Maternal Inflammation Disrupts Fetal Neurodevelopment via Increased Placental Output of Serotonin to the Fetal Brain

Abstract

The mechanisms linking maternal inflammation during pregnancy with increased risk of neurodevelopmental disorders in the offspring are poorly understood. In this study, we show that maternal inflammation in midpregnancy results in an upregulation of tryptophan conversion to serotonin (5-HT) within the placenta. Remarkably, this leads to exposure of the fetal forebrain to increased concentrations of this biogenic amine and to specific alterations of crucially important 5-HT-dependent neurogenic processes. More specifically, we found altered serotonergic axon growth resulting from increased 5-HT in the fetal forebrain. The data provide a new understanding of placental function playing a key role in fetal brain development and how this process is altered by adverse prenatal events such as maternal inflammation. The results uncover important future directions for understanding the early developmental origins of mental disorders.

Fetal de novo mutations and preterm birth

“…Such an association may also be biologically connected with our findings on the perturbation of the fetal nervous system in PTB. Recently, it has been shown that maternal inflammation disrupts fetal neurodevelopment[37, 38], and could even promote neuropsychiatric disorders of fetuses[39, 40]. Therefore, it is possible that fetal brain developmental abnormalities, at least in some cases, is a downstream event of maternal inflammation, both contributing to PTB as components in an integrated system.…”

Impact of Maternal Serotonin Transporter Genotype on Placental Serotonin, Fetal Forebrain Serotonin, and Neurodevelopment

“…Impaired insulin signaling, as found in gestational diabetes, decreases 5-HT uptake in trophoblasts by disrupting plasma membrane SERT expression (Li et al, 2014). Maternal immune activation (MIA) increases placental production of 5-HT; although this effect is at least partially owing to increased placental tryptophan hydroxylase activity (Goeden et al, 2016).…”

Effects of maternal obesity on placental function and fetal development

“…It has been suggested that pregnancy conditions such as maternal stress and inflammation up-regulate placental serotonin production to program the developing fetus for neurodevelopmental disorders (St Pierre et al 2015; Goeden et al 2016; Brummelte et al 2016). Increased IL-1 and IL-6 have been identified as potential cytokines linked to changes in placental function and subsequent neurodevelopmental insults that include forebrain damage and behavioral consequences in rodents (Smith et al 2007; Girard et al 2010).…”

“…Importantly, serotonin neurotransmission is impaired in autism and schizophrenia and both disorders are linked to exposure to increased pro-inflammatory cytokines, such as IL-6 in utero (Brown and Derkits, 2010; Atladóttir et al 2010; Meyer et al 2011). Recent studies found that maternal IL-6 mediated inflammatory responses impacted fetal neurodevelopment through up-regulated conversion of maternal l-tryptophan to serotonin, leading to excess serotonin production by the placenta and blunted fetal forebrain axonal outgrowth (Goeden et al 2016). Given that IL-6 plays a role in both nutrient delivery and serotonin synthesis, increased IL-6 associated with maternal obesity (Christian and Porter, 2014; Stewart et al 2007; Friis et al 2013) could significantly alter fetal serotonin balance and program life-long disease and neurocognitive disorders (Bolton and Bilbo, 2014).…”