social behavior and sexually dimorphic brain neurophysiology in ASD remains unclear. We hypothesize that sex-specific changes in cortical neurophysiology drive the sexual dimorphism observed in social behavior for ASD. To test this, we used male and female Tsc2^+/- mice, a genetic ASD model, to examine cortical neuron morphology, the serotonergic system, E/I balance, structural connectivity, and social behavior. At the cellular level, transgenic males had shorter and less complex cortical basal dendrites, while transgenic females showed the opposite in apical dendrites. Notably, only Tsc2^+/- females exhibited changes in the serotonergic system and E/I balance, with reduced cortical 5-HT_1A receptor density and increased excitability. Additionally, activation of these serotonin receptors in transgenic animals correlated with E/I imbalance, highlighting inherent sexual dimorphisms in neuronal connectivity. In parallel, the TSC2 mouse model displayed sex-dependent changes in the structural connectivity of the cortex-amygdala-hippocampus circuit and social behavior: females showed a reduced number of axonal fiber pathways and reduced sociability, while males exhibited a loss of tissue density and deficits in social novelty. Moreover, in our ASD mouse model, better social performance correlated with the cortical serotonergic system. Our findings suggest that sex-dependent alterations in cortical neurophysiology, particularly in the serotonergic system, may contribute to the sexually dimorphic social behaviors observed in ASD.