A new study published in Scientific progress Research has shed light on the complex mechanisms behind the sex differences in autism. Research suggests that increasing the dose of a gene called Ube3a may influence autism-related traits differently in males and females. By examining mice with extra copies of the gene, the researchers found significant sex-specific effects on brain connectivity and behavior, providing insight into why autism is more prevalent in males.
Autism, or autism spectrum disorder (ASD), is a complex neurodevelopmental disorder characterized by difficulties with social interaction, communication, and a tendency toward repetitive behaviors. These symptoms can vary greatly in severity and manifestation, making autism a spectrum disorder.
Despite extensive research, the exact causes of autism remain unclear. It is thought to result from a combination of genetic, environmental, and neurological factors. One intriguing aspect of autism is its higher prevalence in males, with approximately four males diagnosed for every female. This significant gender difference has led scientists to study potential genetic and biological mechanisms that could explain this disparity.
One of the genetic mechanisms that may contribute to male predominance in autism is the Ube3a gene. This gene is known to be involved in neurodevelopment and is located on chromosome 15. Variations in the Ube3a gene are associated with several neurodevelopmental disorders, including autism. However, its role in interacting with sex-specific mechanisms has not been extensively studied.
“My lab has been studying the genetic and biological causes of autism for many years, particularly the alterations in brain connectivity that characterize these disorders. As part of this research, we scanned the brains of mice with a duplication of the Ube3a gene, which is responsible for autism risk,” said study author Alessandro Gozzi, senior scientist and director of the Functional Neuroimaging Laboratory at the Italian Institute of Technology.
“This research allowed us to serendipitously discover a significant effect of sex on the patterns of alterations we mapped, with male and female mice showing different and divergent effects. This discovery intrigued us and prompted us to explore the functions of Ube3A in more detail. We then realized that this gene plays a little-studied role in controlling the expression of other genes in a sex-dependent manner. Through further research, we discovered that Ube3A acts as a sex-specific switch that controls the expression of many other genes important for autism in rodents and humans.”
To study the effects of increasing the dose of the Ube3a gene, the researchers used a mouse model genetically engineered to mimic the human condition 15q duplication syndrome, which includes duplications of the Ube3a gene and is associated with autism. Specifically, the researchers used Ube3a2X mice, which carry two extra copies of the Ube3a gene, and compared them to a sample of wild-type control mice.
Functional magnetic resonance imaging (fMRI) was used to study brain connectivity. Male and female mice underwent resting-state fMRI (rMRI) to measure functional connections between different brain regions. Structural MRI was also performed to examine possible anatomical changes in the brain.
The fMRI results revealed significant differences in brain connectivity between male and female Ube3a2X mice. Female mice given a higher dose of Ube3a had reduced connectivity in key brain regions, including the hypothalamus and prefrontal cortex. In contrast, male mice had increased connectivity in these areas. These results suggest that Ube3a gene dose affects brain connectivity differently in males and females, which may contribute to the sex-specific prevalence of autism.
“The very divergent effect of the same mutation on brain function in rodents was really striking and surprising, and it became a major lead for our further research,” Gozzi told PsyPost.
To assess autism-related behaviors, the researchers conducted a series of behavioral tests. These included the Open Field Test to measure locomotion and anxiety, the Rotarod Test to assess motor coordination, and the Self-Cleaning Score to observe repetitive behaviors. In addition, social behaviors were assessed using the Habituation/Dishabituation Social Interaction Test and the Three-Compartment Social Interaction Test.
Male Ube3a2X mice exhibited significantly more repetitive behaviors, such as excessive grooming, compared to their wild-type littermates. This increase in stereotypic behavior was not observed in female Ube3a2X mice. The rotarod test also revealed impaired motor coordination in Ube3a2X mice, but these were not sex-specific. In terms of social behavior, the habituation/dishabituation test and the three-chamber test showed no significant differences in social interactions between Ube3a2X mice and wild-type controls, regardless of sex.
The researchers also used RNA sequencing to analyze gene expression in specific brain regions, including the prefrontal cortex and hypothalamus. This allowed them to identify potential differences in gene activity between Ube3a2X mice and their wild-type counterparts, as well as between males and females.
Gene expression analysis provided insight into the sex-specific effects of increasing Ube3a dose. In the prefrontal cortex, many autism-associated genes showed dysregulated expression depending on sex. For example, some genes were upregulated in male Ube3a2X mice but downregulated in females, and vice versa. This differential gene expression was particularly evident in genes located on the X chromosome and those influenced by sex steroid hormones, such as androgen and estrogen receptors.
“The main takeaway from this study is that the sex predominance in autism (with boys being four times more affected than girls) can likely be explained by genetic mechanisms, particularly those that interact with sex hormones,” Gozzi said. “This finding adds to a growing body of evidence suggesting that autism is, in many ways, a genetic condition.”
These findings help us better understand the genetic and biological factors underlying gender bias in autism. However, Gozzi noted that “this is just one of many genetic mechanisms that may lead to gender bias in autism. The challenge now is to understand what other genetic and biological mechanisms contribute to this phenomenon and to what extent.”
“Our long-term goal is to better understand how the genetic alterations that put people at risk for developing autism alter brain function. This is a major gap in our knowledge that we need to fill.”
The study entitled “Influence of sexual bias on the overdose of the Ube3a gene associated with autism at the connectomic, behavioral and transcriptomic levels” was written by Caterina Montani, Luigi Balasco, Marco Pagani, Filomena Grazia Alvino, Noemi Barsotti, A. Elizabeth de Guzman, Alberto Galbusera, Alessia de Felice, Thomas K. Nickl-Jockschat, Sara Migliarini, Simona Casarosa, Pierre Lau, Lorenzo Mattioni, Massimo Pasqualetti, Giovanni Provenzano, Yuri Bozzi, Michael V. Lombardo and Alessandro Gozzi.
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