Vitamin D deficiency is prevalent throughout the world, and growing evidence supports a requirement for optimal vitamin D levels for the healthy developing and adult brain. Vitamin D has important roles in proliferation and differentiation, calcium signaling within the brain, and neurotrophic and neuroprotective actions; it may also alter neurotransmission and synaptic plasticity. Recent experimental studies highlight the impact that vitamin D deficiency has on brain function in health and disease. In addition, results from recent animal studies suggest that vitamin D deficiency during adulthood may exacerbate underlying brain disorders and/or worsen recovery from brain stressors. An increasing number of epidemiological studies indicate that vitamin D deficiency is associated with a wide range of neuropsychiatric disorders and neurodegenerative diseases. Vitamin D supplementation is readily available and affordable, and this review highlights the need for further research.

Epidemiological evidence suggests that low levels of vitamin D may predispose people to develop depression and cognitive impairment. While rodent studies have demonstrated that prenatal vitamin D deficiency is associated with altered brain development, there is a lack of research examining adult vitamin D (AVD) deficiency.The aim of this study was to examine the impact of AVD deficiency on behaviour and brain function in the mouse. Ten-week old male C57BL/6J and BALB/c mice were fed a control or vitamin D deficient diet for 10 weeks prior to, and during behavioural testing. We assessed a broad range of behavioural domains, excitatory and inhibitory neurotransmission in brain tissue, and, in separate groups of mice, locomotor response to D-amphetamine and MK-801. Overall, AVD deficiency resulted in hyperlocomotion in a novel open field and reduced GAD65/67 levels in brain tissue. AVD-deficient BALB/c mice had altered behaviour on the elevated plus maze, altered responses to heat, sound and shock, and decreased levels of glutamate and glutamine, and increased levels of GABA and glycine. By contrast C57BL/6 mice had a more subtle phenotype with no further behavioural changes but significant elevations in serine, homovanillic acid and 5-hydroxyindoleacetic acid.Although the behavioural phenotype of AVD did not seem to model a specific disorder, the overall reduction in GAD65/67 levels associated with AVD deficiency may be relevant to a number of neuropsychiatric conditions. This is the first study to show an association between AVD deficiency and prominent changes in behaviour and brain neurochemistry in the mouse.3

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'.

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