The effect of poly(I:C)-mediated maternal immune activation on fetal, placental and yolk sac outcomes in a rat model

Abstract

Prenatal maternal immune activation (mIA) is associated with increased susceptibility to neurodevelopmental disorders (NDDs) in later life as evidenced by epidemiological studies that have associated prenatal infection with increased risk of NDDs such as schizophrenia (SZ). Prenatal induction of mIA in rodents produces behavioural and neuropathological phenotypes in the offspring, characteristic of NDD cognitive deficits. Previous studies in rodent models of mIA have characterised elicited maternal cytokine responses and altered cytokine balance in the placenta but are lacking with regards to how mIA affects functionality of placental and yolk sac nutrient transport systems. In this study it was hypothesised that mIA and the associated maternal proinflammatory cytokine response, induced by the viral mimetic poly(I:C), impairs placental amino acid transporter capacity, leading to altered fetal brain development and predisposition to NDDs later in life. This study administered poly(I:C) on gestational day (GD) 15 to pregnant Wistar dams to investigate the effects of mIA induction on maternal proinflammatory cytokine release and gestational growth trajectory, as well as characterising inflammatory changes and elicited effects in the fetoplacental unit, as compared to vehicle-treated controls. The molecular properties of poly(I:C) from two major commercial suppliers were found to differ with respect to molecular weight and endotoxin contamination, and this impacted on fetal phenotypic outcomes. Various techniques were employed to investigate the impact of poly(I:C)-mediated mIA induction on placental and yolk sac transport function, with a focus on system L amino acid transporters (LATs), including gene and protein expression analyses of LAT subunits in the placenta and yolk sac at 3 h (GD15), 24 h (GD16) and 6 days (GD21) following poly(I:C) administration and assessment of system L activity by measurement of in vivo maternofetal transfer of 14C-leucine at GD16 and GD21. The effect of poly(I:C) on fetal, placental and yolk sac growth and the concentration of branched amino acids (BCAAs) in these tissues, as well as placental morphology were investigated, and effects were examined according to fetal sex, to determine sexual dimorphic phenomena. At GD16, poly(I:C) induced sex-specific and gestational-dependent inflammatory responses in the placenta and yolk sac as well as on LAT expression and system L activity (reduced accumulation of 14C-leucine in the fetus), accompanied by reduced placental weight (in males) and disrupted labyrinth zone organisation. In contrast, at GD21, placental system L expression (but not yolk sac) and activity was increased in poly(I:C)-treated group, accompanied by an increased fetal plasma BCAA concentration (in males). Fetal bodyweight was unaffected by poly(I:C) treatment at all gestational timepoints, indicative of sustained fetal growth. However, fetal brain: bodyweight ratio was increased post-mIA at all timepoints. A biphasic response in the placenta to mIA characterised by an early impairment of system L transport (GD15, 16) followed by a compensatory upregulation of activity to maintain fetal growth (GD21) was observed. It is proposed that the earlier impairment of amino acid transport alters BCAA provision to the fetus, altering developmental trajectories of fetal organs and potentially influencing neurodevelopmental processes, further supported by decreased expression of SZ-susceptibility gene reelin in fetal brain 3 h post-poly(I:C) administration. This may predispose the fetus to NDD risk in postnatal life, despite the compensatory placental adaptation near term (upregulated system L transport) and maintained fetal growth. The pattern of LAT subtype expression differed between placenta and yolk sac, but supported the capacity for system L–mediated amino acid transport by both tissues. The ability of the rodent yolk sac to respond to mIA is presented for the first time and whilst responding

Date of Award	31 Dec 2020
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Jocelyn Glazier (Supervisor), Reinmar Hager (Supervisor) & Joanna Neill (Supervisor)