The effects of vitamin D on brain development and adult brain function

Molecular and Cellular Endocrinology 347 (2011) 121–127

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Molecular and Cellular Endocrinology journal homepage: www.elsevier.com/locate/mce

Review

The effects of vitamin D on brain development and adult brain function James P. Kesby a, Darryl W. Eyles a,b, Thomas H.J. Burne a,b, John J. McGrath a,b,c,⇑ a

Queensland Brain Institute, University of Queensland, St. Lucia, Qld 4076, Australia Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Wacol, Qld 4076, Australia c Department of Psychiatry, University of Queensland, St. Lucia, Qld 4076, Australia b

a r t i c l e

i n f o

Article history: Received 18 February 2011 Received in revised form 21 April 2011 Accepted 2 May 2011 Available online 1 June 2011 Keywords: Vitamin D Brain Development Schizophrenia Dopamine

a b s t r a c t A role for vitamin D in brain development and function has been gaining support over the last decade. Multiple lines of evidence suggest that this vitamin is actually a neuroactive steroid that acts on brain development, leading to alterations in brain neurochemistry and adult brain function. Early deficiencies have been linked with neuropsychiatric disorders, such as schizophrenia, and adult deficiencies have been associated with a host of adverse brain outcomes, including Parkinson’s disease, Alzheimer’s disease, depression and cognitive decline. This review summarises the current state of research on the actions of vitamin D in the brain and the consequences of deficiencies in this vitamin. Furthermore, we discuss specific implications of vitamin D status on the neurotransmitter, dopamine. Ó 2011 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Synthesising, metabolising and transcriptional mechanics in the brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vitamin D in the developing brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neurotrophic signalling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inflammatory agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neuroprotection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Parkinson disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vitamin D and other neurological disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Animal models of altered vitamin D status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.1. VDR knockout mice. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.2. Vitamin D treatment and adult vitamin D deficiency. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.3. Developmental vitamin D deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Abbreviations: 25(OH)D, 25-hydroxyvitamin D; 1,25(OH)2D, 1,25 dihydroxyvitamin D; 6-OHDA, 6-hydroxydopamine; DA, dopamine; DVD, developmental vitamin D; MK-801, dizocilpine; E, embryonic day; GDNF, glial derived neurotrophic factor; NGF, nerve growth factor; ROS, reactive oxygen species; VDR, vitamin D receptor. ⇑ Corresponding author at: Queensland Brain Institute (QBI), University of Queensland, Brisbane, Qld 4072, Australia. Tel.: +61 7 3346 6372, Queensland Centre for Mental Health Research (QCMHR), The Park Centre for Mental Health, Wacol, Qld 4076, Australia. Tel.: +61 7 3271 8694; fax +61 7 3271 8698. E-mail address: [email protected] (J.J. McGrath). URLs: http://www.qcmhr.uq.edu.au, http://www.qbi.uq.edu.au (J.J. McGrath). 0303-7207/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.mce.2011.05.014

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1. Introduction Vitamin D is involved in numerous processes throughout the body in addition to its role in calcium mobilisation and bone health. These include its diverse roles in cellular differentiation and immune function. Although the role of vitamin D in calcium metabolism has been extensively studied, our understanding of its role in brain development and function is still in its infancy. It was over 50 years after the discovery of vitamin D before any

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evidence of its role in the brain was suggested with most of this pioneering work performed by Stumpf and colleagues (Balabanova et al., 1984; Stumpf et al., 1980; Stumpf and O’Brien, 1987). However, work over the last decade has begun to demonstrate the diverse function and consequences of vitamin D throughout the brain, arguing for its classification as a neurosteroid (McGrath et al., 2001a). The enzymes required for the synthesis of the active metabolite are present in the brain (Zehnder et al., 2001), as is its receptor, the vitamin D receptor (VDR) (Eyles et al., 2005). Furthermore, deficiencies in vitamin D levels at various stages of life have been associated with adverse brain outcomes (Evatt et al., 2008; McGrath et al., 2010a; Newmark and Newmark, 2007; Wilkins et al., 2006). This review will focus exclusively on the role of vitamin D in the brain. In particular, we will outline the evidence that vitamin D status impacts on brain development.

