Elsevier

Psychoneuroendocrinology

Volume 34, Supplement 1, December 2009, Pages S247-S257
Psychoneuroendocrinology

REVIEW
Developmental vitamin D deficiency causes abnormal brain development

https://doi.org/10.1016/j.psyneuen.2009.04.015Get rights and content

Summary

There is now clear evidence that vitamin D is involved in brain development. Our group is interested in environmental factors that shape brain development and how this may be relevant to neuropsychiatric diseases including schizophrenia. The origins of schizophrenia are considered developmental. We hypothesised that developmental vitamin D (DVD) deficiency may be the plausible neurobiological explanation for several important epidemiological correlates of schizophrenia namely: (1) the excess winter/spring birth rate, (2) increased incidence of the disease in 2nd generation Afro-Caribbean migrants and (3) increased urban birth rate. Moreover we have published two pieces of direct epidemiological support for this hypothesis in patients. In order to establish the “Biological Plausibility” of this hypothesis we have developed an animal model to study the effect of DVD deficiency on brain development. We do this by removing vitamin D from the diet of female rats prior to breeding. At birth we return all dams to a vitamin D containing diet. Using this procedure we impose a transient, gestational vitamin D deficiency, while maintaining normal calcium levels throughout. The brains of offspring from DVD-deficient dams are characterised by (1) a mild distortion in brain shape, (2) increased lateral ventricle volumes, (3) reduced differentiation and (4) diminished expression of neurotrophic factors. As adults, the alterations in ventricular volume persist and alterations in brain gene and protein expression emerge. Adult DVD-deficient rats also display behavioural sensitivity to agents that induce psychosis (the NMDA antagonist MK-801) and have impairments in attentional processing. In this review we summarise the literature addressing the function of vitamin D on neuronal and non-neuronal cells as well as in vivo results from DVD-deficient animals. Our conclusions from these data are that vitamin D is a plausible biological risk factor for neuropsychiatric disorders and that vitamin D acts as a neurosteroid with direct effects on brain development.

Introduction

Since its discovery vitamin D biology has largely been considered the domain of endocrinologists. For almost a century we have known that vitamin D is the hormone of calcium mobilisation and bone health (McCollum, 1922). Cancer biologists took note when it was recognised that some of vitamin D's actions in developing osteoclasts were to inhibit cell cycling and to promote cell differentiation (Tuohimaa, 2008). The chase is now on for a chemical analogue of vitamin D that will not have the calcium mobilising effects of the active hormone 1,25 dihydroxy vitamin D3 (1,25(OH)2D). Similarly the immunological properties of vitamin D are under active consideration (Cantorna et al., 2004, Mathieu et al., 2004). The ever-expanding roles for this humble steroid have now expanded into the field of neuroscience. Linking vitamin D and neuropsychiatric disorders has only received attention in the last two decades. The first indirect clue that vitamin D may have some role in the brain was when its metabolites were discovered in the cerebrospinal fluid of healthy adults (Balabanova et al., 1984). This idea was supported by the early work of Walter Stumpf who mapped 1,25(OH)2D binding in rodent brains using radiolabelled 1,25(OH)2D and autoradiography (Stumpf et al., 1992, Stumpf and O’Brien, 1987). However, 1,25(OH)2D binding alone does not prove that there is a specific receptor for the ligand. Establishing the presence of the vitamin D receptor (VDR) in the central nervous system (CNS) by immunohistochemical studies in the brains of several species provided the first real clue that vitamin D may have a role in brain function (Bidmon and Stumpf, 1994, Bidmon and Stumpf, 1996, Musiol et al., 1992). The VDR was found in both the neonatal and adult rat CNS in multiple brain regions (e.g. temporal, orbital and cingulate cortices, thalamus, accumbens, amygdala, olfactory system and pyramidal neurons of the hippocampus), thus adding further support to the hypothesis that vitamin D signalling may be involved in both brain development and adult brain function (Burkert et al., 2003, Prufer et al., 1999, Veenstra et al., 1998). Our later discovery of 1-hydroxylase in the human brain suggests that the CNS can synthesise the active form of vitamin D, 1,25(OH)2D from its inactive precursor 25 hydroxy vitamin D (25(OH)D) (Eyles et al., 2005). Thus, serum 25(OH)D levels may also influence paracrine production of 1,25(OH)2D directly in the CNS (Hosseinpour and Wikvall, 2000, Sutherland et al., 1992, Zehnder et al., 2001), challenging the “endocrine type” assumption that the brain is wholly reliant on circulating 25(OH)D crossing the blood–brain barrier (Gascon-Barre and Huet, 1983, McGrath et al., 2001).

