How does autism develop? While genetics play a major role, researchers know that environmental factors during pregnancy also contribute to autism spectrum disorder.
New research at Cold Spring Harbor Laboratory (CSHL) reveals that inflammation during a critical window of pregnancy can contribute to autism-like traits in male mice. Scientists also uncovered an unexpected link between the placenta and autism risk in some pups.
"To truly understand autism spectrum disorder, we have to look beyond the brain," CSHL Associate Professor Lucas Cheadle says. "Our work suggests that maternal immune activation and changes within the placenta are a gateway to autism for some unique individuals."
Cheadle's lab simulated a viral attack in different stages of pregnancy by injecting mice with a compound that triggers the immune system without causing an infection. At 12.5 days, they found that fetuses were the most susceptible to developing abnormalities following inflammation. About a third showed signs of altered development within just one day, says Irene Sanchez Martin , a postdoc in the Cheadle lab. While maternal immune activation has been studied for a long time, this is the earliest that scientists have ever seen signs of disruption.
Perhaps most remarkably, in all trials, only the male mouse fetuses showed autism-like traits. Females developed as expected. This may provide clues for why autism is diagnosed at a much higher rate in boys than girls, Cheadle says. "It's really fascinating, because we're looking at an age which precedes hormonal surges. It precedes sexual differentiation in the brain and many other regions. So, it's surprising there would be a sex-based difference this early."
To understand why some pups developed abnormalities while others did not, Cheadle and Sanchez Martin turned their attention to the placenta. They focused on spongiotrophoblasts—cells in a region of the mouse placenta where maternal and fetal cells meet. In pups that developed as expected, this region appeared healthy. But in males with developmental abnormalities, spongiotrophoblasts showed signs of damage.
Normally, spongiotrophoblasts help the immune system tolerate a growing fetus. After maternal immune activation, however, these cells can lose their protective function, making the mother's body respond in a way that can harm the fetus.
The data suggest male embryos may have unique proteins that the mother's body reacts negatively to after a viral infection. On the other hand, Cheadle says, "a protective mechanism may exist within the female that could be harnessed to help the male. We're trying to understand how autism emerges in both sexes," he explains. "The evidence says that there are potentially different mechanisms."
Cheadle's lab plans to continue studying both the male and female pups, which could reveal potential targets for therapies. And that could mean new avenues for earlier autism intervention.
