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Keywords:

  • amyotrophic lateral sclerosis;
  • autism;
  • multiple sclerosis;
  • Parkinson's disease;
  • schizophrenia;
  • vitamin D

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Vitamin D metabolism
  5. Vitamin D effector proteins
  6. The effects of vitamin D in the nervous system
  7. Vitamin D and brain development
  8. Vitamin D in psychiatric and neurological disease
  9. Conclusions
  10. Acknowledgements
  11. Conflicts of interest
  12. References

Vitamin D and its metabolites have pleomorphic roles in both nervous system health and disease. Animal models have been paramount in contributing to our knowledge and understanding of the consequences of vitamin D deficiency on brain development and its implications for adult psychiatric and neurological diseases. The conflation of in vitro, ex vivo, and animal model data provide compelling evidence that vitamin D has a crucial role in proliferation, differentiation, neurotrophism, neuroprotection, neurotransmission, and neuroplasticity. Vitamin D exerts its biological function not only by influencing cellular processes directly, but also by influencing gene expression through vitamin D response elements. This review highlights the epidemiological, neuropathological, experimental and molecular genetic evidence implicating vitamin D as a candidate in influencing susceptibility to a number of psychiatric and neurological diseases. The strength of evidence varies for schizophrenia, autism, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, and is especially strong for multiple sclerosis.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Vitamin D metabolism
  5. Vitamin D effector proteins
  6. The effects of vitamin D in the nervous system
  7. Vitamin D and brain development
  8. Vitamin D in psychiatric and neurological disease
  9. Conclusions
  10. Acknowledgements
  11. Conflicts of interest
  12. References

It is well established that the vitamin D endocrine system plays a critical role in calcium homeostasis and bone health; however, in recent decades, the broad range of physiological actions of vitamin D has been increasingly recognized. In addition to its role in proliferation, differentiation and immunomodulation, there is mounting evidence to support an intricate role of vitamin D in brain development and function in health and disease. The current review will summarize key concepts in vitamin D metabolism in the brain, and explore the relationship of vitamin D and brain development. A survey of the role of vitamin D in several psychiatric and neurological disorders including schizophrenia, autism, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and multiple sclerosis (MS) will be presented.

Vitamin D metabolism

  1. Top of page
  2. Abstract
  3. Introduction
  4. Vitamin D metabolism
  5. Vitamin D effector proteins
  6. The effects of vitamin D in the nervous system
  7. Vitamin D and brain development
  8. Vitamin D in psychiatric and neurological disease
  9. Conclusions
  10. Acknowledgements
  11. Conflicts of interest
  12. References

Vitamin D is a seco-steroid hormone that comes in two major forms depending on the source, vitamin D2 (ergocalceiferol) of plant origin, and vitamin D3 (cholecalciferol) of animal origin. Vitamin D3 can be either ingested or produced photochemically in the epidermis by action of ultraviolet light (UVB) on 7-dehydrocholesterol. In both instances, vitamin D2 and D3 are biologically inert and require two separate hydroxylations by 25-hydroxylase (liver) and 1-α-hydroxylase (primarily in the kidney) to give rise to the active form (1,25-dihydroxyvitamin D2 and 1,25-dihydroxyvitamin D3 or calcitriol, respectively) [1] (Figure 1).

figure

Figure 1. Vitamin D metabolism. Vitamin D2 and D3 are biologically inert and require two separate hydroxylations by 25-hydroxylase (liver) and 1-α-hydroxylase (primarily in the kidney) to give rise to the active form (1,25-dihydroxyvitamin D3; calcitriol).

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The potential role of 1,25-dihydroxyvitamin D3 in the brain was first suggested by the discovery of high affinity calcitriol receptors in the pituitary [2], and later in the forebrain, hindbrain, and spinal cord [3] of rats. The presence of vitamin D metabolites in the cerebrospinal fluid of healthy patients further implied a role for vitamin D in the brain [4]. The initial assumption that 1,25-dihydroxyvitamin D3 could access the central nervous system (CNS) via passive and/or active transport across the blood brain barrier [5, 6] was challenged by the detection of 25-hydroxylase and 1-α-hydroxylase activity in extra-renal sites, including the brain [7-9]. These findings highlighted the possibility of paracrine production of 1,25-dihydroxyvitamin D3 production in the CNS. The glial cell expression of the 25(OH)D3 24-hydroxylase gene, CYP24A1, producing the enzyme needed to inactivate calcitriol, suggested further control of 1,25-dihydroxyvitamin D3 levels in the CNS [10]. In a rodent model, Spach and Hayes varied the plasma 25-OHD level by varying dietary vitamin D3 and reported that CNS calcitriol correlated with plasma 25-OHD but not with plasma calcitriol [11]. These data provided evidence for calcitriol synthesis in situ in the CNS. Therefore, the presence of 25-hydroxylase and 1-α-hydroxylase required to synthesize 1,25-dihydroxyvitamin D3 and 24-hydroxylase needed to degrade 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 in the brain, along with evidence of in situ CNS calcitriol synthesis, consolidated the idea that the CNS is poised to locally metabolize (and regulate) the active form of vitamin D implicating the importance of this active hormone in brain health and disease.

Vitamin D effector proteins

  1. Top of page
  2. Abstract
  3. Introduction
  4. Vitamin D metabolism
  5. Vitamin D effector proteins
  6. The effects of vitamin D in the nervous system
  7. Vitamin D and brain development
  8. Vitamin D in psychiatric and neurological disease
  9. Conclusions
  10. Acknowledgements
  11. Conflicts of interest
  12. References

(a) Vitamin D receptor (VDR)

Calcitriol exerts its nuclear effect via the vitamin D receptor (VDR). The discovery of the VDR (mRNA and protein) throughout the brain and spinal cord consolidated the importance of this hormone in modulating nervous system function. Studies from adult rats and hamsters provided a detailed topography of the distribution of VDR in the CNS [2, 3], later shown to be similar in humans [8, 12] (see Figure 2). VDR expression was noted in both neurones and glial cells (microglia, astrocytes, oligodendrocytes) in different CNS regions, including: (i) cortex [temporal (that is, auditory, olfactory, entorhinal), frontal (that is, prefrontal, orbitofrontal, primary motor), parietal, cingulated]; (ii) deep grey matter (thalamus, basal ganglia, hypothalamus, hippocampus, amygdala); (iii) cerebellum (granular and Purkinje cell layers); (iv) brainstem nuclei; (v) spinal cord (anterior horn cells); and (vi) ventricular system (that is, choroid plexus ependymal cells) [13, 14]. VDRs have also been reported in the nuclei of Schwann cells and in peripheral neurones [15, 16].

figure

Figure 2. Nuclear targets of vitamin D in the brain. Sites in the brain that have been identified as nuclear targets for the steroid hormone of sunlight soltriol (vitamsin D) derived from data from autoradiograms from rat and mouse brains following injections of [3H]1,25(OH)2-cholecalciferol. There is a wide distribution of nuclear binding of calcitriol throughout the rodent brain involving major interconnected systems including (i) sensory (red dashed line) with target neurones in spinal ganglia, substantia gelatinose, parabrachial nuclei and reticular thalamic nucleus; (ii) autonomic-neuroendocrine (red solid line) with target neurones in interomediolateral column, nucleus reticularis lateralis magnocellularis (lm), nucleus ambiguus (n. Amb), parabrachial nuclei (n. Parabr.), dorsal raphe nucleus, hypothalamic periventricular and paraventricular parvocellular nuclei, bed nucleus of the stria terminalis, central nucleus of the amygdala and piriform cortex; (iii) motor with target neurones in cranial motor nerve nuclei, motor horn nuclei in the spinal cord, nucleus pontis, and Golgi II cells in the cerebellum; and (iv) ‘mental system’ with input from all of the other systems and to involve soltriol target neurones in allocortex and neocortex, amygdala, striatum and brainstem (figure and text adapted with permission from [12]).

