Maternal immune activation in rats induces dysfunction of placental leucine transport and alters fetal brain growth.

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Abstract

Maternal infection during pregnancy increases the offspring risk of developing a variety of neurodevelopmental disorders (NDDs), including schizophrenia. While the mechanisms remain unclear, dysregulation of placental function is implicated. We hypothesised that maternal infection, leading to maternal immune activation and stimulated cytokine production, alters placental and yolk sac amino acid transport, affecting fetal brain development and thus NDD risk. Using a rat model of maternal immune activation induced by the viral mimetic polyinosinic:polycytidylic acid (poly(I:C)), we investigated placental and yolk sac expression of system L amino acid transporter subtypes which transport several essential amino acids including branched-chain amino acids (BCAA), maternal and fetal BCAA concentration, placental 14C-leucine transport activity and associated impacts on fetal growth and development. Poly(I:C) treatment increased acutely maternal IL-6 and TNFα concentration, contrasting with IL-1β. Transcriptional responses for these pro-inflammatory cytokines were found in placenta and yolk sac following poly(I:C) treatment. Placental and yolk sac weights were reduced by poly(I:C) treatment, yet fetal body weight was unaffected, while fetal brain weight was increased. Maternal plasma BCAA concentration was reduced 24 h post-poly(I:C) treatment, yet placental, but not yolk sac, BCAA concentration was increased. Placental and yolk sac gene expression of Slc7a5, Slc7a8 and Slc43a2 encoding LAT1, LAT2 and LAT4 transporter subtypes, respectively, was altered by poly(I:C) treatment. Placental 14C-leucine transport was significantly reduced 24 h post-treatment, contrasting with a significant increase 6 days following poly(I:C) treatment. Maternal immune activation induces dysregulated placental transport of amino acids affecting fetal brain development, and NDD risk potential in offspring.

Original languageEnglish
Pages (from-to)1117-1137
Number of pages21
JournalClinical Science
Volume136
Issue number15
Early online date19 Jul 2022
DOIs
Publication statusPublished - 12 Aug 2022

Keywords

  • Amino Acids/metabolism
  • Animals
  • Brain/metabolism
  • Cytokines/metabolism
  • Female
  • Fetal Development
  • Leucine/metabolism
  • Placenta/metabolism
  • Poly I-C/pharmacology
  • Pregnancy
  • Rats

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