Material below is adapted from the SfN Short Course The Maternal Interleukin-17a Pathway in Mice Promotes Autism-Like Phenotypes in Offspring, by Gloria B. Choi, PhD, Yeong S. Yim, PhD, Helen Wong, PhD, Sangdoo Kim, PhD, Hyun Ju Kim, PhD, Sangwon V. Kim, PhD, Charles A. Hoeffer, PhD, Jun R. Huh, PhD, and Dan R. Littman, MD, PhD. Short Courses are day-long scientific trainings on emerging neuroscience topics and research techniques held the day before SfN’s annual meeting.
Researchers have shown before that if a mother has a viral infection during pregnancy, her baby has a higher chance of having autism spectrum disorder (ASD). Studies have also shown that activating the maternal immune system in mice leads to ASD-like symptoms in the mouse pups. But it was not clear how the mother’s immune system interacted with the fetal brain.
Now, scientists have found that the development of ASD in offspring after maternal immune system activation requires the presence of IL-17a, a substance secreted by a type of immune cell called a T helper 17 (Th17) cell.
It is possible that targeting the Th17 cells to prevent them from secreting IL-17a could prevent the development of ASD-like symptoms in the children of mothers whose immune systems are activated during pregnancy.
The research team induced an immune response in pregnant mice and found that the presence of a number of immune-related proteins, including IL-17a, increased in the placenta and uterine lining. They learned that this increase was tied to the presence of IL-6, a protein that causes the maturation of Th17 cells.
There was also an increase in the RNA that encodes the receptor that binds IL-17a in the brains of fetuses from mothers that had an immune reaction while pregnant.
In order to determine whether it was IL-17a activation causing the ASD-like symptoms in the pups, the researchers next used antibodies to block IL-17a as they activated the maternal immune system. They found that offspring whose mothers had activated immune systems displayed abnormal development of the cortex, but blocking IL-17a resulted in normal cortex development.
The pups of pregnant mice that received the IL-17a-blocking antibody also did not show the increased expression of IL-17a receptor RNA.
These results suggest that the cortical disorganization observed in pups whose mothers’ immune systems were activated during pregnancy is due to increases in maternal IL-17a and its presence in the pups’ brains.
The authors then investigated whether maternal immune activation affected pups’ communication and behavior. Pups whose mothers had activated immune systems showed fewer social behaviors and more repetitive behaviors — both of which are ASD-like symptoms — and also vocalized more.
When these mothers also received the IL-17a blocking antibody, their pups were indistinguishable from controls. Directly administering IL-17a to the brains of mouse pups in the absence of maternal immune activation also led to cortical disorganization and ASD-like behavior, suggesting that abnormal anatomy and behavior are a result of maternal IL-17a in the fetal brain.
Finally, the researchers activated the maternal immune system and gave the IL-17a-blocking antibody two days later, a situation that models the use of the antibody as a therapeutic. Given in this way, the antibody partially rescued some of the ASD-like behaviors in the offspring, namely the communication and repetitive behaviors, but pups of immune-activated mothers still displayed abnormal social behavior.
Future directions of the work include investigating whether IL-17a has a normal function in the brain and, more generally, how immune activation and inflammation during pregnancy can influence neurological development.