2. Synthesising, metabolising and transcriptional mechanics in the brain There are several lines of evidence that suggest a role for vitamin D in the brain. The enzyme responsible for the conversion of 25OHD3 to 1,25(OH)2D3, CYP27B1, is expressed in both human (Zehnder et al., 2001) and rat brain (Fu et al., 1997). Furthermore, activated microglial cells in vitro have been shown to actively synthesise the active metabolite, 1,25(OH)2D3 (Neveu et al., 1994c). Local inactivation of 1,25(OH)2D3 via hydroxylation by CYP24A1 has also been demonstrated in cultured glial cells (Naveilhan et al., 1993). Taken together, the ability for synthesis and inactivation of 1,25(OH)2D3 suggests the brain can locally alter the levels and availability of 1,25(OH)2D3. 1,25(OH)2D3 signalling is through the VDR, a nuclear receptor. The VDR shares structural characteristics with the broader nuclear steroid receptor family (Mangelsdorf et al., 1995). After ligand binding the VDR forms a heterodimer with the retinoid X receptor. This complex binds to vitamin D response elements (VDREs) in the promoters of a number of genes; initiating transcription (Christakos et al., 2003). However, ligand-independent activation of VDR–retinoic acid X receptor mediated transcription has also been demonstrated using pharmacological agents that induce phosphorylation and by dopamine (DA) in peripheral tissue (Matkovits and Christakos, 1995). This may also have important functional consequences given the VDR is expressed widely throughout the human (Eyles et al., 2005; Sutherland et al., 1992) and rat brain (Clemens et al., 1988; Neveu et al., 1994c; Prufer et al., 1999). Regional and cellular localisation of the VDR is remarkably similar in the brain of humans and rats (Eyles et al., 2005; Prufer et al., 1999; Veenstra et al., 1998). The expression pattern of VDR is also similar to other nuclear steroid receptors in the brain including oestrogen, glucocorticoid, progesterone and androgen receptors (Prufer et al., 1999). Both neurons and glia have been shown to express the VDR (Eyles et al., 2005; Prufer et al., 1999), and expression would appear to be widespread in the CNS. The intense expression of the VDR in large cells in the substantia nigra, one of the largest groups of DA neurons in the brain, is highly relevant considering 1,25(OH)2D3 has been shown to increase the expression of tyrosine hydroxylase in adrenal medullary cells in vitro (Puchacz et al., 1996). Tyrosine hydroxylase is the rate-limiting enzyme in the synthesis of DA. However, this may only be relevant in the brain in vivo, after dopamine depletion (Sanchez et al., 2009). VDR expression is also evident in striatal dopaminergic projecting fields such as the caudate putamen and nucleus accumbens suggesting 1,25(OH)2D3 may have a local effect on DA systems.

