Abstract
Dysfunction in dopamine (DA) systems is a prominent feature in schizophrenia patients and may result from the abnormal development of mesencephalic (mes)DA systems. Maternal immune activation (MIA) and developmental vitamin D (DVD)-deficiency both induce schizophrenia-relevant dopaminergic abnormalities in adult offspring. In this study, we investigated whether maternal administration of the vitamin D hormone (1,25OHD, VITD) could prevent MIA-induced abnormalities in DA-related behaviors and mesDA development. We administrated the viral mimetic polyriboinosinic-polyribocytidylic (poly (I:C)) simultaneously with 1,25OHD and/or their vehicles, to pregnant mouse dams at gestational day 9. Maternal treatment with VITD prevented MIA-induced hypersensitivity to acute DA stimulation induced by amphetamine, whereas it failed to block prepulse inhibition deficiency in MIA-exposed offspring. MIA and VITD both reduced fetal mesDA progenitor (Lmx1a + Sox2+) cells, while VITD treatment increased the number of mature (Nurr1 + TH+) mesDA neurons. Single-cell quantification of protein expression showed that VITD treatment increased the expression of Lmx1a, Nurr1 and TH in individual mesDA cells and restored normal mesDA positioning. Our data demonstrate that VITD prevents abnormal dopaminergic phenotypes in MIA offspring possibly via its early neuroprotective actions on fetal mesDA neurons. Maternal supplementation with the dietary form of vitamin D, cholecalciferol may become a valuable strategy for the prevention of MIA-induced neurodevelopmental abnormalities.
Highlights
Animal models of Maternal immune activation (MIA) and developmental vitamin D (DVD)-deficiency provide support for this hypothesis[7,8,9,10]
We further explored the effects of VITD and MIA on the expression of factors involved in early mesencephalic dopamine (mesDA) neuron maturation
Maternal VITD treatment prevented the emergence of AMPH hypersensitivity in offspring exposed to MIA
Summary
Animal models of MIA and DVD-deficiency provide support for this hypothesis[7,8,9,10]. Using a MIA model that is based on maternal treatment with the viral mimetic polyriboinosinic-polyribocytidylic (poly (I:C)), we have recently shown that when the active vitamin D hormone (1,25OHD) (here on referred to as VITD) is administered to MIA-exposed dams simultaneously with poly(I:C), it prevents certain MIA-induced behavioral deficits in associative learning, stereotyped digging and social interaction in juvenile offspring[27] Such behavioural disruptions are consistent but not exclusive to autism-related phenotypes. We further explored the effects of VITD and MIA on the expression of factors involved in early mesDA neuron maturation To this aim, we established an automated image analysis method for the identification and measurement of individual mesDA cells. One plausible neuroprotective action of VITD may be its pro-differentiating role in mesDA neurogenesis in the MIA-exposed fetuses
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