Review
Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease

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Abstract

Increasingly vitamin D deficiency is being associated with a number of psychiatric conditions. In particular for disorders with a developmental basis, such as autistic spectrum disorder and schizophrenia the neurobiological plausibility of this association is strengthened by the preclinical data indicating vitamin D deficiency in early life affects neuronal differentiation, axonal connectivity, dopamine ontogeny and brain structure and function. More recently epidemiological associations have been made between low vitamin D and psychiatric disorders not typically associated with abnormalities in brain development such as depression and Alzheimer’s disease. Once again the preclinical findings revealing that vitamin D can regulate catecholamine levels and protect against specific Alzheimer-like pathology increase the plausibility of this link. In this review we have attempted to integrate this clinical epidemiology with potential vitamin D-mediated basic mechanisms. Throughout the review we have highlighted areas where we think future research should focus.

Highlights

► Impairments in vitamin D signaling adversely affect brain development. ► Vitamin D is closely associated with dopaminergic neurotransmission. ► Low levels of Vitamin D are associated with various psychiatric conditions. ► It is time for intervention studies with Vitamin D in psychiatric diseases?

Introduction

Ten years ago it was suggested that vitamin D was the ‘forgotten neurosteroid’ (McGrath et al., 2001). Over the past 10–15 years, studies in which the diet or vitamin D signaling have been manipulated in experimental animals have provided convincing evidence that this vitamin, more accurately referred to as a hormone, is required for normal brain homeostasis and development. In order to better understand the exact mechanisms behind the diverse actions of vitamin D in brain, a large number of studies have been conducted in central nervous system (CNS) tissue or isolated cells.

The purpose of this review is fourfold; (a) to provide an up-to-date summary of the work implicating a role for vitamin D in both early and late events in brain cell growth and differentiation; (b) to explore potential mechanisms for some of these findings; (c) to summarise the increasing number of psychiatric conditions now being linked with deficiencies in this vitamin; and (d) to detail the most pressing questions remaining in order for us to more fully understand how the “sunshine hormone” exerts its diverse effects across the CNS.

Section snippets

Vitamin D metabolism

The Nobel Prize was awarded to Adolf Windausin 1928 for his role in the discovery of vitamin D. The synthesis of vitamin D begins with cleavage of the B ring of 7-dehydrocholesterol in the epidermis by ultraviolet UVB radiation (290–315 nM). After spontaneous isomerisation, this creates the secosteroid precursor molecule, cholecalciferol or vitamin D3. A number of forms of vitamin D exist but D3 is the form naturally present in animals and the form referred to in endocrinology studies. Vitamin D3

Vitamin D is a neuroactive steroid

Vitamin D is part of a large family of ligands that signal via nuclear receptors – this includes testosterone, estrogen, corticosteroids, thyroid hormones and vitamin A. Vitamin D is a transcriptional regulator for a large number of genes. To initiate its actions 1,25(OH)2D3 binds the vitamin D receptor (VDR), a member of the nuclear receptor superfamily. In concert with a range of binding partners and coactivators (including the retinoid X receptor), vitamin D can influence the expression of a

Vitamin D and the developing brain; in vivo studies

The effect of vitamin D on the developing brain has been examined largely via manipulation of maternal diet or genetic ablation of some aspect of vitamin D signaling in rodents. While vitamin D toxicity is very rare (mostly related to errors in fortification in food stuffs) vitamin D deficiency is relatively common, particularly in pregnant women (Hollis, 2007, Hollis and Wagner, 2006a, Hollis and Wagner, 2006b). Additionally, the fetus is totally reliant on maternal vitamin D stores. Studies

Vitamin D alters neurotransmitter expression in adult brain

In this section we review the experimental evidence that dietary manipulation or direct addition of 1,25(OH)2D3 to the brain alters cholinergic, dopaminergic and noradrenergic neurotransmitters systems. Abnormalities in these neurotransmitters have been implicated in various neuropsychiatric diseases such as schizophrenia, autism, depression and Alzheimer’s disease. Concurrently, epidemiological studies have also linked vitamin D status with risk of these disorders (see below).

Early studies

What are the mechanisms linking vitamin D with brain development and function?

The vitamin D receptor is a nuclear receptor with pluripotent effects. Clearly there may be a number of possible molecular mechanisms for its diverse actions in the developing and adult brain. The number of functions proposed for this vitamin in the brain over the past 10 years is impressive (McCann and Ames, 2008). Although there are also likely to be a number of peripheral endocrine-like mechanisms also at play, given the early appearance and the broad distribution of the VDR in the developing

Vitamin D and neuropsychiatric disorders

Our aim in this section of this review is to critique the literature regarding vitamin D status specifically as it relates to neuropsychiatric rather than neurological disease. Intentionally we have avoided commenting on the well-established links between vitamin D and certain neurological conditions such as Multiple Sclerosis as this has been excellently reviewed by others (Giovannoni and Ebers, 2007, Handel et al., 2010, Ramagopalan et al., 2011). There is also emerging literature suggesting

Future directions

The evidence continues to accumulate indicating that adequate levels of vitamin D are required for normal brain development and function (McCann and Ames, 2008). In this review we have outlined the literature indicating how vitamin D influences both early and late events in brain ontogeny and we have explored several potential mechanisms for some of these findings. Most notably, recent studies have uncovered the role of 1,25(OH)2D3 in regulating calcium transients via voltage sensitive L-type

Conclusions

The mass of data accumulated over these past 10 years have led to the tentative inclusion of vitamin D into the broader family of neuroactive steroids (Melcangi and Panzica, 2009). This group includes agents such as the sex steroids and glucocorticoids whose actions in shaping brain development and function are well-accepted. Therefore, vitamin D has now finally “emerged from the shadows” and is no-longer “The Neglected Neurosteroid” (McGrath et al., 2001).

The data reviewed here confirms that

Conflict of interest

The authors have no conflict of interest.

Acknowledgments

This research receives funding from the National Health and Medical Research Council and the Queensland State Government.

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