Enhancing rigor and reproducibility in maternal immune activation models: practical considerations and predicting resilience and susceptibility using baseline immune responsiveness before pregnancy

Abstract

Despite the potential of rodent models of maternal immune activation (MIA) to identify new biomarkers and therapeutic interventions for a range of psychiatric disorders, their value is currently limited by issues of scientific rigor and reproducibility. Here, we report three sources of variability-the immunogenicity of the poly(I:C), the baseline immune responsiveness (BIR) of the females prior to pregnancy, and differences in immune responses in C57/B6 dams across vendors. Similar to the variable effects of human maternal infection, MIA in mice does not cause disease-related phenotypes in all offspring and the magnitude and type of maternal response, determined by a combination of poly(I:C) dose and BIR, predicts offspring outcome. Together, our results provide recommendations for optimization of MIA protocols to enhance rigor and reproducibility and reveal new factors that drive susceptibility of some pregnancies and resilience of others to MIA-induced abnormalities in offspring.

Sequential perturbations to mouse corticogenesis following in utero maternal immune activation

“…C57BL/6N females (Charles River, Kingston, NY), were bred in house and maintained on a 12:12 hr light dark cycle at 20 ± 1°C, food and water available ad libitum. Mice utilized in this study do harbor Segmented Filamentous Bacteria (SFB) ( Estes et al, 2019 ). Males and females embryos were analyzed across experiments, sex was determined as previously described ( McFarlane et al, 2013 ).…”

The Inflamed Brain in Schizophrenia: The Convergence of Genetic and Environmental Risk Factors That Lead to Uncontrolled Neuroinflammation

“…), timing of immunogen administration, dosage, route of administration, housing conditions, timing of cage cages and mouse strain used (Careaga et al, 2018;Kentner et al, 2019;Kowash et al, 2019), understanding what causes these differences could aid in understanding the mechanisms underlying vulnerability versus resiliency to MIA (Meyer, 2019). In humans, only a subset of pregnant mothers who are exposed to a viral or bacterial infection have offspring who later develop SCZ (Estes et al, 2019). This is to be expected since immune activation is only one of the many risk factors for SCZ.…”

Investigating the Effect of Reduced Serotonin Transporter Expression in a Maternal Immune Activation Model of Neurodevelopmental Disorders

“…In numerous studies, pup weight is shown to be smaller in poly The results in this chapter were generated to validate and improve understanding of the natural variation in this model, according to recent recommendations and reviews [125,178]. While this evidence does not support maternal weight and pup weight alterations, it does show a fever-driven temperature change in poly I:C group dams.…”

“…Unvalidated and unequal immune responses are estimated to be one of the biggest sources of variation and conflict between MIA studies [125,179]. For example, variable molecular weights in commercial batches of poly I:C have been shown to elicit different strengths of immune response [178,180]. Without reporting poly I:C weight or quantifying immune response, studies that appear to use comparable models may not be.…”