3. Vitamin D in the developing brain Our knowledge of the actions of 1,25(OH)2D3 in the brain is still rudimentary. Expression of the VDR occurs early in the developing rodent brain (Burket et al., 2003; Erben et al., 2002; Fu et al., 1997; Veenstra et al., 1998). VDR expression is first apparent at embryonic day (E) 11.5 in mouse (Erben et al., 2002) and E12 in the rat dorsal root ganglion, spinal cord and midbrain (Veenstra et al., 1998). Increasing levels of VDR expression throughout gestation coincides with increasing levels of apoptosis and decreasing levels of mitosis (Burket et al., 2003) and appears to be localised to the neuroepithelium and differentiating fields (Veenstra et al., 1998). 1,25(OH)2D3 has been shown to decrease the proliferation of multiple neuroblastoma cell lines (Gumireddy et al., 2003) and the modulation of proliferation, differentiation and apoptosis in peripheral tissue is well described (Banerjee and Chatterjee, 2003; Dusso et al., 2005). 4. Neurotrophic signalling 1,25(OH)2D3 has also been shown to regulate neurotrophic signalling, which is important in the survival and migration of developing neurons in the brain (Bernd, 2008; Dicou, 2009). The regulation of brain development is complex. 1,25(OH)2D3 has been shown to regulate two important molecules in brain ontogeny, namely, glial derived neurotrophic factor (GDNF) and nerve growth factor (NGF). Firstly, 1,25(OH)2D3 administration leads to an increase in GDNF synthesis in both C6 glioma cells (Naveilhan et al., 1996b) and in the brain (Wang et al., 2000). GDNF is an important modulator of DA neuron development, survival and function (Chun et al., 2002; Kholodilov et al., 2004; Lin et al., 1993). For example, in rats administered the neurotoxin 6hydroxydopamine (6-OHDA) that specifically kills DA neurons, 1,25(OH)2D3 pre-treatment increases GDNF levels, increases DA cell function (Smith et al., 2006) and attenuates the level of induced DA cell death (Sanchez et al., 2009; Smith et al., 2006). Secondly, 1,25(OH)2D3 is a potent regulator of NGF signalling (Neveu et al., 1994b; Saporito et al., 1993; Wion et al., 1991). NGF is prominent in the growth and survival of developing neurons, especially cholinergic neurons projecting to the hippocampus (Korsching et al., 1985). Consistent with the actions of NGF (Levi-Montalcini et al., 1968), hippocampal explants and cultures treated with 1,25(OH)2D3 display increased neurite outgrowth (Brown et al., 2003; Marini et al., 2010). Moreover, 1,25(OH)2D3 further influences neurotrophic signalling by regulating neurotrophin receptors such as the low affinity neurotrophin receptor p75NTR (Chao, 1994; Naveilhan et al., 1996a) and other neurotrophic factors such as NT-3 and NT-4 (Neveu et al., 1994a). The modulation of these important developmental signalling pathways by 1,25(OH)2D3 could affect the migration, survival and function of many cells within the brain. 5. Inflammatory agents 1,25(OH)2D3 is a potent immunoregulatory agent (Amento, 1987; Griffin et al., 2003; Mathieu et al., 2004). 1,25(OH)2D3 has been shown to suppress the T-helper cells cytokine profile, consequently altering the balance of T-cells in favour of the suppressor T-cells (Adams et al., 2007; Borges et al., 2011). The immunosuppressive effects of 1,25(OH)2D3 may be therefore relevant to autoimmune disorders such as multiple sclerosis (Brown, 2006; Munger et al., 2004, 2006), type 1 diabetes (Hypponen et al., 2001) and rheumatoid arthritis (Merlino et al., 2004) which have all been associated with diminished 25OHD3 levels. Within the brain, administration of 1,25(OH)2D3 and progesterone, a neuro-

