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

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.

Maternal behaviours and adult offspring behavioural deficits are predicted by maternal TNFα concentration in a rat model of neurodevelopmental disorders

“…Therefore, it may be that in our study, female offspring experienced a reduction in growth prenatally, causing postnatal behavioural adaptations to increase maternal resource solicitation behaviours such as USVs. Indeed, data from this model has recently demonstrated sex-specific effects in placental function which would support this, including a more pronounced reduction in amino acid transport in female placentas at GD16, compared to males (Kowash et al, 2022).…”

“…Both IL-6 and TNFα have been shown to be induced during the maternal response to poly I:C and mediate downstream offspring developmental deficits (Murray et al, 2019;Smith et al, 2007). Recent data from our own validation of this model has demonstrated that both maternal IL-6 and TNFα plasma concentration peak at 2-3 h posttreatment with this source of poly I:C in pregnant Wistar rats, which is not seen for other canonical pro-inflammatory cytokines such as IL-1β (Kowash et al, 2022). Therefore, their concentration was measured in maternal plasma at baseline (pre-pregnancy) and 3 h post-treatment using rat-specific ELISAs for IL-6 and TNFα (ab100772 and ab100784 respectively, Abcam, UK).…”

“…Based on the evidence for prenatal programming presented here and elsewhere Meyer et al, 2008;O'Leary et al, 2014;Richetto et al, 2013;Schwendener et al, 2009), placental dysfunction seems a plausible mechanism underpinning altered fetal neurodevelopmental programming and warrants further investigation. It was recently demonstrated that amino acid transport across the placenta is downregulated 24 h after poly I:C treatment (GD16) followed by an adaptive response with upregulated transport at GD21 (Kowash et al, 2022). The function of the visceral yolk sac in rodents, which supports fetal growth by expression of nutrient transporters (Owaydhah et al, 2020), as well as seeding the developing fetal brain with haematopoietic progenitors of tissueresident macrophages (microglia) (Ginhoux et al, 2010;Magalhaes et al, 2022), should also be investigated as a key site for prenatal programming of NDDs.…”

“…injection GD15 between 09:00 and 10:00 to limit circadian variation of immune function (Scheiermann et al, 2013). At 3 h post-treatment, which has previously been shown to correspond to the peak of the maternal inflammatory response to this source of poly I:C by us (Kowash et al, 2022) and others (Clark et al, 2019), dams had a second tail vein blood sample taken as described above. Maternal weight was recorded daily from GD1-21 and then daily from PD1-14.…”

Leucine mediates cognitive dysfunction in early life stress-induced mental disorders by activating autophagy

“…Moreover, Leucine is the most typical amino acid involved in autophagy regulation, it could activate downstream ULK-1 (Ubiquitin-like proteins-1) and Beclin-1, and then facilitate autophagosome formation following their interaction with LC3 (microtubule-associated protein light chain 3) ( Russell et al, 2013 ). Several studies have demonstrated that Leucine enters the brain from the blood more rapidly than any other as a nutritionally essential amino acid ( Yudkoff et al, 2005 ; Duan et al, 2016 ), and it competes with kynurenine for blood-to-brain transport and prevents lipopolysaccharide-induced depression-like behavior in mice ( Walker et al, 2019 ), and even maternal immune activation induces dysregulated placental transport of Leucine affecting fetal brain development in rats ( Kowash et al, 2022 ). Meanwhile, our previous result also found that there is an alteration of leucine content in both serum and feces of MS-induced irritable bowel syndrome rats.…”