Antagonizing actions of vitamin D3 on glucocorticoid functions in hippocampal cells

There is a growing evidence for a role of vitamin D₃ signaling in the brain. In this study, we investigated the influence of vitamin D₃ in combination with glucocorticoids on neuronal differentiation of the rat hippocampal progenitor cell line HIB5. Pre-treatment of HIB5 cells with dexamethasone (Dex) alone inhibited neurite extension and abolished activation of the mitogen-activated protein kinase (MAPK) pathway during differentiation, consistent with previous findings. Interestingly, pre-treatment with vitamin D₃ significantly reduced these effects of Dex. Furthermore, exposure to vitamin D₃ reduced the transactivational function of the glucocorticoid receptor (GR) in transient reporter gene assays. An influence of vitamin D₃ on glucocorticoid effects was also observed in a postnatal rat primary hippocampal culture, which is known to be particularly sensitive to prolonged GR activation. In this model, Dex induced considerable cell death after 72 hours of treatment. However, pre-treatment of the culture for 24 hours with low doses of vitamin D₃ substantially reduced the degree of Dex-induced apoptosis. Taken together, our experiments demonstrate a cross-talk between vitamin D₃ and glucocorticoids in hippocampal cells, a feature that may have important implications in disorders with dysregulated glucocorticoid signaling, including depression.