23 November 2022 12:00
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 socially interact or bond with others. And that 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 drugs and environmental risk factors during embryonic development can lead to changes in this gene, leading to alterations in social behavior similar to those seen in people with autism. To their surprise, the researchers also found that they could reverse some of the effects using an experimental drug.
“This study helps us understand at the molecular level why sociability is disrupted during the very early stages of life,” says Randall T. Peterson, Ph.D., study corresponding author and dean of the University of Utah College. of Pharmacy. . “It also gives us the opportunity to explore potential treatments that could restore sociability in these animals and, perhaps over time, possibly in humans as well.”
More broadly, their findings suggest that the gene – TOP2a – controls a large network of genes known to increase the risk of autism. It may also serve as a link between genetic and environmental factors that contribute to the onset of disorders, adds Peterson.
The study, led by researchers at the University of Utah Health and colleagues nationwide, appears in the Nov. 23 issue of Science Advances.
antisocial animals
Scientists suspect that many social traits are determined before birth. But the precise mechanisms involved in this process remain unclear. A promising area of research suggests that social behavior and other characteristics and traits are influenced not only by our genetic make-up, but also by how and where we live.
To test this model, the scientists assessed whether environmental exposures 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.
VIDEO: After being exposed to certain drugs when they were embryos, juvenile zebrafish were less likely to interact with other zebrafish than those who were not exposed to the drugs, suggesting that normal fish picked up the social cues of stimulating fish that had escaped the experiment. fish. Credit: Randall Peterson/University of Utah Health.
The researchers determined that four of the 1,120 drugs tested significantly reduced zebrafish sociability. Fish exposed to these drugs were less likely to interact with other fish. It turned out that the four drugs all belonged to the same class of antibiotics, called fluoroquinolones. These drugs are used to treat upper and lower respiratory tract infections in humans.
When scientists gave a related drug to pregnant mice, the offspring behaved differently when they became adults. Although they appeared normal, they communicated less with other mice and engaged in more repetitive acts – such as repeatedly poking their heads in the same hole – than other rodents.
A base of sociability
Digging deeper, the researchers found that the drugs suppressed a gene called TOP2a, which, in turn, acted on a group of genes known to be involved in autism in humans.
They also found that the cluster of genes associated with autism shared something else in common: a higher than usual tendency to bind to a group of proteins called PRC2. Researchers have hypothesized that Top2a and PRC2 work together to control the production of many genes associated with autism.
To determine if antisocial behaviors could be reversed, the research team gave embryos 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 closer to other fish, demonstrating that the drug helped restore sociability. They saw similar results with other drugs known to inhibit the same key gene, TOP2a.
“It really surprised me because I would have thought that disrupting brain development when you’re an embryo would be irreversible,” Peterson says. “If you don’t develop sociality as an embryo, you’ve missed the window. But this study suggests that even in these individuals later in life, you can still come in and inhibit this pathway and restore sociality.
In the future, the researchers plan to explore how and why this drug had this effect.
Although scientists have only found four compounds that are inhibitors of Top2a, evidence suggests that hundreds of other drugs and natural compounds in our environment can inhibit its activity.
“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,” says Peterson.
However, Peterson notes that this study was conducted on animals and more research needs to be done before any of its findings can be confirmed in humans. Therefore, he cautions against drawing conclusions about real-world applications.
“We have no evidence that fluroquinolones or any other antibiotics cause autism in humans,” Peterson says. “So 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.
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In addition to Dr. Peterson, U of U Health scientists Yijie Geng, Tejia Zhang, Ivy G. Alonzo, Sean C. Godar, Christopher Yates, Brock 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; the Broad Institute, Cambridge, Massachusetts; 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 of the National Institutes of Health.
Research News Social behavior Autism Genetics
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