Psychoneuroendocrinology (2009) 34S, S247—S257
a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / p s y n e u e n
REVIEW
Developmental vitamin D deficiency causes abnormal brain development D.W. Eyles a,b,c,*, F. Feron a,b,c, X. Cui a, J.P. Kesby b, L.H. Harms a, P. Ko a,c, J.J. McGrath a,c, T.H.J. Burne a,c a
Queensland Brain Institute, The University of Queensland, Brisbane, Qld 4072, Australia School of Biomedical Sciences, The University of Queensland, Brisbane, Qld 4072, Australia c Queensland Centre for Mental Health Research, The Park, Wacol, Qld 4076, Australia b
Received 10 February 2009; received in revised form 7 April 2009; accepted 26 April 2009
KEYWORDS Vitamin D; Brain development; Neurosteroids; Schizophrenia; Animal models
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. Crown Copyright # 2009 Published by Elsevier Ltd. All rights reserved.
* Tel.: +61 7 33466370; fax: +61 7 33466301. E-mail address:
[email protected] (D.W. Eyles). 0306-4530/$ — see front matter. Crown Copyright # 2009 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.psyneuen.2009.04.015
S248 Contents 1. 2.
3. 4. 5. 6. 7.
D.W. Eyles et al.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vitamin D and the developing brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. The vitamin D receptor (VDR) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. VDR polymorphisms and neurodevelopmental disorders . . . . . . . 2.1.2. Vitamin D and neuronal growth factors . . . . . . . . . . . . . . . . . 2.1.3. Is vitamin D neuroprotective? . . . . . . . . . . . . . . . . . . . . . . . 2.2. Vitamin D, cytokines and brain function . . . . . . . . . . . . . . . . . . . . . 2.3. The vitamin D receptor knockout mouse model . . . . . . . . . . . . . . . . . 2.4. The developmental vitamin D (DVD) deficient rat model . . . . . . . . . . . 2.4.1. The DVD-deficient rat and brain development. . . . . . . . . . . . . 2.4.2. Behaviour in the DVD-deficient rat and mouse . . . . . . . . . . . . 2.4.3. The DVD-deficiency rat: a useful animal model for Schizophrenia Developmental vitamin D deficiency and Schizophrenia. . . . . . . . . . . . . . . . Developmental vitamin D deficiency and multiple sclerosis (MS) . . . . . . . . . . Vitamin D and other neuropsychiatric disorders. . . . . . . . . . . . . . . . . . . . . Vitamin D: the forgotten neurosteroid . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. 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, 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
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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.
2. Vitamin D and the developing brain 2.1. 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 subcortical regions. This will become an important consideration later, when we later discuss the potential role of vitamin D in neuropsychiatric disease. The VDR continues to be expressed in differentiating areas of the brain throughout gestation (Cui et al., 2007;
Developmental vitamin D deficiency causes abnormal brain development Veenstra et al., 1998). The VDR emerges somewhat later in the pyramidal cells of the hippocampus at embryonic day 19— 21. Again this represents a time of maximal cell birth and the beginning of differentiation in this brain region (Banker and Cowan, 1977). We have also shown that VDR is densely expressed in the subventricular zone in the neonate brain (Cui et al., 2007). This represents the active site for neural proliferation in the embryo and ongoing proliferation throughout life. This appears to be conserved across species, with the VDR also present in the same proliferating region of the zebra fish brain (Craig et al., 2008). We have shown that there is also a strong inverse correlation between the appearance of VDR in the developing brain and the amount of cell division across a variety of brain regions (Burkert et al., 2003). Furthermore, we have confirmed this at an mRNA level and shown that VDR expression correlates directly with the onset of natural cell elimination (Ko et al., 2004). This is consistent with in vitro evidence showing vitamin D is able to induce cell death pathways in glioma cells (Naveilhan et al., 1994; Zou et al., 2000). Taken together, these data have led to the hypothesis that vitamin D could be regulating neuronal cell cycle and differentiation events directly in the brain (Burkert et al., 2003). 