Maternal Immune Activation Alters Placental and Fetal Brain Amino Acid Transport in Rats

Abstract

ProblemMaternal immune activation (MIA) during pregnancy is an environmental risk factor for neurodevelopmental disorders such as autism and schizophrenia. However, the exact mechanism through which this occurs is unknown. Due to the important roles that amino acids play in neurodevelopment, altered transport of amino acids across the placenta and throughout the developing fetal brain could play a role in neurodevelopmental disorders. Our objectives were to determine whether virally mediated MIA alters amino acid transporter expression in the placenta and fetal brain, and to explore the underlying mechanism(s) associated with these changes.MethodsPregnant rats received poly(I:C) on gestational day 14 and placental and fetal tissues were collected 6, 24, and 48 hours later. Amino acid transporter expression in the placenta and fetal brain was measured using qPCR and immunoblotting. Free amino acid concentrations in the fetal brain were quantified using HPLC. To explore a possible mechanism, the expression and phosphorylation of components of the placental mTOR and AMPK signaling pathways were investigated using immunoblotting.ResultsPoly(I:C) induced the mRNA expression of multiple amino acid transporters in the placenta and fetal brain over all three timepoints. Conversely, poly(I:C) significantly decreased protein expression of ASCT1 and EAAT2 in the placenta, and SNAT5, EAAT1, and GLYT1 in the fetal brain. Changes in transporter expression were accompanied by functional changes in the concentrations of numerous amino acids in the fetal brain. We observed activation of AMPK and inhibition of mTOR signaling in the placentas of poly(I:C)‐treated dams.ConclusionsMIA induced by poly(I:C) significantly alters placental and fetal brain amino acid transporter expression as well as amino acid concentrations in the fetal brain. Due to the importance of amino acids in neurodevelopment, changes in amino acid transporters could contribute to the development of a neurodevelopmental disorder. AMPK and mTOR have been previously shown to regulate amino acid transporter expression. Since poly(I:C) altered the activation of placental and AMPK and mTOR, these could provide novel treatment targets to alleviate MIA‐induced changes in amino acid transport and investigate the implications of these changes in neurodevelopment.Support or Funding InformationThis work was supported by an operating grant from the Canadian Institutes of Health Research (CIHR) awarded to Dr. Piquette‐Miller [MOP 13346]. Eliza McColl was a recipient of a CIHR Canadian Graduate Scholarship (Master’s) and an Ontario Graduate Scholarship, and is currently funded by a CIHR Banting and Best Canadian Graduate Scholarship (Doctoral) [GSD‐164238].