The online version of this article (doi:10.1186/s13229-017-0125-0) contains supplementary material, which is available to authorized users.
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.
Additional file 1: A table describing the absence of any effect of VitD on various aspects of pup development. (DOCX 20 kb)13229_2017_125_MOESM1_ESM.docx
Additional file 2: A graph describing the absence of any effect of VitD on various aspects of dam physiology, fecundity, and pup survival. Assessment of (A) body weight gain (g), (B) water, and (C) food consumption for dams who were exposed to prenatal vehicle (VEH) (n = 8) or prenatal vitamin D treatment (VitD) at GD9 (n = 9). (D) Litter size and (E) pup survival rate (%) in the 72 h post birth were monitored for the treated groups. In all measures, VitD exposure at GD9 leads to no significant effect on GD11, GD13, and GD15 comparing to vehicle injected dams. All values are mean ± SEM. (TIFF 624 kb)13229_2017_125_MOESM2_ESM.tiff
Additional file 3: A graph describing spontaneous locomotion behavior of adult offspring in a novel open field. There is no effect of developmental exposure to VitD. Spontaneous locomotion in an open field in adult offspring who were exposed to prenatal vehicle (VEH) (n = 50) or prenatal vitamin D treatment (VitD) (n = 55). Neither VEH nor VitD treatment affected distance traveled in the open field. All values are mean ± SEM. (TIFF 4380 kb)13229_2017_125_MOESM3_ESM.tiff
Additional file 4: A graph describing anxiety-like behavior in an elevated plus maze in adult offspring. There is no effect of developmental exposure to VitD. Elevated plus maze behaviors in adult offspring who were exposed to prenatal vehicle (VEH) (n = 50) or prenatal vitamin D treatment (VitD) (n = 55). Neither VEH nor VitD treatment affected the time spent in the closed arms, open arms, and center of the elevated plus maze. (B) Similarly, there were no group differences in distance moved in this test. All values are mean ± SEM. (TIFF 324 kb)13229_2017_125_MOESM4_ESM.tiff
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- Vitamin D treatment during pregnancy prevents autism-related phenotypes in a mouse model of maternal immune activation
- BioMed Central