2.1.1. VDR polymorphisms and neurodevelopmental disorders There is little data at present indicating that polymorphisms in the VDR can be linked to neurodevelopmental disorders. Schizophrenia is largely considered a disease of abnormal brain development (see below). Two small studies have been conducted in patients with schizophrenia. In the first common VDR structural variants were examined but no association was found with patients (Yan et al., 2005). More indirectly another study has investigated the cosegregation of psychosis in patients with vitamin D-dependent rickets type II with alopecia (Ozer et al., 2004). This is an autosomal recessive genetic disorder in which defective VDR signalling is postulated. Again these authors could not demonstrate any link between abnormal VDR genotype and schizophrenia. One study has shown an association between over-expression of certain VDR alleles and Parkinson’s disease (Kim et al., 2005). The data for multiple sclerosis (MS) may be more encouraging. Although not largely considered a developmental disease there are some epidemiological features that indicate brain developmental factors may contribute to disease onset. At least one study has shown greater allelic variance in the VDR genome in patients with MS compared to matched controls (Tajouri et al., 2005). 2.1.2. Vitamin D and neuronal growth factors Vitamin D has been shown to modulate a number of neurotrophic agents, such as nerve growth factor (NGF). NGF is essential for the growth and survival of many cells in the brain but in particular the cholinergic basal forebrain neurons which project to the hippocampus (Korsching et al., 1985). Because 1,25(OH)2D potently regulates NGF (Neveu et al., 1994b; Wion et al., 1991), vitamin D could modulate hippocampal development by increasing NGF production. For example, we have shown that the addition of 1,25(OH)2D increased neurite outgrowth in embryonic hippocampal explant cultures, an effect which was most likely due to an induction of NGF in vitro (Brown et al., 2003). The
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addition of 1,25(OH)2D to cultured hippocampal neurons also reduced the number of mitotic cells present and increased the amount of free NGF protein produced (Brown et al., 2003). NGF is capable of binding to the pan-neurotrophin receptor p75NTR (Chao and Hempstead, 1995). The promoter region of this receptor contains a vitamin D response element, and indeed vitamin D has been shown to positively regulate the expression of the p75NTR receptor in glioma cells (Naveilhan et al., 1996a). NGF and p75NTR are essential factors during programmed cell death in the brain (Chao, 1994). Intracerebroventricular administration of vitamin D is also capable of inducing NGF expression within the hippocampus of adult rats (Saporito et al., 1993). It is possible that vitamin D could also modulate neuronal survival and differentiation during development. Vitamin D may also indirectly influence neuronal development by altering neurotrophic factor production in nonneuronal cells. The addition of 1,25(OH)2D to rat primary glial cell cultures has been shown to increase the synthesis of NGF mRNA and protein, neurotrophin-3 (NT-3) mRNA and downregulate neurotrophin-4 (NT-4) mRNA (Neveu et al., 1994a). The addition of 1,25(OH)2D can also increase the synthesis of glial cell line derived neurotrophic factor (GDNF) mRNA in C6 glioma cells (Naveilhan et al., 1996b) but it does not appear to regulate GDNF production in primary glial cell cultures (Remy et al., 2001). GDNF is integral to the development of the dopaminergic (Granholm et al., 2000) and noradrenergic systems (Quintero et al., 2004). Therefore, vitamin D is capable of affecting cellular development in brain regions in which abnormal function is believed to be central to various psychiatric conditions. 