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

Researchers studied male and female mice with autism-like traits to understand why autistic girls and boys might show different social behaviors. They found that male and female mice had different brain changes - males had simpler brain cell structures and struggled with recognizing new social partners, while females had changes in brain chemistry (serotonin system) and were less social overall. This suggests that autism affects male and female brains differently, which might explain why autism presents differently in girls versus boys.

This preclinical study used Tsc2 mice (a genetic autism model) to investigate sex differences in brain networks and social behavior. Male transgenic mice showed shorter, less complex cortical dendrites and deficits in social novelty preference, while females had changes in apical dendrites, reduced serotonin receptor density, increased cortical excitability, and reduced general sociability. Females also showed altered excitatory/inhibitory balance and fewer axonal fiber pathways in cortex-amygdala-hippocampus circuits. Better social performance correlated with cortical serotonergic function.

The findings suggest sex-specific neurobiological mechanisms may underlie observed differences in social behaviors between autistic males and females, particularly involving serotonin system alterations.

Results suggest autism interventions may need sex-specific approaches, particularly targeting serotonin systems in females. Findings support the need for sex-stratified research in autism studies and may inform development of personalized treatments based on neurobiological sex differences.

This is a preclinical mouse study, so findings may not directly translate to humans. Sample sizes are not reported. The relationship between mouse social behaviors and human autism symptoms requires careful interpretation. Long-term developmental outcomes were not assessed.

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 Tsc2mice, 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 Tsc2females exhibited changes in the serotonergic system and E/I balance, with reduced cortical 5-HTreceptor 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.