Maternal immune activation as an epidemiological risk factor for neurodevelopmental disorders: Considerations of timing, severity, individual differences, and sex in human and rodent studies

Abstract

Epidemiological evidence suggests that one's risk of being diagnosed with a neurodevelopmental disorder (NDD)-such as autism, ADHD, or schizophrenia-increases significantly if their mother had a viral or bacterial infection during the first or second trimester of pregnancy. Despite this well-known data, little is known about how developing neural systems are perturbed by events such as early-life immune activation. One theory is that the maternal immune response disrupts neural processes important for typical fetal and postnatal development, which can subsequently result in specific and overlapping behavioral phenotypes in offspring, characteristic of NDDs. As such, rodent models of maternal immune activation (MIA) have been useful in elucidating neural mechanisms that may become dysregulated by MIA. This review will start with an up-to-date and in-depth, critical summary of epidemiological data in humans, examining the association between different types of MIA and NDD outcomes in offspring. Thereafter, we will summarize common rodent models of MIA and discuss their relevance to the human epidemiological data. Finally, we will highlight other factors that may interact with or impact MIA and its associated risk for NDDs, and emphasize the importance for researchers to consider these when designing future human and rodent studies. These points to consider include: the sex of the offspring, the developmental timing of the immune challenge, and other factors that may contribute to individual variability in neural and behavioral responses to MIA, such as genetics, parental age, the gut microbiome, prenatal stress, and placental buffering.

Keywords: autism spectrum disorder; development; individual differences; maternal immune activation; neurodevelopmental disorders; perinatal period; schizophrenia; sex differences.

Figure 1

Proposed model of the association between maternal immune activation (MIA) and neurodevelopmental disorders (NDDs). Blue boxes represent human pathogens and outcomes related to MIA. Green boxes represent rodent immunogens and outcomes related to MIA. Orange boxes represent factors that should be considered in rodent models of MIA and their relevance for human NDDs. Dark orange boxes represent factors that are related to the gestational immune response, whereas light orange boxes represent factors that are related to the immune response both during gestation and in postnatal offspring.