Dysfunctional placental tryptophan metabolism is a molecular mechanism linking maternal inflammation to altered fetal neurodevelopment and adult neurological function

Abstract

In addition to its role as a neurotransmitter and its involvement in the adult pathology of psychiatric disorders, serotonin is increasingly thought to play a critical role in numerous neurodevelopmental processes throughout gestation. Furthermore, dysfunction of the serotonergic system has been implicated in a number of developmental and neuropsychiatric disorders, including major depressive disorder, autism spectrum disorders (ASDs), and schizophrenia. These conditions have been associated epidemiologically with adverse prenatal events, suggesting a link between maternal insults during pregnancy and altered trajectories of fetal neurodevelopment, which ultimately contribute to the onset of neuropsychiatric disorders. However, the exact impact and the mechanisms underlying the link between adverse gestational conditions and altered fetal neurodevelopment remain relatively poorly understood. The goal of this dissertation is to describe a potential mechanism linking maternal infection and inflammation during mid-to-late gestation with altered fetal neurodevelopment and the eventual onset of neuropsychiatric disorders in the offspring. During my research, I discovered that maternal inflammation leads to altered placental tryptophan metabolism by inducing a transcriptional and translational cascade in the placenta, which in turn impacts fetal neurochemistry, neurodevelopment, and ultimately adult neurochemistry and behavior consistent with neuropsychiatric disorders in humans, providing a molecular mechanism linking maternal inflammation to neuropsychiatric disorders in the offspring. ❧ Mild maternal inflammation, induced for 24 hours by the immunostimulant polyinosinic:polycytidylic acid (poly(I:C) actuates transcriptional changes in the placenta 24 and 48 hours after exposure in several genes coding for enzymes involved in the placental metabolism of tryptophan. This in turn leads to downstream changes in enzymatic activity, in which I see altered metabolic output of the placenta to the fetus. This is accompanied by changes in fetal neurochemistry, where I see increased forebrain concentrations of serotonin after 24 and 48 hours, indicating that mild maternal inflammation induces a placental cascade that indirectly impacts fetal neurochemistry during development. Furthermore, this cascade leads to blunted outgrowth of serotonergic axons from the dorsal raphe into the forebrain, and increased cellular proliferation specifically within the thalamus 48 hours after maternal exposure to poly(I:C). ❧ When looking postnatally, I find that prenatal exposure to poly(I:C) and the resulting placental metabolic cascade have long-term consequences on neurological function in the offspring. Adolescent offspring from poly(I:C) exposed dams have significantly increased concentrations of serotonin specifically within the thalamus, and impacted behavior in a manner consistent with sub-phenotypes of human patients suffering from ASD and schizophrenia. Specifically, adolescent offspring exhibit altered depressive- and anxiety-like behavior, and deficits in latent inhibition. This suggests that the prenatal cascade triggered by maternal inflammation has long-term consequences that persist through adolescence: altered placental tryptophan metabolism due to maternal inflammation indirectly impacts fetal neurochemistry, leading to altered fetal neurodevelopment and adolescent neurological function and behavior. Finally, I outline the methodology of our novel placental perfusion system, and demonstrate its efficacy for studying transplacental transfer of other TRP metabolites. While not outlined in this dissertation, it’s also worth noting that I used the ex vivo perfusion system for the study of transplacental transfer dynamics of the maternally derived hormone osteocalcin (Oury et al., 2013), and the transfer of intact viruses such as the zika virus (manuscript in preparation).