A super-sensitive gene that controls social behaviors could help in understanding autism

All humans are social beings, but do you ever wonder why some humans are more social and why others are less? Scientists at the University of Utah College of Pharmacy (UUCP) have found the answer to this weird question. They identified a gene named TOP2a, which is involved in shaping early social behavior in human beings, according to a press release.

The researchers claim that if TOP2a undergoes any changes during the early embryonic stage of an individual due to some drugs, chemicals, or any other environment-related factors. This can adversely affect the social behavior of that individual and even turn him or her into a patient with autism. 

They performed an interesting experiment with zebrafish (a popular freshwater and aquarium fish whose embryos are almost transparent) and discovered that alterations in TOB2a can be fixed up to some extent by the use of an experimental drug (UNC1999). These findings suggest that sociability can also be restored.

“That really surprised me because I would've thought disrupting brain development when you're an embryo would be irreversible. If you don’t develop sociality as an embryo, you’ve missed the window. But this study suggests that even in those individuals later in life, you can still come in and inhibit this pathway and restore sociality,” said Randall Peterson, one of the authors and Dean of UUCP, in a press release.

The zebrafish experiment 

Dr. Peterson tested over 1,120 drugs on multiple zebrafish embryos and observed the changes taking place inside the embryo as well as how the changes shaped the social behavior of the fish after birth. Each drug was tested on at least 20 embryos and out of the 1,120, four drugs were found to be suppressing the TOP2a gene activity.

These four drugs belonged to the same category of antibiotics that are used to treat respiratory tract infections (such as pneumonia) in humans, and are referred to as fluoroquinolones. The fish that grew from fluoroquinolone-exposed embryos turned out to be less social than others. 

The researchers also tested mice embryos with the same class of drugs to further confirm their role in deciding sociability. Interestingly, when those mice reached adulthood, they also turned out to be less social as they interacted less with other mice and spent more time doing repetitive tasks that involved no social interaction.

  Similar to the fluoroquinolone-exposed less social fish and mice, patients with autism also find it difficult to communicate and interact with other people. They experience social awkwardness and also show repetitive behavior, such as speaking the same words over and over.   

Later, it was discovered that the suppressed TOP2a gene actually controls a bunch of other genes that are associated with autism in humans. All the TOP2a-controlled genes were also found to be actively binding with a protein called PRC2. So the researchers assumed that perhaps TOB2a and PRC2 together are linked to the rise of autism in a person.

In order to test this theory, they exposed another batch of zebrafish embryos to a PRC2-inhibiting drug UNC1999. Then the researchers introduced fluoroquinolones into the same embryos. The fish resulting from these embryos were found to be more social, unlike what was previously observed.

This time the fish preferred to stay closer and swim together with other fish in their group. These findings suggest that the researchers were able to restore sociability in fluoroquinolones-exposed fish by subjecting them to UNC1999. The experiment also proved the role of both — the TOB2a gene and PRC2 protein in shaping social behavior and that any drug-driven changes in their activity could lead to conditions like autism.

Things are limited to fish and mice

Since only animal embryos were tested and examined during the study, the researchers are still not sure whether their findings will be 100% applicable to humans. For instance, the researchers argue that although fluoroquinolones are found to be inhibiting the TOP2a gene in animal models, there is still no evidence it is responsible for autism in humans. 

So based on the findings, they won’t suggest discarding the use of these antibiotics by patients who takes fluoroquinolones as medicines. Furthermore, Dr. Peterson and his team conducted experiments using only 1,120 drugs; testing more drugs could reveal more TOP2a-inhibiting chemical compounds. 

“It’s possible that these four compounds are just the tip of the iceberg in terms of substances that could be problematic for embryonic exposure,” said Dr. Peterson. Therefore, further research is required to explore more possibilities and confirm the safety and effectiveness of TOP2a-inhibiting chemicals for humans. 

The study is published in the Nov. 23, 2022, issue of Science Advances.