2.1.3. Is vitamin D neuroprotective? Evidence that vitamin D regulates NGF and GDNF suggests that it may be neuroprotective (Kalueff and Tuohimaa, 2007). The active form of vitamin D (1,25(OH)2D) would appear to provide some protection against excitatory neurotransmitters such as glutamate (Ibi et al., 2001). Vitamin D can also protect the brain against reactive oxygen species via upregulation of antioxidant molecules, such as glutathione, in non-neuronal cells (Garcion et al., 1999). Vitamin D can also suppress macrophage activity in the brain after lipopolysaccharide-induced brain inflammation (Garcion et al., 1998). Inflammatory mechanisms induced by experimental autoimmune encephalitis (EAE) are also diminished by this vitamin (Nataf et al., 1996). It has been shown in vitro that activated microglia can metabolise 25(OH)D and produce the biologically active 1,25(OH)2D (Neveu et al., 1994c). It should also not be forgotten that the enzyme 1 alpha hydroxylase which synthesises the active vitamin 1,25(OH)2D is also present in human glia (Eyles et al., 2005). Thus, non-neuronal cells in the brain may mediate anti-inflammatory effects of vitamin D via its local synthesis. There is a small amount of data indicating vitamin D may also have a neuroprotective effect on dopaminergic pathways in the brain. Pretreating animals with 1,25(OH)2D for one week preserves dopaminergic function when selective DA toxins, such as 6OHDA, are later administered (Smith et al., 2006; Wang et al., 2001). Vitamin D has also been shown to preserve dopamine and serotonin content in the brains of animals repeatedly administered neurotoxic doses of methamphetamine (Cass et al., 2006). Apart from upregulat-
S250 ing neurotrophins such as GDNF that are selective for DA neurons, vitamin D has also been shown to increase DA synthesis itself via increasing it’s synthetic enzyme tyrosine hydroxlase (Puchacz et al., 1996). When vitamin D is administered to neonatal rats it causes a long-lasting increase in DA in the adult brainstem, a finding that persisted in the F2 offspring from female rats that had been exposed to vitamin D as neonates (Tekes et al., 2008, 2009). This may indicate vitamin D has some maternal ‘‘imprinting’’ function on DA signalling. Recognition of these findings has prompted one author to suggest that vitamin D should even be a target for neurotrophic drugs in the future (Kalueff et al., 2006).
2.2. Vitamin D, cytokines and brain function There is now widespread agreement that vitamin D is a potent immunosuppressant. While its actions are diverse it is broadly considered an anti-inflammatory agent with profound effects on Tcell function (Hayes et al., 2003; van Etten and Mathieu, 2005). The recognition that vitamin D is protective against acute inflammatory agents (bacterial membranes) or foreign myeloid components (experimental models of multiple sclerosis) has alerted neuroscientists to the potential immunomodulatory actions of vitamin D in the brain (Cantorna, 2006). One potential mechanism of action for this neuroprotection involves the suppression of proinflammatory cytokines in the brain (van Etten and Mathieu, 2005). However, how vitamin D regulates cytokine production in the non-infected brain and how this may affect brain function and behaviour is not clear. Proinflammatory cytokines, such as Il1b and Il2, can adversely affect behaviour, such as exploration, locomotion and conditioned learning (Exton et al., 2001; Moore et al., 2005; Thomson and Sutherland, 2005; Zalcman et al., 1998). The modulation of catecholamine and indolamine synthesis by these proinflammatory agents may be one potential mechanism underlying these behavioural changes (Anisman et al., 1996; Petitto et al., 1997; Zalcman et al., 1994, 1998; Zalcman, 2002).
2.3. The vitamin D receptor knockout mouse model When studying the effects of vitamin D on the developing brain there are several experimental options. One that others have employed (Kalueff et al., 2004) and that we have explored to some extent is the VDR homozygous mutant mouse (Yoshizawa et al., 1997). VDR null mutant mice develop hypocalcemia, hyperparathyroidism, rickets, osteomalacia and alopecia. VDR knockout mice also show a series of reproductive and immunological abnormalities after weaning when they are fed a standard diet. There are also structural and conceptual limitations to the use of the VDR knockout mouse model. Firstly, we are interested in modelling a likely clinical condition given the high rates of hypovitaminosis in women of child-bearing age (Hollis and Wagner, 2006b). Secondly, the existing gene construct models reflect a severe lifetime absence of vitamin D signalling. Thirdly, the homozygotes develop exercise-induced fatigue and this has adverse effects on behaviours with a motoric component (Burne et al., 2005). We then considered the use of a gene
D.W. Eyles et al. construct that would impair the production of the active hormone 1,25(OH)2D (Panda et al., 2001). This model was rejected for similar reasons as the VDR mutant mouse and because it also displays a confounding Ricketts-like phenotype.