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The VDR is a member of the steroid/thyroid hormone superfamily of transcription regulation factors. On binding of calicitriol, VDR heterodimerizes with the retinoid X receptor (RXR), and subsequently binds specific genomic sequences known as vitamin D response elements (VDREs) to influence gene transcription [17]. Recent construction of a genome-wide map of VDR binding provided evidence of enrichment of VDR-binding sites near autoimmune and cancer-associated genes identified from genome-wide association studies [17] (Figure 3). It is likely, however, that the consequences of VDR binding across the genome will be tissue-specific, thereby influencing disease pathogenesis via unique mechanisms. The ubiquitous distribution of the VDR in the CNS compartment poses the challenge of deciphering the role of VDR binding and gene expression in the brain and how it may relate to health and disease (see Figure 2).

figure

Figure 3. Common traits showing enrichment of VDR (vitamin D receptor) binding within intervals identified by genome-wide association studies (GWAS). Forty-seven traits studied by GWAS (http://www.genome.gov/gwastudies/) were analysed and those showing significant enrichment of VDR binding defined by ChIP-seq in two lymphoblast cell lines after calcitriol stimulation with a 1% false discovery rate (FDR) are shown (figure and text used with permission from [17]).

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(b) ‘Non-genomic’ effector pathways; MARRS

In addition to the genomic actions of 1,25-dihydroxyvitamin D3 via the VDR, there is some evidence to suggest that vitamin D may act via the Membrane Associated, Rapid Response Steroid binding receptor (MARRS) [18]. The MARRS receptor is thought to play a role in a variety of cellular processes, including immune function through the assembly of MHC class I molecules, DNA binding and gene expression, and molecular chaperoning [19]. The distribution of 1,25-dihydroxyvitamin D3-MARRS binding in the human brain and the consequences of vitamin D deficiency on the functions mediated by this receptor pathway have not been elucidated and warrant further study.

The effects of vitamin D in the nervous system

  1. Top of page
  2. Abstract
  3. Introduction
  4. Vitamin D metabolism
  5. Vitamin D effector proteins
  6. The effects of vitamin D in the nervous system
  7. Vitamin D and brain development
  8. Vitamin D in psychiatric and neurological disease
  9. Conclusions
  10. Acknowledgements
  11. Conflicts of interest
  12. References

Vitamin D has been shown to exert a multitude of effects on the nervous system including neurotrophism, neurotransmission, neuroprotection and neuroplasticity. These will be reviewed here.

(a) Neurotrophic support

Vitamin D has been shown to have broad trophic functions related to neuronal differentiation, maturation and growth. The first evidence implicating a neurotrophic role for vitamin D was gleaned from in vitro studies which demonstrated that synthesis of nerve growth factor (NGF) was stimulated by 1,25-dihydroxyvitamin D3 [20, 21]; the biological relevance of this phenomenom was later confirmed in in vivo models of the adult rat [22]. 1,25-dihydroxyvitamin D3 has subsequently been shown to upregulate the synthesis of glial cell line-derived neurotrophic factor (GDNF) [23], and neurotrophin 3 (NT-3) [21, 24], and downregulate levels of neurotrophin 4 (NT-4) [24]. 1,25-dihydroxyvitamin D3 has also been shown to regulate the gene expression of the low-affinity NGF neurotrophic receptor, p75NTR [25]. An elegant experiment using cultured embryonic hippocampal cells demonstrated enhanced neurite outgrowth and NGF production with the addition of 1,25-dihydroxyvitamin D3 [26] whereas vitamin D3 deprivation in pregnant rats decreased NGF expression in both neonates [27] and adult offspring [28, 29]. Given that vitamin D regulates NGF, known to act on cholinergic neurones in the basal forebrain, and GDNF, known to act on basal ganglia dopaminergic neurones, it is intriguing to speculate how 1,25-dihydroxyvitamin D3 may play an important neuroprotective role in patients who may have vulnerability to selective degeneration of these neuronal subtypes as may be seen in cognitive impairment and PD, respectively [27, 30, 31].

(b) Neurotransmission

In addition to vitamin D's role in neuronal growth and survival, vitamin D and its metabolites have been shown to mediate the synthesis of a variety of neurotransmitters, including acetylcholine, catecholamines, serotonin and dopamine [32-37]. While the majority of studies demonstrate a close temporal relationship between vitamin D exposure and changes in neurotransmitter levels, data suggest that the biological effects of vitamin D may be long-lasting and transgenerational. In a study where rats were treated with vitamin D in the neonatal period, it was found that dopamine levels remained elevated well beyond the period of exposure, with the effect being transmitted to the offspring of treated female rats [38, 39]. These data require replication, but are consistent with the concept of metabolic imprinting [40, 41]. Important features of metabolic imprinting include the presence of a critical period during foetal development or early life during which the foetus is sensitive to environmental exposures, and that such exposures lead to changes that persist through adulthood. Recent evidence suggests that epigenetic regulation may be operative in vitamin D converting enzymes raising the intriguing possibility that early vitamin D exposure (or lack thereof) may induce epigenetic alterations that affect gene expression, and perhaps susceptibility to neurodegenerative diseases later in life [42].

(c) Neuroprotection

There are several lines of evidence that suggest vitamin D may have a neuroprotective role. The administration of vitamin D or its metabolites has been shown to reduce neurological injury and/or neurotoxicity in a variety of animal systems, including: (i) the attentuation of the size of cerebral infarction in rats through presumed GDNF upregulation [43]; (ii) the preservation of mechanical hyperalgesia in a streptozotocin-diabetic rat model through the prevention of NGF depletion [44]; (iii) the decrease in neuronal death in rat foetal hippocampal cultures elicited by calcium mediated neurotoxicity through downregulation of L-type voltage-sensitive Ca2+ channels [45]; (iv) the attenuation of hypokinesia and dopamine neuronal toxicity in a rat model of 6-hydroxydopamine-induced neurotoxicity through the sequestration of free radical and reactive oxygen species (ROS) [46, 47]; (v) the protection of rat cultured mesencephalic dopaminergic neurones from glutamate and dopaminergic toxins by facilitating cellular functions that reduce oxidative stress [48, 49]; and (vi) the reduction of glutamate-induced cell death in cultured rat cortical neurones [50]. These latter studies highlight vitamin D's role in antioxidative metabolism, which is further supported by its ability to downregulate the expression of inducible nitric oxide synthase (iNOS) (and subsequently nitric oxide) in monocyte-derived cells [51], and to potentiate the production of γ-Glutamyl transpeptidase (γ-GT), an enzyme important in the glutathione pathway, in astrocytes exposed to a pro-inflammatory milieu [52].

While these experimental data demonstrate that vitamin D appears to exert its neuroprotective influence through diverse (and potentially overlapping) mechanisms, the extent of neuro-axis regional specificity of these effects is not clear. For example, a rodent model of hypervitaminosis D revealed changes in the synthesis of calcium-binding proteins, such as parvalbumin, restricted to the caudate/putamen but not in the cerebral cortex or hippocampus [53]. Similarly, differences in regional specificity have also been observed in vitamin D's influence on iNOS downregulation [52]. These important nuances should caution against the extension of these experimental data unreservedly to the human brain in health and disease. However, it is certainly tempting to speculate that vitamin D may have a protective effect (or a detrimental one in deficiency states) in human disease, especially as similar pathogenic mechanisms (that is, reactive oxygen and nitrogen species, glutamate excitotoxicity, and calcium dysregulation), have been implicated in the pathogenesis of several neuroinflammatory and neurodegenerative disorders, such as multiple sclerosis, Parkinson's disease, and motor neurone disease [51, 54, 55].

