Despite a wealth of research, how and why autism and other neurodevelopmental disorders appear is still unknown. The search is on for any factors that might contribute to these psychological conditions. A recent study focuses on maternal allergies.
However, although these connections have been glimpsed, the cellular mechanisms that underpin them are not understood; how do inflammatory and immune responses influence cognition and behavior?
Research, recently presented at Neuroscience 2016 - the annual meeting of the Society for Neuroscience in San Diego, CA - adds another piece to this unwieldy puzzle. The study was led by Kathryn Lenz, an assistant professor of psychology at Ohio State University.
Autism is three or four times more common in males than females; Lenz and colleagues set out to investigate this gender difference in rats.
To this end, the team first sensitized female rats to an egg white protein, ovalbumin, prior to them becoming pregnant. Fifteen days into the pregnancy, the rats were presented with the allergen to trigger an immune response.
"We're really interested in figuring out unknown factors in psychological disorders and in differences between male and female brain development as it relates to autism, ADHD, and other disorders."
Immune-mediated changes in rat pups
Once they had been sensitized, the team designed experiments to gauge whether the mother's immune response made measurable changes in the pups. Firstly, the levels and types of immune cells in the rat's developing brains were measured.
Secondly, behavioral differences in the rat pups were measured once they were born, such as their ability to learn, anxiety-like behavior, and their overall levels of activity.
Finally, Lenz and her team examined the density of dendritic spines in the pup's brains - points of synaptic connection between nerve cells in the rat's frontal cortex. Dendritic spines are important in cellular-level communication within the brain; a number of cognitive disorders show abnormalities in the numbers of dendritic spines and their maturity level.
The team found that the rats whose mothers had been exposed to an allergen had an increase in certain immune cells in the brain - called mast cells. They also showed a reduction in another type of immune cell - microglia. These differences were the same in both sexes.
Another marked change was seen in their behavior. Allergic mothers' offspring were hyperactive and demonstrated less anxiety-like behavior. Lenz says: "Young rats engage in social play and males are more rough and tumble and usually play much more than females." However, the males in the allergy group were found to roughhouse with their peers significantly less.
As Lenz explains: "The males born to the allergen-exposed mothers looked more like females. They were more socially reserved. They were really hyperactive but socially disengaged. That looks a bit like ADHD."
Mental flexibility altered by immune challenge
Differences were also seen when looking at the mental flexibility of the rats; those born to allergic mothers struggled more when challenged.
The team tested the rats by hiding Cheerios in terra-cotta pots. To find the treat, they had to follow rules and, each time, the researchers would tweak the rules, testing the pup's mental flexibility. Sometimes the pots would be covered in sandpaper, other times in velvet. The rats needed to be adaptable to uncover the prize.
All of the rats in the allergen group, regardless of gender, struggled to adjust to the differing trials. However, the males in the allergen group were found to struggle more than the females.
Further differences were unearthed when data from the dendritic spines was analyzed. The male rats born from allergen-exposed mothers had a reduction in number, whereas the females from the allergen group had an increase in number.
"This is evidence that prenatal exposure to allergens alters brain development and function and that could be an under-appreciated factor in the development of neurodevelopmental disorders."
Further studies will, of course, be necessary to flesh out these findings. However, they are an interesting addition to current knowledge. The connection between immune system and cognitive deficits seems solid; the next challenge will be converting this knowledge into treatments and preventions.