Vitamin D and the brain: key questions for future research.

Over the last decade a convergent body of evidence has emerged from epidemiology, animal experiments and clinical trials which links low vitamin D status with a range of adverse neuropsychiatric outcomes. This research demonstrates that the timing of exposure to low vitamin D influences the nature of brain phenotypes, as exposures during gestation versus adulthood result in different phenotypes. With respect to early life exposures, there is robust evidence from rodent experiments indicating that transient developmental vitamin D (DVD) deficiency is associated with changes in brain structure, neurochemistry, gene and protein expression and behavior. In particular, DVD deficiency is associated with alterations in the dopaminergic neurotransmitter systems. In contrast, recently published animal experiments indicate that adult vitamin D (AVD) deficiency is associated with more subtle neurochemical and behavioral phenotypes. This paper explores key issues that need to be addressed in future research. There is a need to define the timing and duration of the 'critical window' during which low vitamin D status is associated with differential and adverse brain outcomes. We discuss the role for 'two-hit hypotheses', which propose that adult vitamin D deficiency leaves the brain more vulnerable to secondary adverse exposures, and thus may exacerbate disease progression. Finally, we explore the evidence implicating a role for vitamin D in rapid, non-genomic mechanisms that may involve L-type calcium channels and brain function. This article is part of a Special Issue entitled '17th Vitamin D Workshop'.