(d) Neuroplasticity

Vitamin D may have a crucial role in neuroplasticity. Gene array and proteomic studies on brains of adult rats deprived of vitamin D during gestation have demonstrated many genes involved in nervous system development that are differentially regulated. In particular, vitamin D deficiency has been shown to affect the transcript profiling of a multitude of genes, including those involved in (i) cytoskeletal maintenance (e.g. RhoA, microtubule associated protein-2, growth associated protein-43, neurofilament-light chain, glial fibrillary acidic protein); (ii) mitochondrial function (e.g. ATPase H+ transporting V1B2, Mn-containing superoxide dismutase, cytochrome c, catalase); (iii) synaptic plasticity (e.g. aquaporin-4, apolipoprotein B, myristoylated alanin-rich C kinase substrate); and (iv) cellular proliferation and growth (e.g. growth arrest and DNA-damage-inducible 45 alpha, growth arrest specific 5, insulin-like growth factor 1) [28, 50, 56-59].

Gene pathway analysis of vitamin D and the VDR system in neuronally expressed genes accentuates its role in functions critical to neural development, including growth cone spreading and collapse, neurite and axonal outgrowth and retraction, axonal guidance, dendritic spine morphogenesis, actin-filament and microtubule reorganization, and integrin mediate adhesion (see Figure 4A and B). Given the broad impact of vitamin D deficiency on neural developmental regulatory genes, it is not surprising that gestational vitamin D deficiency during a critical developmental period may result in long-standing aberrant molecular regulation of brain function, and hence influence the phenotypic expression of neurodegenerative disease [60]. It remains plausible, therefore, that vitamin D supplementation when taken later in life may not be effective in preventing neurodegenerative diseases where vitamin D is thought to play a role. Clinical trials targeting vitamin D supplementation during pregnancy with long-term follow-up will be needed to address this issue.

figure

Figure 4. Ingenuity Pathway Analysis (IPA) of neuronally expressed genes regulated by vitamin D. (A and B) Vitamin D affects neuronal gene expression through its influence on various neurotrophic factors (including NT3, NT4, and NGF) and downstream pathways. These vitamin D regulated genes impact diverse functions critical to neural development, including growth cone spreading and collapse, neurite and axonal outgrowth and retraction, axonal guidance, dendritic spine morphogenesis, actin-filament and microtubule reorganization, and integrin mediate adhesion.

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Vitamin D and brain development

  1. Top of page
  2. Abstract
  3. Introduction
  4. Vitamin D metabolism
  5. Vitamin D effector proteins
  6. The effects of vitamin D in the nervous system
  7. Vitamin D and brain development
  8. Vitamin D in psychiatric and neurological disease
  9. Conclusions
  10. Acknowledgements
  11. Conflicts of interest
  12. References

Given the diverse roles of vitamin D in the nervous system, it is not surprising that vitamin D influences brain development. In the embryonic rat brain, VDR expression is first detected on the 12th day of gestation and appears to be widely distributed with predominance in the neuroepithelium and subventricular zones [13, 61]. During rat embryonic brain development, VDR expression is dynamic as evidenced by its emergence in differentiating fields [27, 61]. Rodent models have been important at capturing the developmental consequences of vitamin D deficiency on embryogenesis and the neonatal period, and have provided a platform from which the long-term consequences of vitamin D deficiency have been examined. Such experimental models include the developmental vitamin-D-deficient model, and the VDR and 1-α-hydroxylase knockout models.

(a) Developmental vitamin D deficient model

In a developmental vitamin D deficient model, Eyles and colleagues induced maternal dietary deprivation of vitamin D in rats prior to mating and maintained this vitamin D deprived state for the duration of the pregnancy. They overcame the relative infertility associated with vitamin D deficiency and found that pups born of the vitamin D deprived dams exhibited conspicuous morphological changes in the brain. Increased overall brain size and cerebral hemispheric length, cortical layer thinning, and larger lateral ventricles were found compared with vitamin-D-sufficient controls [27]. Microscopically, the vitamin-D-depleted pups had evidence of increased cellular proliferation with higher rates of mitosis and decreased apoptosis than usually observed in neuronal differentiation [56]. Evaluation of the cell cultures derived from the neonatal subventricular zone in these vitamin-D-depleted rats revealed increased neurosphere number suggestive of increased cellular division, which decreased with addition of vitamin D [62]. In keeping with this experimental data, developmental vitamin D deficiency also appears to reduce levels of p75NTR, a key neurotrophic receptor involved in developmental apoptosis, and to deregulate cell cycle related genes [27]. The developmental brain abnormalities secondary to gestational vitamin D deficiency may not be fixed and in fact can normalize, to an extent, on reintroduction of vitamin D during a critical time window in the neonatal period [28, 62].

The behavioural consequences of the developmental vitamin D deficiency model have been extensively studied. In adult life, these rats tend to demonstrate subtle alterations in learning and memory, impaired attentional processing, altered spontaneous locomotion, sensitivity to NMDA antagonists, and altered sensitivity to anti-dopaminergic agents [63-67]. Maternal–pup interactions are also altered which likely further impacts early brain development and behaviour [68]. Given that some aspects of the clinical phenotype (disrupted latent inhibition, NMDA antagonist hypersensitivity) and brain morphological changes (that is, increased lateral ventricular size) resemble those found in schizophrenia, the developmental vitamin-D-deficient rat has gained support as a model for this psychiatric disease [31].

(b) VDR knockout model

The phenotype of the VDR knockout mouse model differs significantly from that of the developmental vitamin D model. Mice who have undergone targeted ablation of the VDR are normal at birth, but typically develop growth retardation, hypocalcaemia, hyperparathyroidism, rickets, osteomalacia, and alopecia [69, 70]. These mice exhibit several abnormalities including symmetrical thalamic calcification [71], a shorter gait and motor dysfunction even in the setting of normocalcaemia [72, 73], food neophobia [74], progressive hearing loss secondary to cochlear neural degeneration [75], vestibular dysfunction [76], increased severity of chemically induced seizures [77], and premature ageing [78]. The consequences of the mouse model on behavioural and cognitive performance measures have been conflicting, with increased grooming and anxiety, and aberrant nest-building being observed by some groups but not others [72, 79-81]. Unlike the developmental vitamin-D-deficient model, VDR knockout mice appear cognitively intact on measures of exploration and working memory [73]. The lifetime absence of 1,25-dihydroxyvitamin D3-VDR signalling, the inability to simulate chronic vitamin D deficiency, and the adverse effect of exercise-induced fatigue on behaviour with motoric components have hindered the popularity of this model in studying nervous system disease [31, 73].

(c) 1-α-hydroxylase knockout model

Similar to the VDR knockout mouse model, 1-α-hydroxylase knockout mice demonstrate growth retardation, hypocalcaemia, hypophosphataemia, hyperparathyroidism, and a clinical phenotype of severe rickets and osteomalacia resembling that seen in humans [82, 83]. From a functional point of view, 1-α-hydroxylase knockout mice do not appear to differ significantly from their wild-type counterparts on measures of motor, vestibular, and behavioural function [76]. It is postulated that the resultant elevation of 25-hydroxyvitamin D in this model is capable of binding to VDR thereby activating downstream signalling of this pathway [76]. Given the predominant rickets phenotype and lack of accompanying behavioural abnormalities, the 1-α-hydroxylase knockout mouse model has not been popular for studying the influence of vitamin D on nervous system disease.

The contrasting phenotypic fates of these vitamin D deficiency models highlights the complexity of vitamin D signalling in nervous system development. It is likely that vitamin D has effects on nervous system function which may be mediated, at least in part, independently of its binding to VDR and/or via non-genomic mechanisms.