2.4. The developmental vitamin D (DVD) deficient rat model An alternative approach to removing the receptor is to modulate the amount of vitamin D present during different stages of development. For example, one can manipulate lighting and dietary conditions to produce a maternal deficiency that is restricted to gestation and the immediate postnatal period. This allows us to explore the impact of transient hypovitaminosis D on brain development and subsequent adult brain structure and function. We refer to this model as the developmental vitamin D (DVD) deficiency model. Briefly to obtain vitamin D depletion, female Sprague—Dawley rats are kept on a vitamin D deficient diet. Animals are housed on a 12-h light/dark cycle (lights on at 06:00 h) using incandescent lighting, to avoid ultraviolet radiation within the vitamin D action spectrum. These conditions are maintained for six weeks prior to mating and throughout gestation. Control animals are kept under similar conditions except they receive a vitamin D replete diet. After the dams have littered, all dams (and corresponding litters) are placed on a standard vitamin D replete diet. The vitamin D deficient dams and DVD-deficient offspring remain normocalcemic (i.e. neither the dams nor their offspring have the ricketslike phenotype that would result from more chronic vitamin D depletion). It is important to stress that this is only a developmental exposure, because from birth all maternal animals and offspring receive a diet containing normal levels of vitamin D. Offspring become vitamin D replete by two weeks of age (O’Loan et al., 2007) and vitamin D levels, calcium, and parathyroid hormone (PTH) levels are all normal when the animals are tested as adults (i.e. 10 weeks). Further details of how this model has been produced appear in several of our publications (Burne et al., 2004a; Eyles et al., 2003). 2.4.1. The DVD-deficient rat and brain development We have shown that the newborn offspring of DVD-deficient rats have changes in the shape and size of the brain as well as alterations in some internal structures (Eyles et al., 2003). For example, the DVD-deficient neonates had larger brains, increased volume of the lateral ventricles and a smaller neocortical width when corrected for an overall larger brain. Vitamin D is a known potent differentiation agent promoting apoptosis and the cessation of cell division in a number of tissues. This has made it a subject of keen interest to the cancer field (Mehta and Mehta, 2002). Therefore, we hypothesised that an absence of vitamin D during development would result in a less differentiated brain. Indeed we have shown that there are more mitotic cells across a number of brain regions in DVD-deficient rats (Eyles et al., 2003). Further studies confirmed that cellular differentiation was profoundly altered in the DVD-deficient developing brain (Ko et al., 2004). The level of apoptosis in the developing brains of DVD-deficient rats follows a different trajectory compared
Developmental vitamin D deficiency causes abnormal brain development to controls; at embryonic day 19 (E19) there was no difference, however, at E21 and at birth DVD-deficient rats had fewer apoptotic cells than controls (Ko et al., 2004). In line with a previous study (Eyles et al., 2003), DVD-deficient rats also showed increased rates of mitosis (Ko et al., 2004). More recently the VDR was shown to be present in neurospheres cultured from the subventricular zone (SVZ) of neonatal rats (Cui et al., 2007). When neurosphere cultures were made from the brains of DVD-deficient neonates, neurosphere number was increased, suggesting greater cellular division (Cui et al., 2007). This same study also revealed that the addition of 1,25(OH)2D decreased neurosphere number. Thus, both the presence and absence of vitamin D is capable of manipulating cellular proliferation in developing brain cells. The timing of the reintroduction of vitamin D appears to be important in the persistence of these developmental changes into adulthood (Feron et al., 2005). The enlarged lateral ventricles seen in the DVD-deficient neonates (Eyles et al., 2003) only persist into adulthood if the introduction of the vitamin D replete diet is delayed until weaning. Thus, readdition of vitamin D to the diet from birth appears to partially ameliorate the lateral ventricle changes in DVDdeficient rats (Feron et al., 2005). A similar phenomenon will be discussed when we examine behaviour in these adult animals (see below). The adult DVD-deficient rats also have altered brain expression of genes involved in cytoskeleton maintenance (MAP2, NF-L) and neurotransmission (GABA-Aa4) (Feron et al., 2005). Gene array and proteomics analysis were later used to explore gene expression in the whole brain and protein expression in the prefrontal cortex and hippocampus of adult DVD-deficient rats (Almeras et al., 2007; Eyles et al., 2007). These studies showed that DVD deficiency resulted in significantly altered expression of 36 proteins and 74 genes involved with cytoskeleton maintenance, calcium homeostasis, synaptic plasticity and neurotransmission, oxidative phosphorylation, redox balance, protein transport, chaperoning, cell cycle control and post-translational modifications (Almeras et al., 2007; Eyles et al., 2007). A recent study has examined protein expression in the nucleus accumbens of the DVD rat (McGrath et al., 2008). While the degree of gene dysregulation was low in this study, it identified significant alterations in several proteins involved in either calcium binding (calbindin1, calbindin2 and hippocalcin), or mitochondrial function. 