REVIEWDevelopmental vitamin D deficiency causes abnormal 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.
References (116)
- et al.
Interleukin-2 decreases accumbal dopamine efflux and responding for rewarding lateral hypothalamic stimulation
Brain Res.
(1996) - et al.
Transient prenatal vitamin D deficiency is associated with subtle alterations in learning and memory functions in adult rats
Behav. Brain Res.
(2005) - et al.
Pharmacological treatment to augment hole board habituation in prenatal Vitamin D-deficient rats
Behav. Brain Res.
(2006) - et al.
Vitamin D deficiency may play a role in depression
Med. Hypotheses
(2007) - et al.
Distribution of target cells for 1,25-dihydroxyvitamin D3 in the brain of the yellow bellied turtle Trachemys scripta
Brain Res.
(1994) - et al.
1,25-Dihydroxyvitamin D3 induces nerve growth factor, promotes neurite outgrowth and inhibits mitosis in embryonic rat hippocampal neurons
Neurosci. Lett.
(2003) - et al.
Vitamin D and neurocognitive dysfunction: preventing “D”ecline?
Mol. Aspects Med.
(2008) - et al.
Transient prenatal vitamin D deficiency is associated with hyperlocomotion in adult rats
Behav. Brain Res.
(2004) - et al.
Combined prenatal and chronic postnatal vitamin D deficiency in rats impairs prepulse inhibition of acoustic startle
Physiol. Behav.
(2004) - et al.
Behavioural characterization of vitamin D receptor knockout mice
Behav. Brain Res.
(2005)
Hyperlocomotion associated with transient prenatal vitamin D deficiency is ameliorated by acute restraint
Behav. Brain Res.
Vitamin D and its role in immunology: multiple sclerosis, and inflammatory bowel disease
Prog. Biophys. Mol. Biol.
Vitamin D status 1,25-dihydroxyvitamin D3, and the immune system
Am. J. Clin. Nutr.
p75 and Trk: a two-receptor system
Trends Neurosci.
Maternal vitamin D depletion alters neurogenesis in the developing rat brain
Int. J. Dev. Neurosci.
Developmental vitamin D deficiency alters the expression of genes encoding mitochondrial, cytoskeletal and synaptic proteins in the adult rat brain
J. Steroid Biochem. Mol. Biol.
Vitamin D3 and brain development
Neuroscience
Developmental vitamin D (DVD) deficiency in the rat alters adult behaviour independently of HPA function
Psychoneuroendocrinology
Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain
J. Chem. Neuroanat.
Developmental vitamin D3 deficiency alters the adult rat brain
Brain Res. Bull.
Developmental vitamin D deficiency alters adult behaviour in 129/SvJ and C57BL/6J mice
Behav. Brain Res.
A unifying multiple sclerosis etiology linking virus infection, sunlight, and vitamin D, through viral interleukin-10
Med. Hypotheses
Environmental factors that influence the cutaneous production of vitamin D
Am. J. Clin. Nutr.
Vitamin D deficiency during pregnancy: an ongoing epidemic
Am. J. Clin. Nutr.
Porcine microsomal vitamin D(3) 25-hydroxylase (CYP2D25). Catalytic properties, tissue distribution, and comparison with human CYP2D6
J. Biol. Chem.
Protective effects of 1 alpha 25-(OH)(2)D-3 against the neurotoxicity of glutamate and reactive oxygen species in mesencephalic culture
Neuropharmacology
Electrophysiological evidence for reduced latent inhibition in schizophrenic patients
Schizophr. Res.
Developmental vitamin D deficiency alters MK 801-induced hyperlocomotion in the adult rat: an animal model of schizophrenia
Biol. Psychiatry
Maternal vitamin D3 deprivation and the regulation of apoptosis and cell cycle during rat brain development
Brain Res. Dev. Brain Res.
Vitamin D and 1, 25-dihydroxyvitamin D3 as modulators in the immune system
J. Steroid Biochem. Mol. Biol.
An experimental demonstration of a vitamin which promotes calcium deposition
J. Biol. Chem.
Low maternal vitamin D as a risk factor for schizophrenia: a pilot study using banked sera
Schizophr. Res.
Vitamin D supplementation during the first year of life and risk of schizophrenia: a Finnish birth cohort study
Schizophr. Res.
Vitamin D and cancer
J. Nutr. Biochem.
Neurosteroids: biochemistry and clinical significance
Trends Endocrinol. Metab.
Vitamin D nuclear binding to neurons of the septal, substriatal and amygdaloid area in the Siberian hamster (Phodopus sungorus) brain
Neuroscience
1,25-Dihydroxyvitamin D3 regulates the expression of the low-affinity neurotrophin receptor
Brain Res. Mol. Brain Res.
1,25-Dihydroxyvitamin D3 regulates the synthesis of nerve growth factor in primary cultures of glial cells
Brain Res. Mol. Brain Res.
Vitamin D deficiency during various stages of pregnancy in the rat; its impact on development and behaviour in adult offspring
Psychoneuroendocrinology
Is vitamin D hypothesis for schizophrenia valid? Independent segregation of psychosis in a family with vitamin-D-dependent rickets type IIA
Prog. Neuropsychopharmacol. Biol. Psychiatry
Modulation of behavioral and neurochemical measures of forebrain dopamine function in mice by species-specific interleukin-2
J. Neuroimmunol.
Distribution of 1,25-dihydroxyvitamin D3 receptor immunoreactivity in the rat brain and spinal cord
J. Chem. Neuroanat.
Vitamin D increases expression of the tyrosine hydroxylase gene in adrenal medullary cells
Brain Res. Mol. Brain Res.
Neurosteroids act on recombinant human GABAA receptors
Neuron
Glial cell line-derived neurotrophic factor is essential for neuronal survival in the locus coeruleus-hippocampal noradrenergic pathway
Neuroscience
Pharmacological induction of nerve growth factor mRNA in adult rat brain
Exp. Neurol.
Characterization of brain neurons that express enzymes mediating neurosteroid biosynthesis
Proc. Natl. Acad. Sci. U.S.A.
Developmental vitamin D deficiency alters brain protein expression in the adult rat: implications for neuropsychiatric disorders
Proteomics
25-Hydroxyvitamin D, 24, 25-dihydroxyvitamin D and 1, 25-dihydroxyvitamin D in human cerebrospinal fluid
Klin. Wochenschr.
Rat hippocampal neurons in dispersed cell culture
Brain Res.
Cited by (204)
Impact of micronutrients and nutraceuticals on cognitive function and performance in Alzheimer's disease
2024, Ageing Research ReviewsTherapeutic and mechanistic intervention of vitamin D in neuropsychiatric disorders
2022, Psychiatry ResearchEarly-life nutrition and neurodevelopment
2022, Early Nutrition and Long-Term Health: Mechanisms, Consequences, and Opportunities, Second EditionVITAMIN D and DEPRESSION in OLDER ADULTS: LESSONS LEARNED from OBSERVATIONAL and CLINICAL STUDIES
2022, Nutrition Research Reviews