Evolution of a maternal immune activation (mIA) model in rats: Early developmental effects

Abstract

Maternal immune activation (mIA) in rodents is rapidly emerging as a key model for neurodevelopmental disorders such as autism spectrum disorder (ASD) and schizophrenia. Here, we optimise a mIA model in rats, aiming to address certain limitations of current work in this field. Specifically, the lack of clear evidence for methodology chosen, identification of successful induction of mIA in the dams and investigation of male offspring only. We focus on gestational and early juvenile changes in offspring following mIA, as detailed information on these critical early developmental time points is sparse. Following strain (Wistar, Lister Hooded, Sprague Dawley) comparison and selection, and polyriboinosinic-polyribocytidylic acid (poly I:C) dose selection (2.5-15 mg/kg single or once daily for 5 days), mIA was induced in pregnant Wistar rats with 10 mg/kg poly I:C i.p. on gestational day (GD) 15. Early morphometric analysis was conducted in male and female offspring at GD21 and postnatal day (PD) 21, eight dams for each treatment at each time point were used, 32 in total. Subsequent microglia analysis was conducted at PD21 in a small group of offspring. Poly I:C at 10 mg/kg i.p. induced a robust, but variable, plasma IL-6 response 3 h post-injection and reduced body weight at 6 h and 24 h post-injection in two separate cohorts of Wistar rats at GD15. Plasma IL-6 was not elevated at PD21 in offspring or dams. Poly I:C-induced mIA did not affect litter numbers, but resulted in PD21 pup, and GD21 placenta growth restriction. Poly I:C significantly increased microglial activation at PD21 in male hippocampi. We have identified 10 mg/kg poly I:C i.p on GD15 as a robust experimental approach for inducing mIA in Wistar rats and used this to identify early neurodevelopmental changes. This work provides a framework to study the developmental trajectory of disease-relevant, sex-specific phenotypic changes in rats.

Building a framework to optimize animal models of maternal immune activation: Like your ongoing home improvements, it’s a work in progress

“…immunogen, dose, species/strain) and other husbandry considerations that are typically under reported yet influential to the immune response and the integrity of our animal models (Estes and McAllister, 2016; Kentner et al, 2018). In this issue of Brain, Behavior, and Immunity , Murray et al (2018) lay groundwork to guide the establishment of best practices for the validation and reporting of our mIA models. These steps built the foundation from which their laboratory explored the early developmental trajectory of morphometric markers in male and female offspring, revealing sexually dimorphic phenotypic changes following mIA.…”

“…Within this context, Murray et al (2018) astutely identified issues in the mIA literature including a lack of defined criteria for how important elements of our study protocols are selected. For example, the immunogens and doses of interest, administration routes and schedules, in addition to the specific strains and sex employed.…”

“…While this list is not exhaustive, these are fundamental components to every mIA study and the rationale for our choices ought to be transparent and evidence-based. The importance of this is highlighted by Murray and colleagues (2018) who point out that while mice are most commonly used in the mIA literature, the use of rats is increasing too. Although some mIA mouse models have been validated, the same methods may not be appropriate for other species and further validation of these models are necessary.…”

“…Each laboratory must now take an initiative to parse out and validate the appropriate conditions under which they effectively induce their mIA models, and duly report (Kentner et al, 2018). As an excellent template of how to go about this, Murray et al (2018) evaluated the pharmacodynamic properties of the peripheral immune response, as activated by polyriboinosinicpolyribocytidylic acid (poly I:C), in three strains of female rats. The investigators focused on plasma interleukin (IL)-6 concentration and body temperature to confirm a mIA response.…”

“…In addition to defining the appropriate poly I:C schedule, Murray et al (2018) verified mIA in all experimental dams via peripheral blood sampling, an accepted method for validating immunogen efficacy (Kentner et al, 2018) that, like other methods, is either underused or underreported. Murray et al’s current work (2018) contributes to a newly growing and important trend in the mIA literature to improve the rigor and reproducibility of these models.…”