The gene that drives early social behaviors could be the key to understanding autism

Summary: The TOP2a gene controls a network of genes that contribute to ASD. Drugs that suppress TOP2a during development can activate a group of other genes that disrupt brain development and increase autism risks. TOP2a gene alterations may be responsible for the social behavioral difficulties associated with ASD.

Source: University of Utah

Little is known about how social behavior develops early in life. But most animals, including humans, are born with an innate ability to interact socially or form bonds with others. And 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 to this gene, leading to alterations in social behavior similar to those found in individuals with autism. Much to their surprise, the researchers also discovered that they could reverse some of the effects using an experimental drug.

“This study helps us understand at a molecular level why sociability is disrupted during the very earliest stages of life,” says Randall T. Peterson, Ph.D., the study’s corresponding author and dean of the University of Utah College of Pharmacy. “It also gives us an opportunity to explore potential treatments that could restore sociability in these animals and, perhaps in time, humans as well.”

More broadly, their findings suggest that the TOP2a gene 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 the disorder, Peterson adds.

The study, conducted by researchers and colleagues at the University of Utah Health nationwide, appears in the November issue. 23 edition of The progress of science.

Antisocial animals

Scientists suspect that many social traits are determined before birth. But the precise mechanisms involved in this process remain unclear. 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 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.

The researchers determined that four of the 1,120 drugs tested significantly reduced sociability among the zebrafish. 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 people.

When the scientists gave a related drug to pregnant mice, the offspring behaved differently when they became adults. While they looked normal, they communicated less with other mice and engaged in more repetitive actions, such as poking their heads into the same hole over and over, compared to other rodents.

A foundation for sociability

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

They also found that the group of genes associated with autism shared another thing in common: a higher-than-usual tendency to bind a group of proteins called PRC2. The researchers hypothesized that Top2a and PRC2 work together to control the production of many genes associated with autism.

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

“That 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 sociability like an embryo, you’ve missed the window. But this study suggests that even in those individuals later in life, you can still go in and inhibit this pathway and restore sociability.

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

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

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Although scientists have found only four compounds that are Top2a inhibitors, evidence suggests that hundreds of other drugs and naturally occurring 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 embryo exposure,” says Peterson.

However, Peterson notes that this study was done in animals and that more research is needed 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 fluoroquinolones or other antibiotics cause autism in humans,” says Peterson. “So, there is no reason to stop using antibiotics. What this article identifies is a new molecular pathway that appears to control social development and is worthy of further exploration.”

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.

I study, “Top2a promotes the development of social behavior via PRC2 and H3K27me3,” appears in Nov. 23, 2022, issue of The progress of science.

Financing: This research was supported by the LS Skaggs Presidential Endowed Chair and the National Institute of Environmental Health Sciences at the National Institutes of Health.

About this genetics and ASD research news

Author: Doug Dollemore
Source: University of Utah
Contact: Doug Dollemore–University of Utah
Image: Image is public domain

Original research: The results will appear in The progress of science

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