2.4.2. Behaviour in the DVD-deficient rat and mouse The behavioural phenotype in adult male DVD-deficient rats is complex. DVD-deficient rats appear to have normal working memory but disrupted latent inhibition, which is a measure of attentional processing (Becker et al., 2005). We have also shown pre-attentive mechanisms (prepulse inhibition) to be abnormal in animals with a profound whole life deprivation of vitamin D (Burne et al., 2004b). However impaired behaviour in these animals would appear to be due to confounding low levels of calcium similar to the VDR knock out homozygous mice (Burne et al., 2005). When vitamin D deficiency is restricted to the developmental period prepulse inhibition was similar to control rats (Kesby et al., 2006). When placed in a novel arena, DVD-deficient rats are hyperlocomotive (Burne et al., 2004a). However, if the animal is
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either briefly physically restrained with or without injection this novelty-induced hyperlocomotion is abolished (Burne et al., 2006; Kesby et al., 2006). This is unlikely to be a stress-mediated mechanism as the animals have normal hypothalamic pituitary adrenal axis-mediated stress responses (Eyles et al., 2006). Adult male DVD-deficient rats are more sensitive to the N-methyl-D-aspartic acid receptor (NMDA-R) antagonist MK-801. Treatment with MK-801 induces hyperlocomotion in the open field in control rats, and DVDdeficient rats responded with an even greater enhancement in locomotor activity (Kesby et al., 2006). The later period of gestation appeared to be most relevant for this effect (O’Loan et al., 2007), because rats experiencing a DVDdeficiency during late gestation also showed this effect, whereas if the period of DVD-deficiency was restricted to early gestation this effect disappeared (O’Loan et al., 2007). DVD-deficient animals also appear to be selectively sensitive to the DA 2 receptor blocker haloperidol (which is a widely used antipsychotic agent). The locomotor retarding effects of haloperidol appear to be greater in DVD-deficient animals in a model where hyperlocomotion has first been induced by MK-801 (Kesby et al., 2006). Also a separate study has shown haloperidol can normalise an endogenous habituation deficit in DVD-deficient animals whereas this will induce habituation deficits if administered to control animals (Becker and Grecksch, 2006). We have also recently been investigating a mouse model of DVD-deficiency using two strains of mice (129/SvJ and C57BL/6J) (Harms et al., 2008). Only one strain (129/SvJ but not C57BL/6J) exhibited spontaneous hyperlocomotion in the open field arena, which was similar to the findings from DVD-deficient rats (Harms et al., 2008). Both strains demonstrated increased frequency of head dips in a hole board arena, indicative of increased exploratory behaviour (Harms et al., 2008). This is in contrast to findings from DVD-deficient rats on the same test (Becker et al., 2005). DVD-deficient mice were also assessed on a comprehensive screen of behavioural tests, including the elevated plus maze, forced swim test, pre-pulse inhibition and social interaction test (Harms et al., 2008). There was no effect of maternal diet or strain on performance in each of these four tests. Similar behavioural pharmacology tests in mice are yet to be completed. A summary of the effects of alterations in vitamin D signalling and potential effects on the developing brain are summarised in Table 1. 2.4.3. The DVD-deficiency rat: a useful animal model for Schizophrenia Schizophrenia is a heterogeneous group of disorders, in which many genetic and environmental factors contribute to an individual’s risk of developing the disease. The task for the research community is to find common systems or pathways that underlie features of the disorder (e.g. ‘final common pathways’). Discovering these pathways may allow the researcher to ‘reverse engineer’ key components of the neurobiological correlates of schizophrenia. We believe the DVD model may lead to discoveries that allow a deeper understanding of the neurobiology of schizophrenia. Like other animal models, the DVD-deficient model does not replicate every aspect of schizophrenia but it has several attractive features when compared to other animal models of this disease: (1) it is based on clues from epidemiology, (2) it
S252 Table 1
D.W. Eyles et al. Vitamin D and brain development.
