Mouse models of maternal immune activation: Mind your caging system!
Prenatal exposure to infection is increasingly recognized to play an important etiological role in neuropsychiatric and neurological disorders with neurodevelopmental components, including schizophrenia and autism. The link between prenatal infection and increased risk of neurodevelopmental brain disorders also receives strong support from experimental work in animal models. One of the most widely used maternal immune activation (MIA) models is based on gestational administration of poly(I:C) (= polyriboinosinic-polyribocytdilic acid), a synthetic viral analog. The effects of poly(I:C)-induced MIA on phenotypic changes in the offspring are known to be influenced by various factors, including the precise prenatal timing, genetic background, and immune stimulus intensity. Thus far, however, it has been largely ignored whether differences in the basic type of laboratory housing can similarly affect the outcomes of MIA models. With this study, we examine this possibility by comparing the poly(I:C)-based MIA model in two housing systems that are commonly used in preclinical mouse research, namely the open cage (OC) and individually ventilated cage (IVC) systems. Here, we demonstrate that maternal poly(I:C) administration on GD9 causes a dose-dependent increase in spontaneous abortion in IVCs but not in OCs, whereas MIA in IVC systems during a later gestational time-point (GD12) does not affect pregnancy outcomes. Moreover, we show that the precise type of caging system markedly affects maternal cytokines and chemokines response to poly(I:C). We further show that the efficacy of MIA to induce deficits in working memory, social interaction, and sensorimotor gating in the adult offspring is influenced by the different housing conditions, the dosing of poly(I:C), and the precise prenatal timing. Taken together, with this study we identify the basic type of caging system as a novel factor that can confound the outcomes of MIA in mice.
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