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active steroid with anti-inflammatory potential (Sayeed and Stein, 2009), reduced the amount of brain inflammation after traumatic brain injury (Cekic et al., 2009). This neuroprotective effect of 1,25(OH)2D3 has also been shown in other models of brain trauma (Cass et al., 2006; Sanchez et al., 2009; Wang et al., 2001). 6. Neuroprotection The ability of 1,25(OH)2D3 to regulate certain neurotrophic factors and influence inflammation has led to the suggestion that 1,25(OH)2D3 is neuroprotective (Kalueff and Tuohimaa, 2007). Reports have shown that pre-treatment with 1,25(OH)2D3 can decrease glutamate-mediated cell death in cultures of cortical (Taniura et al., 2006), hippocampal (Brewer et al., 2001) and mesencephalic neurons (Ibi et al., 2001). These neuroprotective effects have been accompanied by decreases in L-type calcium channel expression (Brewer et al., 2001) and increased VDR levels (Taniura et al., 2006). In addition to attenuating glutamate-induced DA cell death in vitro (Ibi et al., 2001), others have shown the protective effects of 1,25(OH)2D3 on DA cells when treated with other toxins. For example, 1,25(OH)2D3 treatment attenuated repeated methamphetamine-induced decreases in DA and serotonin levels (Cass et al., 2006). Embryonic ventral mesencephalon cultures pre-treated with 1,25(OH)2D3 show decreased DA cell death after 6-OHDA induced neurotoxicity (Wang et al., 2001). In vivo studies have shown that 6-OHDA induced behavioural deficits (Sanchez et al., 2009; Wang et al., 2001), decreases in DA cell function (Smith et al., 2006), increases in DA cell death (Sanchez et al., 2009; Smith et al., 2006) and decreases in tissue DA content (Wang et al., 2001) are attenuated with 1,25(OH)2D3 pre-treatment. Some of these studies have also described increases in GDNF after 6-OHDA induced lesions when animals were pre-treated with 1,25(OH)2D3 (Sanchez et al., 2009; Smith et al., 2006). A common mechanism thought to produce these neuroprotective effects is the regulation of proteins that decrease the levels or inhibit the toxicity of reactive oxygen species (ROS) (Ibi et al., 2001). In fact many studies have demonstrated a reduction in ROS induced cell death or increased anti-oxidant species in glia and neurons by 1,25(OH)2D3 (Garcion et al., 1998, 1999; Ibi et al., 2001; Wang et al., 2001). Apart from its neuroprotective functions in tyrosine hydroxylase positive cells, 1,25(OH)2D3 may have some additional direct effects on DA physiology. For example, rats treated postnatally with a single dose of vitamin D3 display persistently increased DA in the brainstem and alterations in DA metabolism in the caudate putamen and hypothalamus (Tekes et al., 2009a). Considering this literature as a whole it comes as no surprise that vitamin D status has been associated with disorders linked to abnormal DA signalling such as Parkinson disease and schizophrenia. 7. Parkinson disease Parkinson disease is a neurodegenerative disorder characterised by the loss of DA cell bodies in the substantia nigra. Neuron death precedes the onset of motor symptoms and continues to progress after this point. Various epidemiological studies on Parkinson disease have provided tentative links with vitamin D status or duration of sunlight exposure. Parkinson disease incidence in some countries shows a latitudinal gradient (Kurtzke and Goldberg, 1988; Lux and Kurtzke, 1987), as does the efficiency of cutaneous vitamin D3 synthesis in response to sunlight (Holick, 1995). People with Parkinson disease show increased rates of 25OHD3 and 1,25(OH)2D3 deficiencies when compared with healthy controls (Evatt et al., 2008; Sato et al., 1997, 2005). Moreover, many Parkinson disease patients display increased rates of hip fractures (Chiu

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et al., 1992; Grisso et al., 1991; Johnell et al., 1992) that may be linked to decreased calcium mobilisation associated with vitamin D deficiencies. It is important to consider potential caveats to these proposals i.e. motor impairments associated with Parkinson disease may also contribute to decreased outdoor activity and behaviour hence exaggerating the level of 25(OH)D deficiency in these subjects. Other studies have also linked vitamin D status with Parkinson disease. Low levels of 25(OH)D were negatively correlated with scores on the Unified Parkinson’s Disease Rating Scale III (UPDRS III) (Sato et al., 2005) and one case study on Parkinson disease showed significantly improved symptoms after one year of treatment with vitamin D supplements (Derex and Trouillas, 1997). Furthermore, levels of the vitamin D binding protein found in the CSF are significantly increased in Parkinson disease (Zhang et al., 2008) and in a Korean study a significant association between a VDR polymorphism and Parkinson disease was found (Kim et al., 2005). Of the many hypothesised mechanisms attempting to explain the cause of cell death in Parkinson disease, one prominent theory is an increase in oxidative stress, which autopsy studies have suggested may occur (Ambani et al., 1975; Perry and Yong, 1986). Sian and colleagues found a 40% decrease in brain glutathione levels (Sian et al., 1994), which is an anti-oxidant involved in neural protection from ROS. Stimulation of glutathione levels by 1,25(OH)2D3 (Garcion et al., 1999; Shinpo et al., 2000) provides a possible role mechanistically for vitamin D in Parkinson disease. Together these studies suggest that vitamin D may play a role in Parkinson disease (Newmark and Newmark, 2007). Furthermore, the protective effect of 1,25(OH)2D3 in ROS induced cellular damage (to which DA neurons are highly susceptible) supports this possible association (Shinpo et al., 2000).

