The Maternal Interleukin-17a Pathway in Mice Promotes Autism-like Phenotypes in Offspring

Friday, May 13, 2016: 11:30 AM
Hall B (Baltimore Convention Center)
G. Choi, MIT McGovern Insitute for Brain Research, Cambridge, MA
Background: Accumulating evidence points to a central role for immune dysregulation in uteroas as a risk factor in Autism Spectrum Disorder (ASD). Human studies suggest that maternal viral infections early in pregnancy correlate with an increased frequency of ASD in the offspring. This observation, coined maternal immune activation (MIA), has been modeled in rodents by inducing inflammation in pregnant dams. However, The immune cell populations critical in the MIA model have not been identified.

Objectives: Based on previous observations suggesting their involvement in ASD, we tested whether TH17 cell population and its cytokine are necessary for MIA phenotypes.

Methods: N/A

Results: Using both genetic mutants and blocking antibodies targeting their activities, we have recently found that Th17 cells are critical mediators working in pregnant mice to induce behavioral abnormalities in MIA-affected offspring. T cell-specific inactivation of RORgt in mothers (thus selectively removing Th17 cells in pregnant mothers) protected from induction of MIA-dependent behavioral phenotypes in offspring. In addition, we found that maternal inflammation leads to abnormal cortical phenotypes in offspring and this malformation is fully rescued by inhibiting the maternal IL-17a pathway. We also found that the receptor for IL-17 (IL-17R) is expressed in the developing fetal brain and its expression is increased in the cortex upon MIA.

Conclusions: These observations suggest a hypothesis that uncontrolled activation of IL-17R expressed in fetal brain induces abnormal cortical development and these structural abnormalities may be an underlying cause of the MIA-dependent behavioral phenotypes.