Elucidating neural substrates that mediate autism-like behaviors

NIH RePORTER · NIH · R01 · $514,379 · view on reporter.nih.gov ↗

Abstract

ABSTRACT Developing fetus in maternal womb can be exposed to environmental stress, and this may lead to the development of long-lasting neurological and behavioral changes. Uncontrolled Inflammation encountered in utero and its effects on behaviors of offspring have been modeled in rodents and subsequently coined as maternal immune activation (MIA). However, it is still unknown how the immune activation, which takes place in pregnant dams, is translated into neurological and behavioral changes in offspring. Using both genetic mutants lacking a particular subset of pro-inflammatory immune cells and blocking antibodies targeting their activities, we have recently found that pro-inflammatory T helper cells (Th17 cells) expressing intereukin-17a (IL-17a) in mothers induce MIA-dependent behavioral changes and abnormal cortical phenotypes in offspring. We also observed that the receptor for IL-17a (IL-17Ra) is expressed in the fetal brain and its expression is increased in the cortical plate upon MIA. These observations taken together suggest an exciting hypothesis that uncontrolled activation of IL-17Ra expressed in fetal brain induces abnormal cortical patches and these structural abnormalities eventually lead to the MIA- associated behavioral phenotypes. Thus, in this application, we propose 1) to determine if cortical abnormalities could predict behavioral phenotypes in MIA offspring, 2) to characterize cortical abnormalities in adult MIA offspring, and 3) functionally determine if the cortical phenotype is the underlying cause of the MIA behavioral abnormalities.

Key facts

NIH application ID
10215438
Project number
5R01MH115037-05
Recipient
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
Principal Investigator
Gloria Choi
Activity code
R01
Funding institute
NIH
Fiscal year
2021
Award amount
$514,379
Award type
5
Project period
2017-09-12 → 2022-06-30