Vitamin D in psychiatric and neurological disease

  1. Top of page
  2. Abstract
  3. Introduction
  4. Vitamin D metabolism
  5. Vitamin D effector proteins
  6. The effects of vitamin D in the nervous system
  7. Vitamin D and brain development
  8. Vitamin D in psychiatric and neurological disease
  9. Conclusions
  10. Acknowledgements
  11. Conflicts of interest
  12. References

The role of vitamin D in brain development and the consequences of early life vitamin D deficiency on subsequent aberrant behaviours and disease risk in animals likely have implications for human disease. An estimated one billion people worldwide have vitamin D deficiency (usually defined as serum 25(OH)D levels less than 25–50 nmol/l) or insufficiency (serum 25(OH)D levels < 75 nmol/l) with pregnant women being at increased risk because of increased foetal requirements and reduction in outdoor activity, most notably during the third trimester [1]. Vitamin D production is dependent entirely on UVB exposure which, in turn, is influenced by season and more significantly by latitude [84, 85]. The importance of vitamin D on human health is illustrated by indications that lighter skin colour evolved to optimize vitamin D production under conditions of low UVB radiation [84]. From an evolutionary perspective, although depigmentation seen in populations at higher latitudes confers a higher risk of skin cancer, most individuals develop cancer beyond their reproductive age thereby making skin cancer a relatively weak selective force compared with serum vitamin D availability [86].

In addition to rickets and osteomalacia, the convergence of in vitro, animal, and epidemiological research points to vitamin D deficiency as a candidate modifiable risk factor for a host of diseases, including those of the human nervous system. On a population level, evidence linking reduced UVB exposure and subsequent hypovitaminosis D to nervous system disease has been derived from studies associating disease incidence/prevalence with [87]:

  • (i) 
    season of birth – the amount of UVB radiation fluctuates across the seasons, with lower levels of exposure (and serum vitamin D levels) in winter and early spring in regions north/south of the equator – this would implicate hypovitaminosis D during gestation or early life to influence risk of disease later in life;
  • (ii) 
    latitude – the amount of UVB radiation correlates strongly with latitude and vitamin D levels – this would suggest individuals living further from the equator have a higher risk of disease;
  • (iii) 
    migrant studies – people who move from a region of high to low UVB exposure (with resultant high to low vitamin D levels) – this would support an increase in disease risk on moving from areas of high to low UVB exposure before a critical age (and vice versa);
  • (iv) 
    vitamin D supplementation – vitamin D levels are influenced by dietary intake and supplementation independent of UVB exposure – this would suggest individuals at risk of hypovitaminosis D may blunt their risk of disease by increasing their oral vitamin D intake [88].

The traditional caveats certainly apply to the application of these lines of epidemiological data to implicate vitamin D deficiency in the pathogenesis of disease. One must consider that (i) seasonal variations may influence levels of UVB itself (independent of vitamin D), exposure to viruses, and availability of other nutrients; (ii) latitudinal differences may be associated with differences in population genetic structure and socio-economic status; (iii) migration within, into, or out of a study population group may relate to the factor of interest, such as vitamin D status (migration bias); and that (iv) vitamin D supplementation may be associated with other health-protective behaviours that may influence disease risk.

The molecular basis by which vitamin D exerts these effects on human disease is not completely known; however, the aforementioned experimental and animal model data have provided a biological framework that will undoubtedly guide mechanism discovery. Further, emerging evidence suggests an intimate and complex relationship between disease susceptibility genes and vitamin D, mediated through putative vitamin-D-binding sites. A recent study demonstrated that, after calcitriol stimulation, 2776 genomic positions are occupied by a VDR and that 229 genes show significant changes in expression in response to vitamin D [17].

Here we highlight nervous system diseases that have been linked with hypovitaminosis D on an epidemiological level, with a particular focus on those diseases wherein susceptibility genes identified by genome-wide association studies have associated VDR-binding sites. The latter was accomplished by (i) identifying susceptibility genes for these nervous system diseases by consulting the catalogue of published genome-wide association studies (GWAS) (http://www.genome.gov/gwastudies); and then (ii) cross-referencing the identified susceptibilty genes with a database of genes known to have VDR-binding sites within or in close proximity to them [17]. The psychiatric and neurological diseases that fulfilled these criteria and were selected for inclusion are schizophrenia, autism, PD, ALS, MS, and AD. These diseases and the evidence implicating their relationship to vitamin D will be discussed briefly here.

A. Psychiatric disease

(i) Schizophrenia

Schizophrenia is a heterogenous psychotic syndrome which affects approximately 1% of the population. The aetiology of schizophrenia is multifactorial with both environmental and genetic factors thought to play important roles [89]. The neuropathology of schizophrenia remains obscure; however, a number of structural abnormalities have been idenitified and confirmed by meta-analysis including ventricular enlargement and decreased cerebral (cortical and hippocampal) volume in the absence of gliosis [90]. The latter feature fuels support for a neurodevelopmental contribution. Intriguingly, these morphological changes are similar to those observed in the developmental vitamin D deficient rat model, as previously described [27]. Further, NGF, neurotrophin, and p75NTR, known to be regulated by vitamin D, are important in mitigating synaptogenesis, neurite and axonal outgrowth all of which have been shown to be aberrant in schizophrenia. These data form important features of the experimental basis on which vitamin D has been implicated in the susceptibility to this disease.

The environmental influence on susceptibility to schizophrenia has long been discussed, with hypovitaminosis D being a leading suspect. Epidemiological studies have repeatedly pointed to a season-of-birth effect in schizophrenia [91-96]. In northern latitudes, an excess number of births occur in the winter and early spring with a mirror effect occurring in the southern hemisphere – the magnitude of the effect on disease risk increasing with distance from the equator. With regards to latitude, several studies have demonstrated increased incidence and prevalence of schizophrenia at higher latitudes in both hemispheres [97]. Interestingly, children of Afro-Caribbean, Black African, and Asian migrants to northern climates (such as the United Kingdom) have an increased risk of the disease compared with natives, adding further support of a possible contribution of vitamin D in the pathogenesis of the disease [98, 99]. The use of vitamin D supplementation in the gestational and/or perinatal period appears to reduce the risk of developing schizophrenia later in life [100, 101]. A recent study of serum neonatal 25(OH)D levels in a Danish population-based cohort implicated a role of neonatal 25(OH)D with later risk of developing schizophrenia. However, both low and high concentrations were associated with increased disease risk, findings that demand further interrogation [102].

There is a known heritable component in schizophrenia, with clustering being observed within families, especially in monozygotic twin pairs [103]. Monozygotic twins may be discordant for the disease suggesting gene-environment interactions. A recent study suggested a latitude-driven adaptation for both schizophrenia and vitamin D related genes and proposed a model in which schizophrenia is, at least in part, a maladaptive by-product of latitude dependent adaptive changes in vitamin D metabolism [104]. Interestingly, GWAS have highlighted several genes associated with susceptibility to schizophrenia, many of which have a VDR-binding site within or close to them. The genes that are potentially regulated by vitamin D subserve a diverse range of biological functions including membrane transport, maintenance of nucleosome structure, and signal transduction to name a few (see Table 1). Some of these vitamin D mediated genes have an intimate relationship with brain morphology and function as evidenced by their demonstrated role in neuronal migration and gyration, dendritic spine morphology, and neuronal connectivity (see Table 1) [105-108]. The full scope of the functional impact of vitamin D on the expression of these schizophrenia-associated genes in the brain warrants further study.

Table 1. Schizophrenia and autism associated gene regions with VDR (vitamin D receptor) binding
DiseaseGene symbolGene nameGene locationProtein function*Role in brain function
  1. *Data derived from NCBI Gene (http://www.ncbi.nlm.nih.gov/gene); Ensembl (http://www.ensembl.org); Human Protein Reference Database (http://www.hprd.org).

