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.

Keywords: cytokine; epigenetic regulation; fetal brain; infection; placenta; pregnancy.

Figure 1. Infection in pregnancy and implications for offspring neurodevelopment

Maternal infection during pregnancy evokes maternal immune activation and increased systemic proinflammatory cytokine release. This results in the activation of maternal monocytes at the placental interface, resulting in placental immune activation and inflammation, associated with an increased placental concentration of proinflammatory cytokines. This leads to altered placental signalling and function and subsequent fetal brain neuroinflammation and disrupted cytokine balance, which affects epigenetic regulation of key neurodevelopmental pathways and impacts on neurodevelopmental signalling, causing microglial priming, disturbed neural progenitor cell proliferation, impaired neuronal migration and synaptogenesis, along with reduced myelin plasticity, which, together, can result in altered offspring neurodevelopment. Offspring affected by maternal immune activation have an increased risk of developing neurodevelopmental disorders (NDDs), including schizophrenia, autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (AHDH). Created with BioRender.