Viral model of maternal immune activation alters placental AMPK and mTORC1 signaling in rats

Introduction: Maternal immune activation (MIA) is associated with neurodevelopmental disorders in offspring. We previously demonstrated that poly(I:C)-mediated MIA alters placental and fetal brain amino acid transporter expression in rats, which could potentially play a role in altered neurodevelopment; however, the mechanism(s) underlying these changes in amino acid transporter expression remain unknown. The objective of the current study was to investigate the mechanism(s) underlying poly(I:C)-mediated changes in the expression of the amino acid transporters in the placenta. Methods: Pregnant rats received poly(I:C) on gestational day 14 and placentas were collected 6 h later. Mass spectrometry-based proteomics of placentas was performed followed by pathway enrichment analysis. Activation of mTORC1 and its upstream regulator, AMPK, was investigated using immunoblotting. Finally, the role of mTORC1 and AMPK in regulating the expression and localization of the amino acid transporters EAAT2 and ASCT1 was investigated in the human choriocarcinoma cell line JAR. Results: The impact of poly(I:C) on the placental proteome was highly sexually dimorphic. While proteomics-based pathway enrichment analysis indicated enrichment of mTOR signaling in male placentas only, further investigation revealed inhibition of mTORC1 in both male and female placentas in addition to activation of AMPK. In vitro, activation of AMPK and inhibition of mTORC1 decreased membrane localization of EAAT2 and ASCT1. Discussion: Poly(I:C)-mediated MIA activates AMPK and inhibits mTORC1 in rat placenta, both of which decrease expression and membrane localization of EAAT2 and ASCT1 in vitro. Thus, AMPK/mTORC1 signaling could be a novel treatment target for alleviating MIA-mediated changes in placental amino acid transport.

Automated summary

Maternal immune activation (MIA) has been linked to neurodevelopmental disorders in offspring. This study demonstrated that poly(I:C)-mediated MIA affects placental proteome in a sexually dimorphic manner, with enrichment of mTOR signaling in male placentas. Inhibition of mTORC1 and activation of AMPK in response to MIA decreased membrane localization of EAAT2 and ASCT1, suggesting a potential treatment target for MIA-related placental amino acid transport changes.