Model system
Potential effect on brain development
Experimental findings
Reference
Primary neuron and glioma cell culture
Neurotrophic actions
Vitamin D promotes neurite outgrowth, NGF, NT-3 and GDNF expression.
Primary and secondary neuronal culture and experimental autoimmune encephalitis
Neuroprotective effects
DVD-deficient rat
Brain structure and gene expression
Vitamin D protects cells in culture against reactive oxygen species. It also protects against autoimmune mediated myeloid degradation. It also appears to have some selectivity for dopaminergic neurotoxins. DVD-deficient brains have increased lateral ventricles, altered rates of apoptosis, mitosis and neurogenesis, There is also altered expression of cytoskeletal, synaptic and calcium processing genes.
DVD-deficient rat
Altered behaviour
Brown et al. (2003), Naveilhan et al. (1996b), Neveu et al. (1994a,b), Saporito et al. (1993) and Wion et al. (1991) Cass et al. (2006), Garcion et al. (1999), Ibi et al. (2001), Nataf et al. (1996), Smith et al. (2006) and Wang et al. (2001) Almeras et al. (2007), Cui et al. (2007), Eyles et al. (2007), Eyles et al. (2003), Feron et al. (2005), Ko et al. (2004) and McGrath et al. (2008) Becker et al. (2005), Becker and Grecksch (2006), Burne et al. (2004a), Kesby et al. (2006) and O’Loan et al. (2007)
DVD-deficient rats have altered spontaneous locomotion, sensitivity to NMDA antagonists, impaired attentional processing and altered sensitivity to anti-dopaminergic agents.
reproduces the increase in lateral ventricle size (one of the most consistent neurobiological correlates of schizophrenia (Harrison and Weinberger, 2005), and (3) it reproduces two crucial behavioural endophenotypes associated with schizophrenia, i.e. behavioural sensitivity to NMDA antagonists (Laruelle et al., 2005) and disrupted latent inhibition (Kathmann et al., 2000). We consider the subtle and discrete nature of the behavioural phenotype of the DVD-deficiency model to be one of its strengths. It produces adult offspring with no gross neurological deficits and who are normal in size and weight but still display (a) abnormal motor responses to psychomimetic agents (often used in screens for treatment of the positive symptoms of schizophrenia) and (b) cognitive deficits (analogous to the negative symptoms of schizophrenia). The DVD-deficient mouse phenotype would appear less useful at present in modelling schizophrenia but it has not been as thoroughly investigated.
3. 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 dark-skinned migrants compared to the native born (Cantor-Graae and Selten, 2005). Given that hypovita-
minosis D is more common (a) during winter and spring, (b) at high latitudes, and (c) in dark-skinned individuals (Holick, 1995), low prenatal vitamin D ‘fits’ these key environmental features. Preliminary evidence from analytical epidemiology studies also links low prenatal vitamin D with enhanced risk of schizophrenia. We examined the association between the use of vitamin D supplements in the first year of life and risk of schizophrenia based on the Northern Finnish Birth Cohort. We found a direct link between reported maternal supplementation and reduced risk of schizophrenia in male offspring (McGrath et al., 2004). In a second study, we directly measured 25(OH)D levels in a small cohort of maternal sera taken during the third trimester and banked for over three decades. We found a greater rate of vitamin D deficiency (20 years) neonatal or maternal blood (collected at parturi-
Developmental vitamin D deficiency causes abnormal brain development tion) would be required. Fortunately such a tissue repository exists in the form of frozen neonatal dried blood spots within a Danish Biobank based within the Statens Serum Institut in Copenhagen. We have developed a sufficiently sensitive technique to examine 25(OH)D vitamin D3 from this dried archived source and we expect our analysis of patient samples to be completed by mid-2009.
