Developmental Vitamin D Deficiency Research Articles

Early life exposure to vitamin D deficiency impairs molecular mechanisms that regulate liver cholesterol biosynthesis, energy metabolism, inflammation, and detoxification.

Emerging data suggests liver disease may be initiated during development when there is high genome plasticity and the molecular pathways supporting liver function are being developed. Here, we leveraged our Collaborative Cross mouse model of developmental vitamin D deficiency (DVD) to investigate the role of DVD in dysregulating the molecular mechanisms underlying liver disease. We defined the effects on the adult liver transcriptome and metabolome and examined the role of epigenetic dysregulation. Given that the parental origin of the genome (POG) influences response to DVD, we used our established POG model [POG1-(CC011xCC001)F1 and POG2-(CC001xCC011)F1] to identify interindividual differences. We found that DVD altered the adult liver transcriptome, primarily downregulating genes controlling liver development, response to injury/infection (detoxification & inflammation), cholesterol biosynthesis, and energy production. In concordance with these transcriptional changes, we found that DVD decreased liver cell membrane-associated lipids (including cholesterol) and pentose phosphate pathway metabolites. Each POG also exhibited distinct responses. POG1 exhibited almost 2X more differentially expressed genes (DEGs) with effects indicative of increased energy utilization. This included upregulation of lipid and amino acid metabolism genes and increased intermediate lipid and amino acid metabolites, increased energy cofactors, and decreased energy substrates. POG2 exhibited broader downregulation of cholesterol biosynthesis genes with a metabolomics profile indicative of decreased energy utilization. Although DVD primarily caused loss of liver DNA methylation for both POGs, only one epimutation was shared, and POG2 had 6.5X more differentially methylated genes. Differential methylation was detected at DEGs regulating developmental processes such as amino acid transport (POG1) and cell growth & differentiation (e.g., Wnt & cadherin signaling, POG2). These findings implicate a novel role for maternal vitamin D in programming essential offspring liver functions that are dysregulated in liver disease. Importantly, impairment of these processes was not rescued by vitamin D treatment at weaning, suggesting these effects require preventative measures. Substantial differences in POG response to DVD demonstrate that the parental genomic context of exposure determines offspring susceptibility.

Vitamin D: A potent regulator of dopaminergic neuron differentiation and function.

Vitamin D has been identified as a key factor in dopaminergic neurogenesis and differentiation. Consequently, developmental vitamin D (DVD) deficiency has been linked to disorders of abnormal dopamine signalling with a neurodevelopmental basis such as schizophrenia. Here we provide further evidence of vitamin D's role as a mediator of dopaminergic development by showing that it increases neurite outgrowth, neurite branching, presynaptic protein re-distribution, dopamine production and functional release in various in vitro models of developing dopaminergic cells including SH-SY5Y cells, primary mesencephalic cultures and mesencephalic/striatal explant co-cultures. This study continues to establish vitamin D as an important differentiation agent for developing dopamine neurons, and now for the first time shows chronic exposure to the active vitamin D hormone increases the capacity of developing neurons to release dopamine. This study also has implications for understanding mechanisms behind the link between DVD deficiency and schizophrenia.

Dysregulation of Angiopoietin‐like Proteins is a Potential Link Between Vitamin D Deficiency and Dyslipidemia

