Vitamin D treatment during pregnancy prevents autism-related phenotypes in a mouse model of maternal immune activation

Abstract

Background: Prenatal exposure to infection is a recognized environmental risk factor for neuropsychiatric disorders
of developmental origins such as autism or schizophrenia. Experimental work in animals indicates that this link is
mediated by maternal immune activation (MIA) involving interactions between cytokine-associated inflammatory
events, oxidative stress, and other pathophysiological processes such as hypoferremia and zinc deficiency. Maternal
administration of the viral mimic polyriboinosinic-polyribocytidylic acid (poly(I:C)) in mice produces several
behavioral phenotypes in adult offspring of relevance to autism spectrum disorder (ASD) and other
neurodevelopmental disorders.
Methods: Here, we investigated whether some of these phenotypes might also present in juveniles. In addition, given
the known immunomodulatory and neuroprotective effects of vitamin D, we also investigated whether the
co-administration of vitamin D could block MIA-induced ASD-related behaviors. We co-administered the hormonally
active form of vitamin D, 1α,25 dihydroxy vitamin D3 (1,25OHD), simultaneously with poly(I:C) and examined (i) social
interaction, stereotyped behavior, emotional learning and memory, and innate anxiety-like behavior in juveniles and (ii)
the levels of the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α in maternal plasma and fetal brains.
Results: We show that like adult offspring that were exposed to MIA, juveniles display similar deficits in social approach
behavior. Juvenile MIA offspring also show abnormal stereotyped digging and impaired acquisition and expression of
tone-cued fear conditioning. Importantly, our study reveals that prenatal administration of 1,25OHD abolishes all these
behavioral deficits in poly(I:C)-treated juveniles. However, prenatal administration of vitamin D had no effect on
pro-inflammatory cytokine levels in dams or in fetal brains suggesting the anti-inflammatory actions of vitamin D are
not the critical mechanism for its preventive actions in this ASD animal model.
Conclusions: This work raises the possibility that early dietary supplementation with vitamin D may open new avenues
for a successful attenuation or even prevention of neurodevelopmental disorders following maternal inflammation
during pregnancy.