Molecular mechanisms underlying the models of neurodevelopmental disorders in maternal immune activation relevant to the placenta

Abstract

The rapid rise in the prevalence of autism spectrum disorders (ASD) and other psychiatric disorders displaying similar traits has increased the need to elucidate their molecular mechanisms.Epidemiological studies have shown that maternal infection during mid-pregnancy is associated with increased risk of neurodevelopmental disorders such as ASD in offspring. Using maternal infection models, researchers have gathered evidence relevant to such disorders. A comprehensive summary of the changes in the brain structure, function, and behavior in offspring induced by maternal immune activation (MIA) has been reported. However, the molecular mechanisms underlying the association between MIA and improper brain development, which ultimately lead to neurodevelopmental disorders, have not been fully reviewed. This paper summarizes the currently known molecular mechanisms associated with the MIA model, with a special focus on the role of the placenta in fetal brain development.K E Y W O R D S fetal brain development, interleukin-6 (IL-6) family signaling pathway, maternal immune activation (MIA), neurodevelopmental disorders, placenta

Placental neurotrophin levels in gestational diabetes mellitus

“…Placental response to disturbances in the maternal environment is known to play a key role in programming the fetus toward risk for diseases in adulthood (Tsukada et al., 2019). Decreased expression of NGF or BDNF in the fetus and placenta in the context of maternal infection has been suggested to affect fetal brain development in rats (Gilmore et al, 2003).…”

“…Decreased expression of NGF or BDNF in the fetus and placenta in the context of maternal infection has been suggested to affect fetal brain development in rats (Gilmore et al, 2003). A review described that maternal immune activation causes a decrease in NGF and BDNF in the placenta and highlighted the role of the placenta in fetal brain development (Tsukada et al., 2019).…”

Leukemia Inhibitory Factor Induces Proopiomelanocortin via CRH/CRHR Pathway in Mouse Trophoblast

“…In contrast to LIF, IL-6 is induced under a pathological state. After MIA induction by infection, IL-6 in maternal serum is elevated, and placental SOCS3 and CRH are upregulated in response to the increased IL-6 ( Wu et al, 2017 ; Tsukada et al, 2018 ). As SOCS3 negatively regulates the JAK/STAT3 pathway, placental ACTH secretion is inhibited leading to decreased fetal LIF.…”

Environmental influences on placental programming and offspring outcomes following maternal immune activation

“…While EE appeared to have a discrete influence on glucocorticoid-associated placental mediators such as Hsd11b2, this intervention may have instead exerted its protective influence through separate molecular or immune pathways. For example, placental hemorrhage, hypoxia, interruptions in neural progenitor cell proliferation, tumor necrosis factor-α, and the maternalfetal leukemia inhibitory factor (LIF) signal pathway have all been implicated in LPS-induced disruptions of fetal brain development (Izvolskaia et al, 2018;Tsukada et al, 2019). Moreover, in poly I:C MIA models, IL-6 (Smith et al, 2007;Hsiao & Patterson, 2011) and IL-17a/activated Th17 cells (Choi et al, 2016) are well recognized to underlie the associated phenotypes in offspring, as are changes in placental morphology (Murray et al, 2019).…”

“…While EE appeared to have a discrete influence on glucocorticoid-associated placental mediators such as Hsd11b2, this intervention may have instead exerted its protective influence through seperate molecular or immune pathways. For example, placental hemorrhage, hypoxia, interruptions in neural progenitor cell proliferation, tumor necrosis factor-alpha, and the maternal-fetal leukemia inhibitory factor (LIF) signal pathway have all been implicated in LPSinduced disruptions of fetal brain development (Izvolskaia et al, 2018;Tsukada et al, 2019).…”