Vitamin D deficiency (VDD) is one of the prime nutritional problem globally. Low levels of vitamin D have been shown to correlate with obesity and dyslipidemia, but the mechanism(s) of these effects has not been well studied. Angiopoietin like proteins (ANGPTLs) are a group of proteins known to be involved in lipid metabolism by affecting the lipoprotein lipase activity. A few studies in adults have indicated that vitamin D deficiency regulates ANGPTL3,4 and 8 secretion but the effects of developmental vitamin D deficiency (DVDD) has not been well investigated. In this study, we investigated the effects of DVDD on ANGPTL3, 4 and 8 levels in rat pups. Wistar rat pups were made vitamin D deficient at different developmental stages, namely during gestation (dG group), during lactation (dL group) and during gestation and lactation (dGL group). Liver tissues and serum samples from control (C) and the three DVDD groups were used in this study. Gene expression of ANGPTL3, 4 and 8 in liver tissues were analyzed by RT‐PCR, whereas levels of ANGPTL3 and 4 in serum samples were assessed by using sandwich ELISA. One way ANOVA test revealed that gene expression of ANGPTL3 in dGL and dL groups were significantly increased (p<0.05) compared to control and dG groups. However, gene expression of ANGPTL4 in dGL and dG were significantly decreased (p<0.05) compared to control and dG groups. In addition, gene expression of ANGPTL8 was significantly increased in the dGL group, compared to control (p<0.01). The levels of ANGPTL3 in serum samples showed a significant increase in dGL groups only compared to control (p<0.05) whereas levels of ANGPTL4 were significantly decreased in dL and dGL groups compared to control (p<0.01). These results suggest that combined prenatal and postnatal vitamin D deficiency in rat pups increase the levels of ANGPTL3 and 8 and decrease expression of ANGPTL4. The modulations of these ANGPLs due to vitamin D deficiency may be involved in dyslipidemia and its subsequent health effects. Further research is needed to investigate the mechanisms of ANGPTLs‐modulating effects of vitamin D.

Developmental Vitamin D-Deficiency Increases the Expression of MicroRNAs Involved in Dopamine Neuron Development

Developmental Vitamin D-Deficiency Increases the Expression of MicroRNAs Involved in Dopamine Neuron Development

Perinatal Brain Docosahexaenoic Acid Concentration Has a Lasting Impact on Cognition in Mice

Background: Vitamin D deficiency is a global problem. Recent evidence suggests that vitamin D is involved in brain development and function. Vitamin D deficiency has been associated with poor cognitive function in adults, but the effect of developmental vitamin D deficiency (DVDD) on cognitive function and brain development in children has not been well established.Objective: We explored the effects of DVDD on cognitive functions and brain morphology of rat pups.Methods: Wistar rat pups born to control and vitamin D-deficient dams were divided into 4 groups: control (C), deficient during gestation (dG), deficient during lactation (dL), and deficient during gestation and lactation (dGL). Spatial learning and memory were assessed by the Morris water maze test at postnatal day (PND) 24 and PND 45. Cortical thickness at the level of the hippocampus was measured at PND 63, and synapses were counted in specified areas of the hippocampus at PND 32 and PND 63.Results: Repeated-measures ANOVA revealed that at PND 24, learning (escape latency) was impaired (by 42%) in the dGL group, whereas at PND 45, both the dL and the dGL groups showed learning impairment (by 47% and 45%, respectively) compared with their respective C groups (P < 0.05). Short-term or long-term memory was largely unaffected by DVDD either at PND 24 or PND 45. Compared with the C group, all the DVDD groups had fewer synapses in the molecular layer of the hippocampus (P < 0.001). The synapse number decreased by 54% in the dGL group at PND 33 and by 70% in the dL and dGL groups at PND 63. All the DVDD groups at PND 63 showed a reduced cortical thickness (by 22%) compared with the C group (P < 0.05).Conclusion: These results suggest that a combined prenatal and postnatal DVDD for ≥6 wk in rat pups affects learning but not memory.

Developmental vitamin D deficiency alters multiple neurotransmitter systems in the neonatal rat brain