SchizophreniaVRK2vaccinia related kinase 22p16.1Member of vaccinia-related kinase (VRK) family of serine/threonine protein kinasesNeuronal migration and gyration; Dendritic spine morphology [105]
ZNF804Azinc finger protein 804A2q32.1Member of zinc-finger protein family of unknown functionDorsolateral prefrontal, orbitofrontal, hippocampus, and amygdala connectivity [106]
SLC17A3solute carrier family 17 (sodium phosphate), member 36p21.3Membrane protein involved in phosphate transportNone known
BTN3A2butyrophilin, subfamily 3, member A26p22.1Part of butyrophilin (BTN) and immunoglobulin superfamilies, residing in the juxta-telomeric region of the MHC class 1 locusNone known
BTN2A2butyrophilin, subfamily 2, member A26p22.1
BTN3A1butyrophilin, subfamily 3, member A16p22.1
HIST1H2BJhistone cluster 1, H2bj6p22.1Core histones responsible for the nucleosome structure of the chromosomal fibre in eukaryotesDendritic spine morphology [107]
HIST1H2AGhistone cluster 1, H2ag6p22.1None known
PRSS16protease, serine, 16 (thymus)6p21Serine protease expressed exclusively in the thymus with role in the alternative antigen presenting pathway during positive T-cell selectionNone known
NOTCH4notch 46p21.3Member of Type 1 transmembrane protein family – cell surface receptor linked to signal transduction important for developmental processes by controlling cell fate decisionsFrontal lobe (executive) function [108]
HLA-DQA1major histocompatibility complex, class II, DQ alpha 16p21.3Part of MHC class II molecule – heterodimer with beta chain (DQB); plays central role in immune system by presenting peptides derived from extracellular proteinsNone known
AutismPPP2R5Cprotein phosphatase 2, regulatory subunit B′, gamma14q32.31Serine/threonine phosphatase implicated in the negative control of cell growth and divisionRetinogenesis and photoreceptor development [126]
(ii) Autism

Autism is part of a spectrum of developmental disorders characterized by deficits in social cognition, language, communication, and stereotypical patterns of behaviour [109]. Neuropathological features lack clear definition; however, the disorder shows changes consistent with pre- and post-natal developmental abnormalities that involve multiple brain regions, including the cerebral cortex, subcortical white matter, amygdala, brainstem, and cerebellum [110]. It has been proposed that autism demonstrates developmentally specific neural changes, with early brain overgrowth at the beginning of life (thought to be secondary to excessive neurone number), slowing or arrest of growth during early childhood, and neurodegeneration in adult life, at least in a subset of patients [111]. As vitamin D has been shown to inhibit excessive cellular proliferation in early rat brain development [27, 62], it has been argued that gestational hypovitaminosis D contributes to excessive neuronal proliferation in the developing brain and, therefore, could serve as a useful model for autism [112].

Epidemiological evidence for a contribution of vitamin D to the pathogenesis of autism exists but is less striking than for schizophrenia. This, in part, relates to issues of ascertainment, sensitivity/specificity of diagnosis, and differences in study methodology. Seasonality of birth has been reported to be associated with autism in the early spring in Scandinavia, Japan, United Kingdom, and the USA [113-115]. Some studies report an increased peak of births during summer months [116], and others show this effect restricted to men [114] or not existent at all [117]. A latitude effect has been illustrated on both the magnitude of the month of birth effect and in overall disease prevalence [118]; however, the effect has only been discernible in a cohort prior to the surge in autism prevalence in the 1990s. Migration appears to affect prevalence rates of autism. Gillberg and colleagues, while reporting on prevalence rates of autism in immigrant families in Sweden, observed an increased prevalence of autism in first born children of mothers who had recently immigrated [119]. A more recent study found that autism was 3–4 times more prevalent in children of Somali immigrant families to Sweden compared with the non-Somali population [120, 121]. The evidence that vitamin D supplementation affects rates of autism has been circumstantial at best. There is some data suggesting that vitamin D intake may positively influence measures of cognition, and that deficiency states result in increased risk of lower verbal IQs, suboptimal outcomes in communication and social development, features observed in autism [122, 123].

Genetic contribution to autism risk is strong, based on family and twin studies, and there is some overlap of autism spectrum disorders with known genetic disorders [124, 125]. The list of candidate autism risk genes identified by GWAS is proliferating exponentially. Given the complex genetic architecture of the disease, it has been suggested that gene-environment interactions must play a substantial role. On review of the GWAS identified genes, the PPP2R5C gene, a serine/threonine phosphatase implicated in the control of cell growth and division, appears to have a VDR-binding site. PPP2R5C has been implicated in retinogenesis and photoreceptor development [126], an interesting finding considering abnormal retinal function determined by electroretinography has been described in the disease (see Table 1) [127]. The role this susceptibility gene may play (if any) with the more broad and complex neurological phenotype is not known; however, it is clear that its regulation by vitamin D accentuates possible gene-environment interactions in a genetically susceptible individual.

B. Neurological disease

(i) Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disease characterized by the cardinal features of tremor, rigidity, akinesia, and postural instability. Pathologically, PD affects the central dopaminergic pathways with neuronal loss and α-synuclein aggregates in multiple brain regions [128, 129]. As previously discussed, a biological basis for a potential role of vitamin D in PD has been illustrated in various experimental rodent models wherein vitamin D exerts a neuroprotective effect on mesencephalic dopaminergic neurones exposed to a variety of toxic conditions [46-49].

The relationship between hypovitaminosis D and risk of Parkinson's disease has long been suggested from epidemiological studies. A season-of-birth effect has been observed in various PD cohorts, with an excess of births being reported in winter and early spring in England and Scotland [130]. A latitude effect may be operative in PD risk with a north-to-south latitude gradient (higher prevalence in the north) being observed in several studies [131-134]. Vitamin D status has been implicated in PD; low serum 25(OH)D levels have been shown in PD patients compared with age-matched controls and patients with Alzheimer's dementia (controlled for duration of disease), and observational studies have demonstrated an increased risk of osteoporosis and hip fractures in PD patients [135-137]. Clearly, as low vitamin D status and its clinical consequences may be secondary to a host of factors, including advanced age, reduced mobility from disease, reverse causation cannot be excluded. Studies investigating the effect of migration and vitamin D supplementation on PD risk are lacking.

There is a clear heritable component in PD. Genetic studies have pointed to a possible role of vitamin D in susceptibility to the disease. Polymorphisms in the VDR gene have been shown to associate with PD risk in American and Korean cohorts, with the former cohort also showing an age of onset effect [138, 139]. The relatively small sample sizes and the inconsistent replication of SNPs in the VDR gene in discovery and validation sets dampen the impact of these findings. GWAS have identified an increasing number of candidate risk genes in PD, several of which have VDR-binding sites closely associated with them raising the possibility that vitamin D may influence their expression. The biological relevance of a subset of these susceptibility genes with associated VDR binding on brain function has been well delineated with evidence for roles in nigrostriatal dopaminergic neurotransmission, neurogenesis and neurite outgrowth, and neural ectodermal expression (especially within the marginal and subventricular zones) (see Table 2) [140-144].

Table 2. PD (Parkinson's disease) and ALS (amyotrophic lateral sclerosis) associated gene regions with VDR (vitamin D receptor) binding
DiseaseGene symbolGene nameGene locationProtein function*Role in brain function
  1. *Data derived from NCBI Gene (http://www.ncbi.nlm.nih.gov/gene); Ensembl (http://www.ensembl.org); Human Protein Reference Database (http://www.hprd.org).

