Unraveling the Mechanisms Promoting Sex Differences in ASD Using a Pogz Mouse Model
Abstract
Boys are four times more likely to be diagnosed with autism spectrum disorder (ASD) than girls. The mechanisms underlying this well-known sex bias are still not understood. In humans, it is very difficult to separate the role of gender socialization and social biases inherent in the diagnosis from the true biological differences between boys and girls. Known biological mechanisms include genetic and hormonal factors that may affect brain development and function, leading to differences between the sexes in symptoms and vulnerability to the disorder. Multiple studies have identified an increased burden of deleterious variants in female ASD patients, supporting the hypothesis that females are somehow protected from genetic variants that increase the risk of ASD and require more severe genetic insults to develop ASD. Previous studies still leave open the nature of both protetive mechanisms and sex bias. Furthermore, existing ASD mouse models do not recapitulate this male bias. In our project, we will address the sex-dependent manifestation of ASD using a mouse model that exhibits differences in social behavior between males and females. This mouse model bears a mutation that disrupts the function of a gene known in humans to be mutated in individuals with ASD with a distinctive symptom of overly friendly behavior. Importantly, we found that only male mice carrying the mutation exhibit an abnormal increase in social investigation. The abnormal behavior was accompanied by an increase in the activity of specific cells in brain regions whose structure and function are known to be affected in ASD. Using this mouse model has a unique advantage in that it reflects the sex bias of ASD in humans, allowing us an opportunity to compare genetically similar mice (with or without the mutation) and study males and females separately to tease apart the contributions of each of these factors. We will use this mouse model to ask which differences in the brain contribute to sex-dependent abnormal social behavior. We will employ new behavioral tests to compare how animals with and without the mutation differ in social behaviors in males and females. Second, we will study how the ASD mutation affects the expression of other genes in the brain and discover which brain regions and cell types contribute most strongly to the male- specific differences. Third, we will measure the electrical activity of brain cells during social behavior to determine how their activity is connected to the behaviors. Finally, we will link the gene expression and electrical properties of the most affected brain cells to understand the mechanistic basis for the atypical behaviors. Together, these experiments will uncover brain mechanisms that may help explain the male-specific differences seen in human ASD. Establishing these new methods and the new mouse model could identify factors that can increase risk or protect from ASD, which in the long run, could guide informed and effective treatments for this disorder.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210567
Entities
People
- Shlomo Wagner
Organizations
- United States Army
- University of Haifa