Gene that guides social behaviours may be linked to autism

Thursday, 08 December, 2022

Gene that guides social behaviours may be linked to autism

Little is known about how social behaviour develops in the earliest stages of life, but most animals (including humans) are born with an innate ability to interact socially or form bonds with others. Now, a new study led by the University of Utah has pointed to a gene that is important for the earliest development of basic social behaviours.

The work, published in the journal Science Advances, suggests that exposure to certain drugs and environmental risk factors during embryonic development can cause changes to this gene, leading to alterations in social behaviour that are similar to those found in individuals who have autism. The study authors also found they could reverse some of the effects using an experimental drug.

Scientists suspect that many social traits are determined before birth, but the precise mechanisms involved in this process remain murky. One promising area of research suggests that social behaviour 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, US scientists evaluated whether environmental exposures during embryonic development could influence social behaviour. Corresponding author Dr Randall T Peterson and colleagues exposed zebrafish embryos to more than 1100 known drugs — one drug per 20 embryos — for 72 hours beginning three days after conception.

The researchers determined that four of the 1120 tested drugs significantly reduced sociability among the zebrafish, with fish exposed to these drugs less likely to interact with other fish. It turned out that the four medications 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. Even though they appeared normal, they communicated less with other mice and engaged in more repetitive acts — like repeatedly poking their head in the same hole — than other rodents.

Digging deeper, the researchers found that the drugs suppressed a gene called TOP2a, which, in turn, acted on a cluster of genes that are known to be involved in autism in humans. They also found that the cluster of autism-associated genes shared another thing in common — a higher than usual tendency to bind a group of proteins called the PRC2. The researchers hypothesised that TOP2a and the PRC2 work together to control the production of many autism-associated genes, with the former potentially serving as a link between genetic and environmental factors that contribute to onset of autism.

To determine whether the antisocial behaviours could be reversed, the research team gave embryonic and young zebrafish an experimental drug called UNC1999, which is known to inhibit the 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 TOP2a.

“That really surprised me, because I would’ve thought disrupting brain development when you’re an embryo would be irreversible,” Peterson said. “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.”

Although the scientists only found four compounds that are TOP2a inhibitors, evidence suggests hundreds of other drugs and naturally occurring compounds in our environment can inhibit its activity. Peter noted, “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.”

Peterson acknowledged that the study was conducted in animals, and more research needs to be done 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,” he said. “So there is no reason to stop using antibiotics. What this paper does identify is a new molecular pathway that appears to control social development and is worthy of further exploration.

“This study helps us understand at the molecular level why sociability is disrupted during the very earliest stages of life,” Peterson concluded. “It also gives us an opportunity to explore potential treatments that could restore sociability in these animals and, perhaps in time, eventually in humans as well.”

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