Viral infection during pregnancy causes autism-like behaviors in mice

Viral infection during pregnancy causes autism-like behaviors in mice

A study published in the journal Science found that activation in pregnant mice of a particular immune response, similar to what may occur with certain viral infections during pregnancy, alters the brain structure of the mouse offspring and causes behavioral changes, reminiscent of those observed in humans with autism spectrum disorder (ASD).

Several past human studies have suggested a correlative link between maternal viral infection during pregnancy and risk of autism spectrum disorder. Mouse models have been created and used to study how maternal immune activation influences autism-like behavior, but the mechanism underlying this was not known until now.

The new study centers on T lymphocytes, immune cells that react to infections by expanding into a cellular army that attacks the invading microbe at hand. A subset of T cells, Th17 cells release interleukin 17 (IL-17), a signaling protein (cytokine) that amplifies normal immune responses to fend off infections. When overactive or off target, cytokines contribute to inflammatory and autoimmune diseases like psoriasis and inflammatory bowel disease. Th17 cells supply most of a version of IL-17 called IL-17a.

Specifically, the study found that activation of Th17 cells and related IL-17a production are the core mechanisms by which inflammation in mouse mothers create behavioral abnormalities in their litters. The results in particular point to Th17 cell activation regulated by retinoid-related orphan receptor gamma t (ROR gamma t), which turns on genes that enable T cells to mature and produce IL-17a in humans and mice.

In behavioral experiments, the study authors found that exposure in the womb to IL-17a, produced in higher levels in reaction to injecting the mother with poly-I:C, created autism-like symptoms. For example, mice exposed to higher IL-17a levels in the womb had trouble telling the difference between another live mouse and a toy. They interacted with both equally, whereas normal mice spent more time socially interacting with live mice.

In terms of communication differences, mouse pups are known to cry to their mothers, but recordings revealed that offspring exposed to IL-17a inflammation vocalized abnormally. Mice exposed to this kind of immune response were also more likely to bury marbles found in their cages one after the other in a compulsive, repetitive behavior.

The research team also found that Th17-driven inflammation via IL-17a interfered with normal development of certain regions of the brain. Otherwise carefully ordered nerve cell layers became chaotic in the cortex, the part of the brain that sculpts sights and sounds into thoughts. The team focused on this feature because disorganized cortical architecture had been found in past studies of human patients with autism.

Blocking the action of Th17 cells completely restored normal structure and function to the brains of the study offspring, regardless of whether this was accomplished by treatment with anti-IL17a antibodies or by blocking the expression of ROR gamma to shut down the IL-17a gene.