Vitamin D in fetal brain development

Abstract

In this review we will provide a concise summary of the evidence implicating a role for vitamin D in the developing brain. Vitamin D is known to affect a diverse array of cellular functions. Over the past 10 years data has emerged implicating numerous ways in which this vitamin could also affect the developing brain including its effects on cell differentiation, neurotrophic factor expression, cytokine regulation, neurotransmitter synthesis, intracellular calcium signaling, anti-oxidant activity, and the expression of genes/proteins involved in neuronal differentiation, structure and metabolism. Dysfunction in any of these processes could adversely affect development. Although there are many ways to study the effects of vitamin D on the developing CNS in vivo, we will concentrate on one experimental model that has examined the impact of the dietary absence of vitamin D in utero. Finally, we discuss the epidemiological data that suggests that vitamin D deficiency either in utero or in early life may have adverse neuropsychiatric implications.

Introduction

The biochemical formation of vitamin D begins with ultraviolet B (UVB) radiation on the epidermis converting a cholesterol metabolite (7-dehydrocholesterol) to vitamin D₃, a secosteroid (cholecalciferol; a preprohormone). This is subsequently hydroxylated to 25-hydroxyvitamin D₃ (25(OH)D₃) a prehormone and the form most commonly used to measure vitamin D status. A second hydroxylation of this molecule converts 25(OH)D₃ to the active hormone 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃). Catabolism of this active moiety is via a subsequent further hydroxylation to 24,25-dihydroxyvitamin D₃ (24,25(OH)₂D₃). Vitamin D is part of a large family of ligands that signal via nuclear receptors including testosterone, estrogen, corticosterones, 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 host of genes in a variety of pathways. Some of these pathways are known to play crucial roles in brain development. However, the evidence that vitamin D status during gestation may influence brain development has only been appreciated in the last decade. It is the breadth and strength of these findings that have led to the suggestion that vitamin D should be included within the broader family of neuroactive steroids [1], [2]. This group includes agents such as the sex steroids and glucocorticoids whose actions in shaping brain development and function are well accepted.