8. Schizophrenia Schizophrenia is a complex and poorly understood group of neuropsychiatric disorders characterised by abnormalities in perception, cognition and affect (Andreasen, 1995). Typically the onset of psychotic symptoms is in the second and third decades of life (Delisi, 1992) yet current hypotheses on the aetiology of schizophrenia suggest the involvement of early adverse neurodevelopmental factors (Weinberger, 1987). There are three pieces of epidemiological evidence that implicate low maternal levels of vitamin D as a potential candidate risk factor for schizophrenia. Firstly, people born in the winter/spring months of the year have an increased risk of developing schizophrenia later in life (Davies et al., 2003; Hultman et al., 1999; McGrath and Welham, 1999; Torrey and Miller, 1997). Moreover, the magnitude of this effect is positively correlated with increasing latitude (Davies et al., 2003). Vitamin D3 production is associated with both season and latitude with the cutaneous synthesis of vitamin D3 being less efficient during winter and at increasing latitudes (Holick, 1995). Secondly, people born in urban environments, compared with those born in a rural setting, have an increased risk of later developing schizophrenia (McGrath, 2000; Torrey et al., 1997) – people living in the city are more likely to have vitamin D deficiencies compared to those living in rural settings (McGrath et al., 2001b). Finally, the relative risk of developing schizophrenia is higher in second generation than first generation migrants with dark skin who migrate to colder climates (CantorGraae and Selten, 2005). Dark-skinned individuals are more prone to developing 25OHD3 deficiencies due to increased melanin content in the skin (Clemens et al., 1982; Holick, 1995); increasing the probability of DVD-deficiency in their children. Apart from these ecological findings, evidence obtained from epidemiological studies has directly assessed whether variations in maternal vitamin D levels are associated with schizophrenia. For example, one study reported a trend toward decreased levels

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of 25OHD in dark-skinned mothers and increased rates of schizophrenia in their offspring in a small cohort of subjects (McGrath et al., 2003). In a second study there was a reduced risk of developing schizophrenia in a group of Finnish male offspring who received adequate vitamin D supplementation during their first year of life (McGrath et al., 2004). However, the most important and thorough study to date was based on Danish neonatal dried blood spots. This study showed that neonates with low levels of 25OHD3 in newborns conferred a twofold increased risk of developing schizophrenia later in life (McGrath et al., 2010b). This relationship could not be explained by any confounding or additional variables. Furthermore, molecular links between schizophrenia, vitamin D and latitude-related genes further supports this association (Amato et al., 2010). Taken together, this evidence supports the hypothesis that vitamin D deficiency during development may lead to an increased risk of schizophrenia, but replication studies are required (McGrath et al., 2010a). 9. Vitamin D and other neurological disorders In addition to Parkinson disease and schizophrenia, vitamin D status has been associated with a range of psychiatric conditions providing further evidence that vitamin D can affect brain function. For example, vitamin D3 treatment improves depression in people with seasonal affective disorder (SAD) (Gloth et al., 1999; Lansdowne and Provost, 1998) and low levels of 25OHD3 has been associated with depression (Jorde et al., 2008; May et al., 2010). Moreover, 25OHD deficiency in the elderly is associated with both depressed mood and cognitive decline (Llewellyn et al., 2010; Wilkins et al., 2006). However, a clear link between 25OHD levels and cognition has not yet been established (Annweiler et al., 2009). Dementia (Buell et al., 2010; Grant, 2009) and in particular, Alzheimer’s disease have also been linked with low 25OHD levels (Evatt et al., 2008). However, in many cases the role of vitamin D deficiency as a causal or circumstantial factor/mechanism is still debated (Bertone-Johnson, 2009; Schneider et al., 2000) and 1,25(OH)2D3 function in the developing and adult brain is still poorly understood (McCann and Ames, 2008). The manipulation of both 1,25(OH)2D3 signalling and levels in animal models, however, is helping to further understand the complex role of vitamin D in the brain. 10. Animal models of altered vitamin D status 10.1. VDR knockout mice VDR null mice have display behavioural deficits such as increased anxiety (Kalueff et al., 2004), impaired prepulse inhibition (Kalueff et al., 2004), neophobia (Minasyan et al., 2007) and altered nest building (Keisala et al., 2007). However, these behavioural impairments are compromised by factors after weaning such as growth retardation and hypocalcaemia (Burne et al., 2005; Kalueff et al., 2004), an inability to float and post-exercise fatigue (Burne et al., 2006b). Moreover, progressive brain impairments such as hearing loss (Zou et al., 2008) and brain calcification (Kalueff et al., 2006) make any interpretation of these behavioural impairments difficult. These progressive impairments have lead to the suggestion that VDR knock out mice show premature aging (Keisala et al., 2009). A more direct way of studying the effects of vitamin D on the CNS is to directly manipulate levels of the ligand. 10.2. Vitamin D treatment and adult vitamin D deficiency The administration of vitamin D has been shown to alter brain neurochemistry, specifically the DA system. For example, when

