Infection During Pregnancy Downregulates the Expression of Amino Acid Transporters in Rat and Human Placentas

Abstract

Maternal immune activation (MIA) resulting from infection during pregnancy increases the chance of offspring having a neurodevelopmental disorder such as autism or schizophrenia. However, the mechanism underlying this association is unknown. Placental transport of amino acids from maternal to fetal circulation is essential for proper fetal neurodevelopment. We hypothesized that MIA could alter the expression of placental amino acid transporters, thereby altering fetal exposure to the amino acids required for proper brain development. Thus, the objective of this study was to examine whether MIA impacts the expression of amino acid transporters in the placentas of rats and humans. MIA was induced in pregnant rats through the administration of the viral mimetic poly(I:C) on gestational day 14. Placental and fetal tissues were collected 24 and 48 hours later. Human placentas isolated at term from pregnancies complicated with either chorioamnionitis (n = 17) or an unidentified active infection causing flu‐like symptoms (n = 6) were compared to healthy gestational age‐matched controls (n = 18). Protein expression of amino acid transporters in rat or human placentas, as well as fetal rat brains, was determined using immunoblotting. Levels of free amino acids in fetal rat brains were also quantified using reverse‐phase HPLC. In rats, poly(I:C) significantly downregulated the amino acid transporters ASCT1 and EAAT2 in the placenta, with a trend towards decreased SNAT2. SNAT5, EAAT1, and GLYT1 were also significantly reduced in fetal brains from poly(I:C)‐treated dams. Furthermore, the levels of multiple amino acids were significantly altered in fetal brains of poly(I:C)‐treated rats. In human placentas, ASCT1 was significantly downregulated in active infection cases, but not in chorioamnionitis cases. A pronounced trend of decreased SNAT2 expression was also seen in active infection cases, but this did not reach significance. To conclude, MIA decreases the expression of amino acid transporters in the placentas of rats and is associated with altered levels of free amino acids in fetal rat brains. Moreover, decreased expression of amino acid transporters is also seen in human placentas obtained from pregnancies with active infection. As amino acids are required for proper neurodevelopment, these changes in transport could provide a link between MIA and neurodevelopmental disorders.