Gene directing early social behaviors may be key to understanding autism – ScienceDaily


Little is known about how social behavior develops in the early stages of life. But most animals – including humans – are born with an innate ability to interact socially or form bonds with others. This contributes to lifelong success.

Now, a new animal study points to a gene important for the early development of basic social behaviors.

The work also suggests that exposure to certain medications and environmental risk factors during embryonic development can cause changes in this gene, leading to changes in social behavior similar to those found in individuals with autism. Much to their surprise, the researchers also found that they could reverse some of the effects with an experimental drug.

says Randall T. Peterson, PhD, corresponding author of the study and dean of the University of Utah College of Pharmacy. “It also gives us an opportunity to explore potential therapies that could restore social communication in these animals and, perhaps over time, eventually in humans as well.”

More broadly, their findings suggest that a gene — TOP2a — controls a large network of genes known to increase the risk of autism. It may also act as a link between genetic and environmental factors that contribute to the onset of the disorder, Peterson adds.

The study, conducted by researchers and colleagues at University of Utah Nationwide Health, is published in the November 23 issue. Science advances.

Antisocial animals

Scientists believe that many social traits are determined before birth. But the exact mechanisms involved in this process remain obscure. One promising area of ​​research suggests that social behavior and other characteristics and traits are influenced not only by our genetic makeup but also by how and where we live.

To test this model, the scientists evaluated whether environmental exposure during embryonic development could influence social behavior. Peterson and his colleagues exposed zebrafish embryos to more than 1,100 known drugs — one drug for every 20 embryos — for 72 hours starting three days after conception.

Researchers determined that four of the 1,120 drugs tested significantly reduced social contact among zebrafish. Fish exposed to these drugs were less likely to interact with other fish. It turns out that the four drugs all belong to the same class of antibiotics called fluoroquinolones. These medications are used to treat upper and lower respiratory tract infections in people.

When the scientists gave a related drug to pregnant mice, the offspring behaved differently as they became adults. Although they appeared normal, they communicated less with other mice and engaged in more repetitive actions–such as repeatedly poking their heads into the same hole–than other rodents.

The basis of sociability

Digging deeper, the researchers found that the drugs inhibit a gene called TOP2a, which in turn acts on a group of genes known to be involved in autism in humans.

They also found that the cluster of genes associated with autism had something else in common — a higher-than-normal tendency to bind a group of proteins called PRC2. The researchers hypothesized that Top2a and PRC2 work together to control the production of several genes associated with autism.

To determine whether antisocial behaviors could be reversed, the research team administered embryonic and young zebrafish an experimental drug called UNC1999, which is known to inhibit PRC2. After treatment with the drug, fish exposed to fluoroquinolones were more likely to swim close to other fish, which indicates that the drug helped restore social communication. They saw similar results with other drugs known to inhibit the same key gene, TOP2a.

“It really surprised me because I had thought that disrupting brain development when you’re a fetus would be irreversible,” says Peterson. “If you don’t develop sociality as a fetus, you’ve missed the window. But this study suggests that even in these individuals later in life, you can still go in and inhibit that pathway and restore social connection.”

Going forward, the researchers plan to explore how and why this drug had this effect.

Although scientists only found four compounds that are Top2a inhibitors, evidence suggests that hundreds of other drugs and compounds that occur naturally in our environment can block its activity.

“These four compounds are probably just the tip of the iceberg in terms of potentially problematic substances for fetal exposure,” says Peterson.

However, Peterson points out that this study was conducted on animals, and that more research is needed before any of its results can be confirmed in humans. Therefore, he cautions against drawing conclusions about real-world applications.

“We have no evidence that fluoroquinolones or any other antibiotic causes autism in humans,” says Peterson. “Therefore, there is no reason to stop using antibiotics. What this paper identifies is a new molecular pathway that appears to control social development and deserves further exploration.”

In addition to Dr. Peterson, U Health scientists Yijie Jing, Tiejia Zhang, Ivy G. Alonzo, Sean C. Godard, Christopher Yates, Brooke Plummer, and Marco Bortolato contributed to this study. Other participating institutions include the University of Chicago. Beth Israel Deaconess Medical Center in Boston; Massachusetts General Hospital and Harvard Medical School; Broad Institute, Cambridge, MA; and MDI Biological Laboratory, Bar Harbor, Maine.

the study, “Top2a promotes the development of social behavior via PRC2 and H3K27me3,” Appears in the November 23, 2022 issue of Science advances. This research was supported by the LS Skaggs Presidential Chair and the National Institute of Environmental Health Sciences at the National Institutes of Health.



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