Differential effects of early or late exposure to prenatal maternal immune activation on mouse embryonic neurodevelopment

Abstract

Exposure to maternal immune activation (MIA) in utero is a risk factor for neurodevelopmental and psychiatric disorders. MIA-induced deficits in adolescent and adult offspring have been well characterized, however, less is known about the effects of MIA-exposure on embryo development. To address this gap, we performed high-resolution ex vivo magnetic resonance imaging (MRI) to investigate the effects of early (gestational day [GD]9) and late (GD17) MIA-exposure on embryo (GD18) brain structure. We identify striking neuroanatomical changes in the embryo brain, particularly in the late exposed offspring. We further examined hippocampal neuroanatomy using electron microscopy and identified differential effects due to MIA-timing. An increase in apoptotic cell density was observed in the GD9 exposed offspring, while an increase in the density of dark neurons and glia, putative markers for increased neuroinflammation and oxidative stress, was observed in GD17 exposed offspring, particularly in females. Overall, our findings integrate imaging techniques across different scales to identify differential impact of MIA-timing on the earliest stages of neurodevelopment.

Examining litter specific variability in mice and its impact on neurodevelopmental studies

“…However, our group also demonstrated that the gestational timing of MIA-exposure could further modulate neurodevelopmental outcomes (Guma, do Couto Bordignon, et al, 2021;Guma et al, 2022;. At an even more basic level, litter-dependent modulation of body and brain weight have been reported using linear and linear mixed-effect models; these effects are further affected by sex (Golub & Sobin, 2020;Jiménez & Zylka, 2021).…”

“…Table S3.1: Detailed distribution of male and female (m:f) control pups assessed per litter and by timepoints (Guma et al, 2022).…”

Examining Litter Specific Variability in Mice and its Impact on Neurodevelopmental Studies

“…These studies are further motivated by recent observations that offspring exposed to MIA (modeling the exposure to maternal infection during pregnancy, a known risk factor for neurodevelopmental disorders) show litter-dependent variance in resilience and susceptibility to the risk factor exposure (Mueller et al, 2021). However, our group also demonstrated that the gestational timing of MIA-exposure could further modulate neurodevelopmental outcomes (Guma, do Couto Bordignon, et al, 2021;Guma et al, 2022;. At an even more basic level, litter-dependent modulation of body and brain weight have been reported using linear and linear mixed-effect models; these effects are further affected by sex (Golub & Sobin, 2020;Jiménez & Zylka, 2021).…”