Abstract
Maternal immune activation (MIA) during pregnancy induces a cytokine storm that alters neurodevelopment and behavior in the progeny. In humans, MIA increases the odds of developing neuropsychiatric disorders such as autism spectrum disorder (ASD). In mice, MIA can be induced by injecting the viral mimic polyinosinic:polycytidylic acid (poly(I:C)) to pregnant dams. Although the murine model of MIA has been extensively studied, it is not clear whether MIA results in cytokine changes in the progeny at early postnatal stages. Further, the murine model of MIA suffers from a lack of reproducibility and high inter-individual variability. Multivariable (MV) statistical analysis is widely used in human studies to control for confounders and covariates such as sex, age and exposure to environmental factors. We therefore reasoned that animal studies in general and studies on the MIA model in particular could benefit from MV analyses to account for complex phenotype interactions and high inter-individual variability. Here, we used MV statistical analysis to identify cytokines associated with MIA after adjustment for covariates. Besides confirming the association between previously described variables and MIA, we identified new cytokines that could play a role in behavioural alterations in the progeny during the early postnatal period.
Highlights
A large body of evidence suggests that neurodevelopment before and after birth, as well as behaviour during the postnatal period are regulated by cytokines
Pup’s variables were litter size at P4, body mass at P15, time spent mobile and distance travelled at P13, number of emitted Ultrasonic vocalizations (USV) at P8 and serum levels of IFNγ, IL-1β, IL-5, IL-6, IL-15, IL-16, IL-17A, IL-27p28/IL-30, IL-33, Chemokine C-C motif Ligand (CCL)2, CCL3, CCL20, Chemokine C-X-C motif Ligand (CXCL)1, CXCL2, CXCL10, and TNF-α at P15
We found that serum levels of CXCL10 and IL-5 levels were positively associated with maternal immune activation (MIA) while IL-15 and TNF- α levels were negatively associated
Summary
A large body of evidence suggests that neurodevelopment before and after birth, as well as behaviour during the postnatal period are regulated by cytokines. Cytokine levels in both blood and brain are tightly regulated during the prenatal and postnatal periods [1, 2]. Cell culture experiments using both human and rodent cells have shown that cytokines regulate neurogenesis, neuronal migration, synaptogenesis, synaptic pruning, angiogenesis, myelination and apoptosis in vitro [3, 4]. Mice deficient in cytokine or cytokine receptor genes often exhibit behavioural alterations [4]. Maternal immune activation (MIA) during pregnancy increases the odds of neuropsychiatric disorders such as autism spectrum disorders (ASD) [5, 6].
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