PDBST1bone marrow stromal cell antigen 14p15Stromal cell line-derived glycosylphosphatidylinositol-anchored molecule that facilitates pre-B-cell growth and calcium homeostasisDopaminergic neuronal vulnerability via aberrant calcium homeostasis [140]
GAKcyclin G associated kinase4p16Serine/threonine kinase involved in regulating cell cycle controlNeuronal development [141]
STBD1starch binding domain 14q21.1Integral membrane protein of unknown functionNone known
HLA-DRAmajor histocompatibility complex, class II, DR alpha6p21.3Member of HLA class II expressed on antigen presenting cells involved in presenting peptides derived from extracellular proteinsNone known
SFXN2sideroflexin 210q24.32Transport/cargo protein in mitochondrial membrane involved in iron transportNeural ectodermal expression (esp. marginal/subventricular zones) [142]
LRRK2leucine-rich repeat kinase 212q12Leucine-rich repeat kinase family that encodes a primarily cytoplasmic protein; associates with mitochondrial outer membrane – interacts with parkin, phosphoproteins, miRNAsNeurogenesis and neurite outgrowth [143, 144]
ALSCSNK1G3casein kinase 1, gamma 35q23Member of serine/threonine kinase family that preferentially phosphorylates acidic substrates using ATP as a phosphate donorSynapse plasticity; TDP-43 hyperphosphorylation [155]
ATXN1ataxin 16p23RNA binding protein involved in regulation of nucleobase, nucleoside, nucleotide and nucleic acid metabolismNeuronal survival; spinocerebellar function [156]
MOBKL2BMOB1, Mps One Binder kinase activator-like 2B9p21.2Protein known to bind Mps1p, a kinase essential for spindle pole body duplication and mitotic checkpoint regulationNeuronal brain/spinal cord apoptosis (overexpression) [157]
SUSD1sushi domain containing 19q31.3-q33.1Calcium binding protein with unknown functionNone known
IFNKinterferon, kappa9Member of type I interferon family – glycoprotein involved in host defences against viral infectionsNone known
C9orf72chromosome 9 open reading frame 729p21.2An unclassified protein of unknown functionNone known
ITPR2inositol 1,4,5-triphosphate receptor, type 212p11Transport protein involved in chemoattractant signal transduction and spatiotemporal organization of calcium microdomains facilitating cellular processes such as cell migrationMotor neurone intracellular calcium regulation; glutamate mediated neurotransmission [158]
LIPClipase, hepatic15q21-q23Hepatic triglyceride lipase with dual function of a triglyceride hydrolase and ligand/bridging factor for receptor-mediated lipoprotein uptakeNone known
UNC13Aunc-13 homolog A19p13.11Diacylglycerol and phorbol ester receptor thought to play a role in synaptic vesicle primingPresynaptic vesicle priming (esp. glutamate) [159]
SOD1superoxide dismutase 121q22.11Isozyme that binds copper/zinc ions to convert free superoxide radicals to molecular oxygen and hydrogen peroxideNeuritogeneiss, axonal growth, guidance, and synaptogenesis [161, 162]
(ii) Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting both the central and peripheral nervous systems [145]. ALS pathology reveals degeneration of motor neurones and corticospinal tracts, brainstem nuclei, and spinal cord anterior horn cells, with a subset of patients having intracytoplasmic transactive responsive DNA-binding protein inclusions (TDP-43) [146]. Multiple effector pathways are thought to contribute to ALS pathology including neurotrophic factor deficiency, glutamate toxicity, and damage from ROS [54]. Given that many of these effector pathways are influenced by vitamin D in rodent models, there has been growing interest in the concept that this secosteroid may influence susceptibility to and disease progression in ALS.

The epidemiological evidence incriminating vitamin D as a possible risk factor in ALS is sparse. The relatively low population prevalence probably contributes but there may be no association. Season of birth observations have been conflicting with a few studies reporting excess births between April and July [147], and others reporting birth excess in between October and December (with a trough between April and July) [148]. A latitude gradient has been suggested, but the results are divergent. An American cohort outlining the geographic distribution of ALS using mortality data demonstrated a north-west to south-east gradient [149], a finding mirrored in a more recent study which found a higher ALS-associated death rate in more northern states [150]. On the contrary, a reverse latitude gradient (that is, south-to-north) was captured in separate Italian cohorts. However, the results from these studies are difficult to interpret given ascertainment bias [151, 152]. Similarly, a study evaluating the role of environmental factors in ALS in the UK found clustering of ALS cases in South-East England within certain postcode districts, especially in high population density areas [153, 154].

Similar to PD, studies have highlighted that vitamin D deficiency is prevalent in patients with ALS. However, it is probable that this is secondary to the consequences of the disease, such as decreased UVB exposure from reduced mobility and advance aged. The impact of vitamin D supplementation on subsequent disease susceptibility and progression in ALS is not known.

There is a genetic component to susceptibility to ALS. In addition to familial ALS wherein several risk genes have been established, there is increasing evidence of a complex genetic architecture even in patients with the ‘sporadic’ form of the disease. GWAS have identified a number of biologically relevant candidate genes, some of which have VDR-binding sites within or in close proximity to them fuelling support to a link between vitamin D and the pathogenesis of ALS (see Table 2). Epidemiological evidence linking vitamin D status and ALS is weak at best but molecular evidence may support a role for vitamin D in the pathogenesis of the disease. Several of the ALS susceptibility genes with associated VDR-binding sites have been implicated in salient brain functions such as neuritogenesis, axonal growth, guidance, and synaptogenesis, motor neurone intracellular calcium regulation and glutamate mediated neurotransmission, and hyperphosphorylation of TDP-43 (see Table 2) [155-162].

(iii) Multiple sclerosis

Multiple sclerosis (MS) is a CNS disorder primarily affecting young adults which demonstrates substantial clinical heterogeneity [163]. MS pathology demonstrates foci of demyelination characterized by the nature and extent of inflammatory infiltration, with acute MS lesions having a preponderence of macrophages, lymphocytes (mostly Th1 and Th17), and ROS (such as nitric oxide) throughout and chronic lesions having inflammation, if present, concentrated along the outer rim [164]. The recognition of diffuse changes in normal appearing white matter and axonal loss both within and outside of plaques has broadened this plaque-centred view [165-167]. The mechanistic link of vitamin D in influencing susceptibility to and disease activity in MS has concentrated on vitamin D's neuroimmunomodulatory role first appreciated in the animal model, experimental allergic encephalomyelitis (EAE). In EAE, vitamin D both prevents onset of clinical symptoms and reversibly blocks progression of clinical signs depending on the time of its administration [168, 169], an effect which disappears in VDR knockout EAE mice [170]. It is thought that vitamin D mediates these affects through a plethora of neuroimmunomoedulatory mechanisms which go beyond the scope of this review.

From an epidemiological standpoint, vitamin D deficiency has long been considered a suspect in MS susceptibility. A month-of-birth effect in MS is unequivocal, with MS risk being increased for late spring birth and decreased for those in late autumn [171]. More strikingly, in Scotland, which has the world's highest MS rate, risk differences between April and November birth reach an astonishing 50%, confirmed in three independent studies [171]. The mechanism by which gestational vitamin D deficiency contributes to increased MS risk later in life is not clear; however, animal model data suggest that developmental vitamin D deficiency may alter thymic development, impact T-cell selection, and disrupt T-cell homeostasis to favour a proinflammatory phenotype [172]. The neurodevelopmental impact of gestational vitamin D deficiency in relation to MS risk is not clear and warrants further study. A latitude gradient has been noted in MS with the prevalence of the disease being minimal at the equator and increased in both Northern and Southern latitudes, observations that have been replicated in multiple cohorts [173] (reviewed in [174] and [175]). Further dissection of a latitudinal gradient performed in the ethnically homogenous farmer population from France revealed that a north-east to south-west gradient in MS prevalence mirrored mean annual solar irradiation and mean regional serum vitamin D levels in normal adults [88, 173]. The relationship between latitude and MS disease prevalence is further illustrated by migration studies. Small but influential studies suggest that people younger than 15 years at the time of migration tend to adopt the MS risk of the country to which they migrate, whereas those older than 15 years carry the risk of MS of their country of origin [176]. The precise timing of this effect is unclear; however, the critical age of migration may extend into early adulthood [177].