4. 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., 1996). The concordance rate of MS in monozygotic twins is only 30%, indicating there is a strong environmental influence on the development of the disease. However, the evidence base implicating a role for vitamin D in development is still reasonably weak. Two Northern hemisphere studies have described a season of birth effect (e.g. those born in winter and spring have an increased risk) for MS. The first, a small Danish study described an excess of MS births in Spring (Templer et al., 1992). A much larger study pooled analysis of patients from Canada, Britain, Denmark and Sweden and described an increase in the percentage of people with MS born in May (Spring) and a decrease in the percentage born in November (Autumn) (Willer et al., 2005). This evidence whilst still much weaker than that for schizophrenia may mean that early life exposure to vitamin D could also be important in this disease.
5. 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 association between 25(OH)D and neuropsychiatric outcome may simply indicate that patients with depression or impaired cognitive ability may be less likely to go outside, and thus may develop hypovitaminosis D as a consequence of their neuropsychiatric condition rather than it being a causal factor. While the animal experimental data supports an association between low developmental vitamin D and altered brain development, the impact of hypovitaminosis D during adulthood on brain function remains to be clarified. Recently, a detailed narrative review of the field reached similar conclusions (McCann and Ames, 2008). More animal experimental work should help clarify the role of vitamin D on adult brain function; however more
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focussed analytic epidemiological experiments are also required.
6. 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 same super family of nuclear transcription regulators. We have shown that the receptor for vitamin D is widely distributed throughout both the developing and adult rat brain and is also present in the adult human brain. Results from the DVD-deficient model indicate that its absence during development can affect the transcription of a number of important factors in neuronal cell function (Almeras et al., 2007; Eyles et al., 2007). We have also shown that local synthesis of the active form of the vitamin 1,25(OH)2D occurs in the human brain (Eyles et al., 2005) similar to the case for other neurosteroids such as pregnenolone and dehydroepiandrosterone (DHEA) (Agis-Balboa et al., 2006; Mellon and Griffin, 2002). The direct effects of vitamin D on neuronal signalling are largely unexplored. For example, It is not known whether vitamin D modifies neuronal signalling in a manner similar to the pregnenolone or DHEA by modulating GABAa signalling (Hosie et al., 2006; Puia et al., 1990). However, sensitivity to post-synaptic DA 2 receptor blockade (Kesby et al., 2006) and reduced trophic support for developing DA neurons (Eyles et al., 2003) have alerted us to the possibility that DA signalling may be affected in this model. We are currently focused on studies examining the absence of vitamin D during brain development and alterations in DA release, synthesis and turnover in the adult offspring. The maternal absence of vitamin D creates a host of changes in brain ontogeny at very fundamental levels. The delay in cessation of cell division and the failure to promote programmed cell elimination means brain maturational mechanisms are delayed. This may in some way explain alterations in internal brain architecture such as the increase in lateral ventricles. A decrease in the expression of certain neurotrophic factors and their receptors may leave the developing brain more vulnerable to toxic insults. In the case of GDNF this may be highly relevant for DA signalling in the adult. Thus, there is great scope for vitamin D to act on the CNS in a developmental, cell and tissue-specific manner.
7. 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
S254 humans. Low levels of vitamin D are common in the community, and prevalent in pregnancy (Hollis and Wagner, 2006a,b). A recent perspective listed no less than fourteen publications all reporting a disturbing high incidence of hypovitaminosis D in women who were either of child-bearing age; pregnant or who were nursing mothers (Dawodu and Wagner, 2007). Therefore along with public health implications for bone development we suggest low maternal vitamin D’s effects on the developing brain should not be ignored. Vitamin D is the hormone of the Sun. Its actions in the body are diverse. Our hope in this brief review is that the light emitted from this research illuminates the neurosteroid community to yet another function for this fascinating molecule, that of a developmental neurosteroid.
Conflict of interest statement None declared.
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