Poly(I:C) alters placental and fetal brain amino acid transport in a rat model of maternal immune activation

Abstract

Problem Maternal immune activation (MIA) during pregnancy is associated with increased chances of neurodevelopmental disorders including schizophrenia and autism spectrum disorder (ASD). However, the exact mechanism through which MIA contributes to altered neurodevelopment is unknown. Due to the important role that amino acids play in neurodevelopment, altered amino acid transport could play a role in neurodevelopmental disorders. Indeed, altered plasma concentrations of multiple amino acids have been reported in individuals with ASD or schizophrenia. Therefore, our objective was to determine whether virally mediated MIA induces changes in amino acid transporters in the placenta and fetal brain. Method of study Pregnant rats were administered poly(I:C) on gestational day 14, and placental and fetal tissues were collected 6, 24, and 48 hours later. Amino acid transporter expression was measured in the placenta and fetal brain using qPCR, Western blotting, and Simple Western. Free amino acid concentrations in the fetal brain were quantified using HPLC. Results Poly(I:C) increased mRNA expression of several amino acid transporters in the placenta and fetal brain over these timepoints. Conversely, poly(I:C) imposed significant decreases in the protein expression of ASCT1 and EAAT2 in placenta and expression of SNAT5, EAAT1, and GLYT1 in fetal brain. Functional consequences of altered transporter expression were demonstrated through widespread changes in the concentrations of free amino acids in the fetal brains. Conclusion Together, these results represent novel findings with the poly(I:C) MIA model and contribute to the understanding of how MIA during pregnancy potentially leads to neurodevelopmental disorders.

Impact of Viral Inflammation on the Expression of Renal Drug Transporters in Pregnant Rats

“…A potential mechanism behind altered transporter expression may stem from cytokine-mediated pathways. Poly I:C induced the expression of pro-inflammatory cytokines in the serum [17] and kidneys of pregnant rats. Indeed, numerous studies have demonstrated poly I:C-mediated induction of pro-inflammatory cytokines both in vivo in the liver, placenta, and brain [15,36,37] and in vitro [38][39][40].…”

“…As compared to saline controls, the mRNA expression of IL-6, IL-1β, and TNF-α in the kidneys was significantly higher in the poly I:C-treated groups at 6 and 24 h. While the levels of IL-1β and TNF-α returned to baseline at 48 h, levels of IL-6 remained significantly higher at 48 h in the poly I:Ctreated group (Figure 1). Maternal serum concentrations of IL-6 were elevated by approximately 16fold at 6 h after poly I:C administration (p < 0.05) and returned to baseline by 24 h, as determined by ELISA [17].…”

“…injections of either 10 mg/kg poly I:C (Sigma Aldrich, Oakville, ON, Canada) dissolved in saline (0.9% NaCl) or saline on gestational day 14 (n = 23-24/group). This dose is well-tolerated by pregnant animals and a full immune response is elicited [17]. Rats were then anesthetized using isoflurane (Fresenius Kabi Canada, Toronto, ON, Canada) and euthanized at 6, 24, or 48 h after injection (n = 7-8/group per time point).…”

Antiviral Inflammation during Early Pregnancy Reduces Placental and Fetal Growth Trajectories

“…Interestingly, mice lacking these transmembrane proteins are protected from PolyI:C-induced placental maldevelopment and embryonic loss, implicating placental maldevelopment as a critical determinant causing adverse pregnancy outcomes during viral inflammation (18). In rats, PolyI:C administration at midgestation is associated with altered expression of amino acid and drug transporters in the placenta, resulting in a corresponding change in amino acid concentrations in the fetus (48,49). Term human placental explants also exhibit altered expression and function of multidrug resistance transporters following challenge with PolyI:C (50).…”

LPS versus Poly I:C model: comparison of long-term effects of bacterial and viral maternal immune activation on the offspring

“…Other changes reported for the placenta after exposure to MIA include a decrease in placenta weight (36). Furthermore, upregulation of certain amino acids transporters was reported (42), potentially leading to nutritional changes of the fetus. Damage or irreversible changes to the placenta caused by MIA could affect outcomes in the offspring.…”