rats were treated repeatedly with high dose 1,25(OH)2D3, both basal striatal DA levels and evoked DA release were increased (Smith et al., 2006). Moreover, rats treated in the early postnatal period with a single dose of vitamin D3 display persistently increased DA in the brainstem and alterations in DA metabolism in the caudate putamen and hypothalamus (Tekes et al., 2009a). Furthermore, increased DA levels in the brainstem and altered serotonin levels after a single early dose of vitamin D3 are evident in the adult offspring of these animals (Tekes et al., 2009b) suggesting transgenerational imprinting is possible. There is some evidence that chronic vitamin D3 deficiency in adult animals is associated with altered brain function. For example, Alzheimeric adult rats (generated by an intracerebroventricular injection of amyloid beta 1–42) fed a vitamin D3-free diet showed greater spatial learning deficits than those fed a vitamin D3 containing diet (Taghizadeh et al., 2011). Chronic vitamin D3 deficiency in adult animals is also associated with altered DA levels and metabolism (Baksi and Hughes, 1982; Tenenhouse et al., 1991). However, all of these models had calcium deficiencies and chronic vitamin D3 deficiencies presented a rickets-like phenotype. 10.3. Developmental vitamin D deficiency The effects of vitamin D deficiency on brain development have largely been explored using a developmental vitamin D (DVD) deficient rat model (Almeras et al., 2007; Burne et al., 2006a; Eyles et al., 2003, 2009; Kesby et al., 2006; O’Loan et al., 2007). One feature of this model is the transient nature of vitamin D deficiency restricted to the gestational period. This is achieved by depleting 4-week old female rats of 1,25(OH)2D3 (by removing vitamin D3 from the diet and excluding UV light within the vitamin D spectrum) for 6 weeks prior to mating (10 weeks of age) and throughout gestation. The absence of vitamin D in DVD-deficient embryos is associated with a range of molecular and structural changes. For example, DVD-deficient embryos showed decreased levels of apoptosis and increased mitosis (Eyles et al., 2003; Ko et al., 2004) in agreement with the known actions of 1,25(OH)2D3 on cell proliferation. Levels of the neurotrophins NGF and GDNF along with the p75NTR receptor are decreased in DVD-deficient neonates (Eyles et al., 2003). Brain morphology was also altered; DVD-deficient neonatal animals displayed a longer brain in addition to decreased cortical thickness and increased lateral ventricle size (Eyles et al., 2003). Some of these traits such as decreased NGF persist to adulthood (Feron et al., 2005). 1,25(OH)2D3 signalling may also be important in progenitor cell regulation. The VDR is heavily expressed in the ventricular walls of the brain (Veenstra et al., 1998) the predominant site for neurogenesis in the brain. A study that prepared neurosphere cultures from DVD-deficient neonates observed more neurospheres in cultures from DVD-deficient embryos compared with controls (Cui et al., 2007). As expected, 1,25(OH)2D3 administration inhibited neurosphere formation in control cultures, however DVDdeficient cultures were unresponsive even though the VDR was expressed. This suggests that exposure to low 1,25(OH)2D3 during critical periods of brain development permanently alters the properties of these progenitor cells. Recently it has also been shown that DVD-deficiency decreases the levels of factors crucial for DA neuron specification such as Nurr1 and p57Kip2 early in brain development (Cui et al., 2010). Moreover, altered DA metabolism and decreased levels of catechol-O-methyl-transferase (COMT), an important enzyme in DA metabolism, have been observed in the forebrain of neonatal DVD-deficient rats (Kesby et al., 2009). Taken together, these data suggest that vitamin D may be an important factor in DA ontogeny. Behavioural investigations on DVD-deficient animals have demonstrated altered responses that reflect a possible DA dysfunction

