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



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.



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.



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.
Swiss Federal Institute of Technology (ETH) Zurich, 8603 Schwerzenbach, Switzerland.
Stephanie
S
Vuillermot
Queensland Brain Institute, The University of Queensland, Brisbane, 4072 Queensland Australia.
Wei
W
Luan
Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland.
Urs
U
Meyer
Queensland Brain Institute, The University of Queensland, Brisbane, 4072 Queensland Australia.|Queensland Centre for Mental Health Research, Brisbane, Queensland 4076 Australia.
Darryl
D
Eyles
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002659:Child Development Disorders, Pervasive / Q000139:chemically induced / Q000517:prevention & control*; D016207:Cytokines / Q000097:blood*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D010641:Phenotype; D011070:Poly I-C; D011119:Polynucleotides / Q000009:adverse effects*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000517:prevention & control*; D012919:Social Behavior; D013239:Stereotyped Behavior / Q000187:drug effects*; D014807:Vitamin D / Q000008:administration & dosage*
D016207:Cytokines; D011119:Polynucleotides; D014807:Vitamin D; D011070:Poly I-C
Autism; Cytokines; Dopamine; Maternal immune activation; Neurodevelopmental disorders; Schizophrenia; Vitamin D