Additional lines of evidence of hypovitaminosis D in MS risk come from serological data of 25(OH)D levels and effect of vitamin D supplementation on MS disease risk and clinical activity. Hypovitaminosis D has been commonly found in MS patients, but the influence of increasing age, sensitivity to heat, and disability may all negatively influence serum 25(OH)D levels [178, 179]. A prospective longitudinal study of a large number of individuals serving in the US military implemented a nested case-control design comparing serum 25(OH)D levels collected before the date of onset of MS symptoms, and demonstrated an inverse correlation of MS risk with serum 25(OH)D levels, particularly before the age of 20 years [180]. Vitamin D supplementation has been suggested to reduce the risk of MS. A study that prospectively followed two cohorts of nurses within the USA found that vitamin D supplementation was inversely related to MS susceptibility in people who consumed at least 400 IU/day of vitamin D, which is considered a modest intake and only marginally increases serum 25(OH)D levels [181]. Individuals drawn from the same cohort were used to evaluate the impact of dietary vitamin D during adolescence and found that intake ≥400 IU/day of vitamin D from multivitamins was associated with a reduced risk of MS, although the findings were not statistically significant [182] possibly because of the small sample size. In addition to influencing MS risk, there is increasing evidence to suggest that vitamin D may modify clinical and radiographic activity of disease [183, 184].

A genetic component to MS susceptibility is unequivocal. Genetic epidemiological studies have highlighted that first-degree relatives of individuals with MS have a 15–35 fold greater risk of developing the disorder compared with the general population [185]. The greatest influence of genetic risk in MS is nestled in the class II region of the MHC, specifically on haplotypes bearing the HLA-DRB1*15 allele but there is a large influence of epistatic interactions. Several non-MHC loci with much smaller effect size than the MHC region have been identified in GWAS [186]. Variants of one such gene, CYP27B1 (known to encode the 1-α-hydroxylase enzyme and therefore important for vitamin D metabolism) have been associated with MS susceptibility in Australian, Swedish and Canadian cohorts [187-189]. The discovery of VDREs in the classical promotor position of the main risk allele HLA-DRB1*15 [190] and VDR-binding sites associated with several non-MHC MS susceptibility genes identified by GWAS [191], highlight the intricate interplay between MS susceptibility genes and vitamin D (see Table 3).

Table 3. MS (multiple sclerosis) associated gene regions with VDR (vitamin D receptor) binding
DiseaseGene symbolGene nameGene locationProtein function*Role in brain function
  1. *Data derived from NCBI Gene (http://www.ncbi.nlm.nih.gov/gene); Ensembl (http://www.ensembl.org); Human Protein Reference Database (http://www.hprd.org).

MSEVI5ecotropic viral integration site 51p22.1Function not known but thought to be involved in regulation of cell cycle progressionNone known (mRNA detected in foetal/adult brain) [193]
RPL5ribosomal protein L51p22.1Ribosomal protein (60S subunit) – binds 5S rRNA to transport nonribosome-associated cytoplasmic 5S rRNA to the nucleolus for assembly into ribosomesNone known
CXCR4chemokine (C-X-C motif) receptor 42q21A CXC chemokine receptor (G-protein coupled) specific for stromal cell-derived factor-1 which demonstrates chemotactic activity for lymphocytesNeuronal/oligodendrocyte precursor survivor and migration; interneurone migration; neuronal cell cycle regulation [194-197]
HLA-Bmajor histocompatibility complex, class I, B6p21.3Member of HLA class I expressed in nearly all cells involved in antigen presentationNone known
HLA-DRAmajor histocompatibility complex, class II, DR alpha6p21.3Member of HLA class II expressed on antigen presenting cells involved in presenting peptides derived from extracellular proteinsNone known
HLA-DRB1major histocompatibility complex, class II, DR beta 16p21.3
HLA-DQB1major histocompatibility complex, class II, DQ beta 16p21.3
ASAP1ArfGAP with SH3 domain, ankyrin repeat and PH domain 18q24.1-q24.2GTPase activating protein involved in membrane traffickingNone known
SH3GL2SH3-domain GRB2-like 29p22SH3 domain involved in signalling for cell polarization, motility, enzymatic activation, and transcriptional regulation.CNS development; found in abundance in presynaptic neuroganglia [198]
ZMIZ1zinc finger, MIZ-type containing 110q22.3Member of PIAS (protein inhibitor of activated STAT) family – regulate activity of various transcription factorsNone known
TNFRSF1ATumour necrosis factor receptor superfamily, member 1A12p13.2Member of TNF-receptor superfamily – activates NF-kappaB, mediates apoptosis, and regulates inflammationNeurodevelopment and neuroprotection [199, 200]
METTL1methyltransferase like 112q13RNA methyltransferase involved in regulation of nucleobase, nucleoside, nucleotide and nucleic acid metabolismNone known
CYP27B1cytochrome P450, family 27, subfamily B, polypeptide 112q13.1-q13.3Member of cytochrome P450 superfamily – hydroxylation of 25-hydroxyvitamin D3 to form 1alpha,25-dihydroxyvitamin D3, the active form of vitamin D31-alpha-hydroxylase diffusely expressed throughout brain (neurones and glial cells) [8]
MPHOSPH9M-phase phosphoprotein 912q24.31Cell cycle control protein – induction of transition from G2 to M phaseNeuronal survival and synaptic plasticity [201]
CLEC16AC-type lectin domain family 16, member A16p13.13Function not knownNone known
IRF8interferon regulatory factor 816q24.1Member of IRF family – regulates expression of genes stimulated by IFN-alpha and IFN-beta; controls expression of IFN-alpha and IFN-beta-regulated genes induced by viral infectionNone known
ZNF433zinc finger protein 43319p13.2DNA binding protein of unknown functionNone known
CD40CD40 molecule, TNF receptor superfamily member 520q12-q13.2Member of TNF-receptor superfamily – mediates several immune and inflammatory responses including T cell-dependent immunoglobulin class switching, memory B cell development, and germinal centre formationNeuronal development, maintenance, and protection (expressed in neurones, astrocytes, glial cells, and cerebral vasculature) [202-204]

The premise that MS is an inflammatory-mediated demyelinating disease has sculpted the view that the discovered susceptibility genes primarily play a role in immunological processes. There is evidence, however, that inflammatory demyelination does not completely account for the extent of neurodegeneration observed in the disease [167]. Genes, such as those found in the MHC, are also expressed in neurones and glial cells in the CNS and may, therefore, subserve broader biological functions [192]. On review of the MS susceptibility genes with evidence of VDR binding, their role is far more complex than has been appreciated and likely extends beyond the traditional immunological point-of-view. In a subset of these genes, there are varying degrees of experimental evidence to suggest an influence of these genes on the brain (beyond inflammation) in processes including (but not limited to) neuronal/oligodendrocyte precursor survival, proliferation and migration, neuronal cell cycle regulation, synaptic plasticity, and motor axon trajectory delineation (see Table 3 for cited examples) [8, 193-204]. It is clear that further study aimed at unravelling the effect of vitamin D on the expression of these genes, the impact of these genes on both immunological and brain function and how they influence MS susceptibility needs to take centre stage.