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and are analogous to the positive symptoms in schizophrenia. The most consistently reported behavioural abnormality in DVD-deficient adult animals is an increase in novelty-induced locomotion (Burne et al., 2004, 2006a; Eyles et al., 2006; Kesby et al., 2006). Novelty-induced behavioural activation is largely dependent on subcortical DA function (Hooks and Kalivas, 1995) and increases are often considered to reflect a hyperactive sub-cortical DA system. DVD-deficient rats show an increased sensitivity to amphetamine treatment along with altered DA transporter levels in the caudate putamen (Kesby et al., 2010). Moreover, DVD-deficient rats also show increased locomotion after treatment with the psychomimetic dizocilpine (MK-801), which is an N-methyl-D-Aspartate (NMDA) receptor antagonist (Kesby et al., 2006; O’Loan et al., 2007). Pre-treatment with the antipsychotic, haloperidol, significantly decreased the locomotor response to MK-801 in DVDdeficient rats without significantly affecting the locomotor response to MK-801 in control rats (Kesby et al., 2006). Although haloperidol is not highly specific, antipsychotic drug efficacy is believed to be via the blockade of dopamine 2 receptors (Creese et al., 1976; Seeman and Lee, 1975). These results lead to the hypothesis that sub-cortical DA activation by MK-801 was enhanced in DVD-deficient rats (Kesby et al., 2006). In support of this hypothesis, the sensitivity to MK-801 in DVD-deficient rats is dependent on vitamin D deficiency in the later portion rather than the early portion of gestation (O’Loan et al., 2007), a time that accompanies DA neuron migration, differentiation and innervation in the developing brain (Gates et al., 2006; Lauder and Bloom, 1974; Smidt and Burbach, 2007; Voorn et al., 1988). DVD-deficiency has also been shown to alter a large range of proteins in the adult brain (Almeras et al., 2007; McGrath et al., 2008) and some of these proteins have also been associated with DA-stimulant induced neurotoxicity, such as Atpb and Uchl1 (Liao et al., 2005). Taken together, these data support a role for vitamin D in the developing brain and indirectly suggest that DA systems are susceptible to 1,25(OH)2D3 deficiency. 11. Conclusions This review has highlighted that vitamin D is a neurosteroid that can impact on brain development and function by influencing numerous regulatory processes. 25OHD3 deficiency is wide-spread in both developed and developing nations (Chapuy et al., 1997; Holick, 2007; McGrath et al., 2001b; Vieth et al., 2001). More importantly, 25OHD3 deficiency is prevalent in women of childbearing age (Hollis and Wagner, 2006; Looker and Gunter, 1998; Vieth et al., 2001). The multiple pieces of evidence linking vitamin D with DA development and disorders of DA signalling highlight the need for further research into the role of vitamin D in DA ontogeny. Moreover, potential links between vitamin D deficiency and other developmental disorders warrants further scrutiny. Acknowledgements This work was supported by QHealth, and the National Health and Medical Research Council. References Adams, J.S., Liu, P.T., Chun, R., Modlin, R.L., Hewison, M., 2007. Vitamin D in defense of the human immune response. Ann. N.Y. Acad. Sci. 1117, 94–105. Almeras, L., Eyles, D., Benech, P., Laffite, D., Villard, C., Patatian, A., Boucraut, J., Mackay-Sim, A., McGrath, J., Feron, F., 2007. Developmental vitamin D deficiency alters brain protein expression in the adult rat: implications for neuropsychiatric disorders. Proteomics 7, 769–780. Amato, R., Pinelli, M., Monticelli, A., Miele, G., Cocozza, S., 2010. Schizophrenia and vitamin D related genes could have been subject to latitude-driven adaptation. BMC Evol. Biol. 10, 351.

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