The cause of autism spectrum disorder (ASD) is complex and highly debatable, but a research team led by the Massachusetts Institute of Technology (MIT) may have found a possibility within mice. Their study in Science reveals that inducing an immune response in pregnant mice produces a molecule that interferes with brain development in their offspring, causing behavioral abnormalities reminiscent of ASD in humans.
ASD refers to a range of lifelong neurodevelopmental conditions that have no clear underlying causal mechanism. Researchers cannot be sure whether ASD is the result of one genetic or environmental factor, or whether a complex series of changes, all interlinked, result in the condition.
Certain links between ASD and viral or bacterial infections have been made in the past, with one landmark 2010 study suggesting that women who suffered a severe, hospitalizing infection during pregnancy were more likely to produce a child with ASD. Despite revealing this link, the reason why an infection during pregnancy could lead to ASD remained unknown.
The MIT-led research team thought that it may be something to do with the T-cells – a type of white blood cell – produced during the infection. These cells work in tandem with B-cells when dealing with an infection. B-cells are responsible for producing antibodies, the “handcuffs” that pin down foreign invaders, whereas some types of T-cells called “helpers” assist by signaling to B-cells which invaders to target.
A subset of T-cells, Th17 cells, release a variant of a signaling protein called interleukin (IL-17a) that's involved in the communication between T-cells and B-cells. It also causes inflammation in the body, a normal response to the release of these molecules into the infected part of the body.
On occasion, these types of signaling proteins can become overactive, causing inflammatory diseases. The team hoped to simulate this type of immune response in pregnant mice – without using an actual infection – to see what effect it has on their offspring.
Does IL-17a have the same effect during human pregnancy as it does in mice? Mirko Sobotta/Shutterstock
The mice whose wombs were artificially exposed to IL-17a appeared to show inflammation that interfered with neurological development. Otherwise ordered layers of neurons became chaotically arranged within the cortex, the part of the brain that, among other things, converts visual and sound-based stimuli into thoughts.
This appeared to cause the offspring to have severe behavioral difficulties. Pups were unable to properly vocalize to their mothers, and had difficulty distinguishing between a toy mouse and a real one. When given marbles, they tended to repeatedly and meticulously bury them one by one into their cages.
All these behaviors are strongly reminiscent of humans with ASD. By blocking the Th17 cells’ ability to produce IL-17a in pregnant mice, either by shutting off the gene responsible for its production or by producing anti-IL-17a antibodies, the inflammatory response was interrupted and offspring developed normally.
Although the mechanism behind producing ASD-like behavior in mice appears clear, the human link is still rather tenuous. “We need to find out…whether Th17 cells have the same key function in human mothers as in mice,” Jun R. Huh, an assistant professor of medicine at MIT and a corresponding author on the study, said in a statement.