(iv) Alzheimer's disease

Alzheimer's disease is a neurodegenerative disease characterized by memory dysfunction and impairment in other cognitive domains. Epidemiological studies have established several risk factors for the development of AD, the most striking of which is increasing age. Other important risk factors include hypertension, hyperlipidaemia, hyperhomocysteinaemia, diabetes/insulin resistance, obesity, physical inactivity, smoking, low education, and inflammatory factors [205]. Neuropathologically, the AD brain features neuronal, neurite and synaptic loss, most pronounced in specific brain regions (that is, entorhinal cortex, subiculum/CA1 regions of the hippocampus, and association cortex) and a stage-dependent distribution of amyloid and, in particular, tau pathology [205]. Given the role of vitamin D in maintaining neurite outgrowth, promoting synaptic plasticity, facilitating neurotransmitter synthesis (e.g. acetylcholine), protecting against oxidative stress and mitochondrial dysfunction, reducing pro-inflammatory responses, and regulating the rate of ageing, there is a plausible biological basis to support a role for vitamin D in the pathogenesis of cognitive impairment and AD.

The evidence linking vitamin D deficiency to AD is limited. Data evaluating the influence of season-of-birth, latitude, and migration data on AD risk are scarce and, when present, are conflicting [206]. Similarly, a role for vitamin D insufficiency in AD disease pathogenesis and/or phenotypic expression has been a source of debate [207, 208]. Discrepant results on the role of vitamin D in AD risk likely stem from several factors, including underpowered sample sizes, cross-sectional study design, retrospective analysis of vitamin D levels and cognitive function, and lack of adjustment for confounding clinical variables. Further, where associations between low serum vitamin D levels and dementia have been reported, the issue of reverse causation (that is, vitamin D deficiency is a consequence rather than a cause of dementia) hinders definitive interpretation. However, recent prospective, longitudinal cohort studies do provide some support to the idea that hypovitaminosis D may influence subsequent risk of AD. Annweiler et al. prospectively followed a cohort of women aged 75 years and older and found that those who developed AD had lower baseline vitamin D intake than non-demented women or those who developed other dementias. In addition, they reported that women in the highest quintile of dietary vitamin D intake substantially decreased the risk of an AD diagnosis 7 years later compared with individuals in the lowest four quintiles combined (adjusted OR = 0.23, P = 0.007) [209]. Similarly, in a population-based, prospective cohort study of 858 Italian adults 65 years and older, Llewellyn et al. showed that patients with vitamin D deficiency at baseline had an increased risk of cognitive decline over a median follow-up period of 6 years, an effect which remained after adjusting for relevant comorbidities and excluding subjects with known dementia at baseline [210]. Interestingly, a trend toward a dose–response relationship between vitamin D status and cognitive measures was also observed with subjects in the lowest quartiles of serum vitamin D performing lower on the Mini-Mental Status Examination than those in the upper quartiles, a finding that has been replicated in other studies [211]. These studies do not demonstrate causality between serum vitamin D levels and cognitive status especially given that vitamin D status may be a surrogate for other lifestyle factors that are difficult to control. That being said, with the increasing number of people affected by AD and the relative safety and cost-effectiveness of vitamin D supplementation, it may be reasonable to consider exploring a possible link between vitamin D and AD more closely in well-controlled, prospective, longitudinal studies and/or clinical trials.

Alzheimer's disease susceptibility demonstrates a heritable component with recent GWAS pointing to an increasing number of genes of modest effect associated with late onset AD [212]. Genetic studies have supported a role for vitamin D in AD risk as evidenced by association of the disease with genetic variation in the vitamin D receptor gene (Vdr) [213-215]. The observation that VDR-binding sites are closely associated with several candidate AD susceptibility genes adds further support to this claim; however, detailed study exploring the role of vitamin D on gene expression and disease susceptibility is needed. The brain function of a selection of the AD susceptibility genes with associated VDR binding sites is outlined in Tables 4 [216-225].

Table 4. AD associated gene regions with VDR (vitamin D receptor) binding
DiseaseGene symbolGene namegene locationProtein function*Role in brain function
  1. *Data derived from NCBI Gene (http://www.ncbi.nlm.nih.gov/gene); Ensembl (http://www.ensembl.org); Human Protein Reference Database (http://www.hprd.org).

Alzheimer's diseaseABCA7ATP-binding casette, subfamily A, member 719p13.3Member of family of transporter proteins that exhibits a regulatory response to cholesterol influx and effluxHighly expressed in brain including hippocampal CA1 neurones and microglia; regulates amyloid precursor protein processing [216, 217]
DIP2Cdisco-interacting protein 2, homolog C10p15.3Protein with zinc-finger domains that interacts with the transcription factor discoNeuroblast/neuronal expression throughout embryologic development; highly expressed in neocortex, striatum, and thalamus [218]
FRMD4AFERM domain containing-4A10p13Member of FERM superfamily involved in cell structure, transport, and signalling functionsInteracts with Arf6 which has been shown to regulate dendritic branching in hippocampal neurones and neurite outgrowth; possible role in amyloid precursor protein processing [219-221]
PICALMPhosphatidylinositol-binding clathrin assembly protein11q14.2Clathrin assembly protein that recruits clathrin and adaptor protein complex 2 (AP2) to cell membranes at sites of coated-pit formation and clathrin-vesicle assemblyExpressed in hippocampal and cortical neurones (pre- and post-synaptically), brain vascular endothelial cells; possible role in amyloid precursor protein processing [222-224]
ZNF224Zinc finger protein 2419q13.2Contains a Kruppel-associated box (KRAB) domain and functions as a transcriptional repressorNone known; associated with intermediate phenotypes in AD (neurofibillary tangle burden) [225]

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Vitamin D metabolism
  5. Vitamin D effector proteins
  6. The effects of vitamin D in the nervous system
  7. Vitamin D and brain development
  8. Vitamin D in psychiatric and neurological disease
  9. Conclusions
  10. Acknowledgements
  11. Conflicts of interest
  12. References

This review has highlighted the extensively diverse role of vitamin D and its metabolites in both nervous system health and disease. The convergence of in vitro, ex vivo, and animal model data provides compelling evidence that vitamin D has a crucial role in proliferation, differentiation, neurotrophism, neuroprotection, neurotransmission, and neuroplasticity. Animal models have also contributed to our knowledge and understanding of the consequences of vitamin D deficiency on brain development and its implications for adult psychiatric and neurological diseases. The role of vitamin D likely goes beyond its direct function on cellular processes in that this secosteroid may influence the expression of genes via vitamin D response elements. The culmination of epidemiological, neuropathological, experimental, and molecular genetic findings certainly implicate vitamin D in influencing susceptibility to a number of psychiatric and neurological diseases, such as schizophrenia, autism, Parkinson's disease, ALS, MS, and AD. Much more needs to be done to unravel how vitamin D deficiency may alter disease risk. The timing of vitamin D deficiency (and supplementation) and its influence on disease risk, the tissue-specific consequences of vitamin D deficiency on gene expression, and the regional influence of vitamin D status on the CNS structure and function, are a few key issues to be addressed. Given the enormous morbidity and mortality associated with these devastating diseases, the potential impact of vitamin D supplementation at a population level is staggering and is certainly worthy of further investigation in well-designed clinical trials.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Vitamin D metabolism
  5. Vitamin D effector proteins
  6. The effects of vitamin D in the nervous system
  7. Vitamin D and brain development
  8. Vitamin D in psychiatric and neurological disease
  9. Conclusions
  10. Acknowledgements
  11. Conflicts of interest
  12. References

G. D and G. E. conceived the idea of the review. G. D., S. K., J. K., S. R., and G. E. drafted the manuscript and critically reviewed the content. G. D. is supported by the AANF/CMSC John F. Kurtzke Clinician-Scientist Award, a Goodger Scholarship (University of Oxford), and the NIHR Biomedical Research Centre, Oxford.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Vitamin D metabolism
  5. Vitamin D effector proteins
  6. The effects of vitamin D in the nervous system
  7. Vitamin D and brain development
  8. Vitamin D in psychiatric and neurological disease
  9. Conclusions
  10. Acknowledgements
  11. Conflicts of interest
  12. References
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