Maternal immune activation and role of placenta in the prenatal programming of neurodevelopmental disorders

Abstract

Maternal infection during pregnancy, leading to maternal immune activation (mIA) and cytokine release, increases the offspring risk of developing a variety of neurodevelopmental disorders (NDDs), including schizophrenia. Animal models have provided evidence to support these mechanistic links, with placental inflammatory responses and dysregulation of placental function implicated. This leads to changes in fetal brain cytokine balance and altered epigenetic regulation of key neurodevelopmental pathways. The prenatal timing of such mIA-evoked changes, and the accompanying fetal developmental responses to an altered in utero environment, will determine the scope of the impacts on neurodevelopmental processes. Such dysregulation can impart enduring neuropathological changes, which manifest subsequently in the postnatal period as altered neurodevelopmental behaviours in the offspring. Hence, elucidation of the functional changes that occur at the molecular level in the placenta is vital in improving our understanding of the mechanisms that underlie the pathogenesis of NDDs. This has notable relevance to the recent Covid-19 pandemic, where inflammatory responses in the placenta to SARS-CoV-2 infection during pregnancy and NDDs in early childhood have been reported. This review presents an integrated overview of these collective topics and describes the possible contribution of prenatal programming through placental effects as an underlying mechanism that links to NDD risk, underpinned by altered epigenetic regulation of neurodevelopmental pathways.

Impact of respiratory viral infections during pregnancy on the neurological outcomes of the newborn: current knowledge

“…Alternatively to vertical transmission, accumulating evidence in the literature supports the hypothesis that maternal immune activation (MIA) constitutes one of the crucial mechanisms through which prenatal infections exert their effects on neurodevelopment ( Han et al, 2021 ; Kwon et al, 2022 ; Woods et al, 2023 ; Figure 2 ). Maternal systemic immune response against infections leads to the production of cytokines and inflammatory mediators, such as interleukin (IL)-6, IL-17a, IL-1β, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ, which may cross the placental barrier depending on the gestational age by diffusion through paracellular trans-trophoblastic water-filled channels ( Kwon et al, 2022 ; Woods et al, 2023 ). In a rat model, Dahlgren and colleagues proved that the transfer of IL-6 to the fetal circulation was significantly higher during mid-gestation than in late pregnancy ( Dahlgren et al, 2006 ).…”

“…These inflammatory factors can affect NPCs development, resulting in cortical defects and neurodevelopmental disorders. Particularly, it has been proved that IL-1β influences neuronal migration, and IL-6 affects the temporal regulation of neurogenesis and reduces the neuronal pool within the cortical layers, promoting an early switch to gliogenic cells and inducing an alteration in the ratio of the neuronal/glial cells ( Sloan and Barres, 2014 ; Woods et al, 2023 ). Additionally, IL-6 induces differentiation of naïve T cells to a Th17 phenotype, producing IL-17a, a cytokine that disorganises the cortical cytoarchitecture.…”

“…Noteworthy, neuropsychiatric disorders associated with MIA have heterogeneous clinical phenotypes. Therefore, some authors suggested that neurodevelopment is influenced by multiple risk factors and that MIA, by regulating gene expression and disrupting the neuronal differentiation and arborization, represents only one of the numerous “hits” that intervene in the onset of these conditions ( Garbett et al, 2012 ; Woods et al, 2023 ).…”

“…However, it has been proposed that the damage to the fetal brain due to SARS-CoV-2 infection is mainly caused by vascular injury, leading to placental ischemia and inflammation ( Sharps et al, 2020 ; Lye et al, 2021 ; Liu et al, 2022 ). In fact, MIA response to SARS-CoV-2 infection is considered the main mediator of the neurodevelopmental disruption in the fetus ( Woods et al, 2023 ). Particularly, increased levels of IL-1β, IL-6, IL-17, and TNF-α have been detected in the peripheral blood of pregnant women compared to controls ( Fenizia et al, 2020 ; Figure 3 ).…”

Neuroimmune mechanisms in autism etiology - untangling a complex problem using human cellular models

“…Activation of the immune system in animal models of MIA has been shown to correlate with elevated levels of pro-inflammatory cytokines including interleukins IL-6, IL-17A, IL-1β, IL-10 and cytokines - Tumor necrosis Factor − 1 alpha (TNF-1α) and Interferon gamma (IFN-γ) [ 21 ]. However, studies in children with ASD provide contradicting evidence with respect to IL-10 findings in animal models, as decreased levels of IL-10 were reported in two independent clinical studies [ 22 , 23 ].…”