This review has a number of main aims. We will first summarise the published evidence linking vitamin D to brain development and brain function. Most of this evidence is based on animal experiments from the authors where vitamin D has been removed from the maternal diet. Second, we summarise the emerging epidemiological clues that link low levels of vitamin D during development to adult brain diseases such as schizophrenia and multiple sclerosis. Finally we present the case for vitamin D to be recognised as an important developmental neurosteroid.

Section snippets

The vitamin D receptor (VDR)

Expression of the VDR is temporally regulated in various regions within the developing rat CNS (Veenstra et al., 1998). The earliest expression of VDR occurs from day 12 of gestation in the mesencephalon. The timing of VDR expression coincides precisely with the birth of the majority of dopamine neurons within this region (Gates et al., 2006). The mesencephalon will later differentiate into the adult midbrain containing the bulk of the dopamine neurons that will innervate cortical, limbic and

Developmental vitamin D deficiency and Schizophrenia

Many studies have shown that those born in winter and spring have a significantly increased risk of developing schizophrenia (Torrey et al., 1997) and that those born at higher latitudes are also at increased risk (Saha et al., 2006) with both the incidence and prevalence of schizophrenia being significantly greater in sites from higher latitudes (Davies et al., 2003). Furthermore, based on data from cold climates, the incidence of schizophrenia is significantly higher in the children of

Developmental vitamin D deficiency and multiple sclerosis (MS)

The epidemiological evidence implicating an inverse correlation with vitamin D and MS appears robust. MS decreases as populations live nearer the equator where presumably they have greater levels of vitamin D (Hayes, 2000, Hayes and Donald Acheson, 2008, Ponsonby et al., 2005). Vitamin D supplementation also appears to reduce risk (Munger et al., 2004). Additionally the protective actions of vitamin D on the experimental model of MS are robust and well-known (Cantorna, 2006, Cantorna et al.,

Vitamin D and other neuropsychiatric disorders

Low levels of 25(OH)D in the adult patient have also been linked with other psychiatric disorders including seasonal affective disorder (Stumpf and Privette, 1989), depression (Berk et al., 2007, Hoogendijk et al., 2008) and Alzheimer's disease (Buell and Dawson-Hughes, 2008, Oudshoorn et al., 2008). Positive associations need to be interpreted with caution, however, as many of these studies did not included adjustments for physical activity, season or sunlight exposure. Thus any apparent

Vitamin D: the forgotten neurosteroid

It is timely that vitamin D and brain development are being discussed at a dedicated conference for steroids and the nervous system. Work from our group over the past eight years has clarified multiple roles for this steroid in brain tissue, in particular in the developing brain. Neuroactive steroids such as vitamin A and the sex steroids testosterone and oestrogen exert their effects on gene expression in the brain via intracellular nuclear steroid hormone receptors. Vitamin D is part of this

Conclusions

In this review we have summarised the data implicating a role for vitamin D in brain development. The downstream effects of this on molecular and behavioural outcomes in the adult animal would appear to be highly relevant for neuropsychiatric conditions, such as schizophrenia. While the results from the DVD-deficient animal experiments indicate that brain structure and function are altered in rodents, it remains to be seen if this deficiency is directly associated with schizophrenia in humans.

Conflict of interest statement

None declared.

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