202 | Unraveling the role of brain masculinization in gender bias within autism spectrum disorders

Disorders of the Nervous System

Author: Araceli Seiffe | Email: aseiffe@gmail.com

Araceli Seiffe 1°2°, Amaicha Mara Depino 1°2°

2° DBBE, FCEN, University of Buenos Aires, CABA, Argentina

Autism spectrum disorders (ASD) are characterized by reduced sociability and repetitive behaviors. Notably, this disorder is approximately 4 times more prevalent in boys than girls. To investigate this bias, we used a mouse model: valproic acid (VPA). This model is particularly interesting because it mirrors the gender bias seen in humans.
Our hypothesis posits that the process of brain masculinization is necessary for VPA to impact autism-related behaviors. To test this, in the VPA model, we injected pups with 5 µg 17β-estradiol benzoate (E2) on postnatal days 2, 5, and 8, replicating the testosterone surge males experience during early development.
When we analyzed juvenile behavior, we observed that VPA-exposed females displayed altered social behavior, with the phenotype rescued by estradiol exposure. Conversely, in adulthood we observed that VPA-E2 females did not habituate to social stimuli in both the social interaction test and the social habituation and novelty recognition task.
By assessing different parameters including ovaries development, sexually dimorphic brain nuclei and hormone concentrations in plasma, we were able to validate the successful implementation of the masculinization protocol. Other areas relevant to the model—such as the cerebellum, CA2 region of the hippocampus, and piriform cortex—showed no differences between the groups.
In summary, we can affirm that gonadal hormones drive ASD sex bias, impacting perinatal and juvenile stages.