BackgroundEpidemiological evidence suggests that developmental vitamin D (DVD) deficiency is a risk factor for neuropsychiatric disorders, such as schizophrenia. DVD deficiency in rats is associated with altered brain structure and adult behaviours indicating alterations in dopamine and glutamate signalling. Developmental alterations in dopamine neurotransmission have also been observed in DVD-deficient rats but a comprehensive assessment of brain neurochemistry has not been undertaken. Thus, the current study determined the regional concentrations of dopamine, noradrenaline, serotonin, glutamine, glutamate and γ-aminobutyric acid (GABA), and associated metabolites, in DVD-deficient neonates. MethodsSprague-Dawley rats were fed a vitamin D deficient diet or control diet six weeks prior to mating until birth and housed under UVB-free lighting conditions. Neurotransmitter concentration was assessed by high-performance liquid chromatography on post-mortem neonatal brain tissue. ResultsUbiquitous reductions in the levels of glutamine (12–24%) were observed in DVD-deficient neonates compared with control neonates. Similarly, in multiple brain regions DVD-deficient neonates had increased levels of noradrenaline and serine compared with control neonates. In contrast, increased levels of dopamine and decreased levels of serotonin in DVD-deficient neonates were limited to striatal subregions compared with controls. ConclusionsOur results confirm that DVD deficiency leads to changes in multiple neurotransmitter systems in the neonate brain. Importantly, this regionally-based assessment in DVD-deficient neonates identified both widespread neurotransmitter changes (glutamine/noradrenaline) and regionally selective neurotransmitter changes (dopamine/serotonin). Thus, vitamin D may have both general and local actions depending on the neurotransmitter system being investigated. Taken together, these data suggest that DVD deficiency alters neurotransmitter systems relevant to schizophrenia in the developing rat brain.

Developmental Vitamin D (DVD) Deficiency Reduces Nurr1 and TH Expression in Post-mitotic Dopamine Neurons in Rat Mesencephalon.

Developmental vitamin D (DVD) deficiency has been proposed as an important risk factor for schizophrenia. Our previous study using Sprague Dawley rats found that DVD deficiency disrupted the ontogeny of mesencephalic dopamine neurons by decreasing the mRNA level of a crucial differentiation factor of dopamine cells, the nuclear receptor related 1 protein (Nurr1). However, it remains unknown whether this reflects a reduction in dopamine cell number or in Nurr1 expression. It is also unclear if any particular subset of developing dopamine neurons in the mesencephalon is selectively affected. In this study, we employed state-of-the-art spinning disk confocal microscopy optimized for the imaging of tissue sections and 3D segmentation to assess post-mitotic dopamine cells on a single-cell basis in the rat mesencephalon at embryonic day 15. Our results showed that DVD deficiency did not alter the number, morphology, or positioning of post-mitotic dopamine cells. However, the ratio of Nurr1+TH+ cells in the substantia nigra pars compacta (SNc) compared with the ventral tegmental area (VTA) was increased in DVD-deficient embryos. In addition, the expression of Nurr1 in immature dopamine cells and mature dopamine neurons in the VTA was decreased in DVD-deficient group. Tyrosine hydroxylase was selectively reduced in SNc of DVD-deficient mesencephalon. We conclude that DVD deficiency induced early alterations in mesencephalic dopamine development may in part explain the abnormal dopamine-related behaviors found in this model. Our findings may have broader implications for how certain environmental risk factors for schizophrenia may shape the ontogeny of dopaminergic systems and by inference increase the risk of schizophrenia.

Developmental vitamin D deficiency and schizophrenia: the role of animal models.

Schizophrenia is a debilitating neuropsychiatric disorder that affects 1% of the US population. Based on twin and genome-wide association studies, it is clear that both genetics and environmental factors increase the risk for developing schizophrenia. Moreover, there is evidence that conditions in utero, either alone or in concert with genetic factors, may alter neurodevelopment and lead to an increased risk for schizophrenia. There has been progress in identifying genetic loci and environmental exposures that increase risk, but there are still considerable gaps in our knowledge. Furthermore, very little is known about the specific neurodevelopmental mechanisms upon which genetics and the environment act to increase disposition to developing schizophrenia in adulthood. Vitamin D deficiency during the perinatal period has been hypothesized to increase risk for schizophrenia in humans. The developmental vitamin D (DVD) deficiency hypothesis of schizophrenia arises from the observation that disease risk is increased in individuals who are born in winter or spring, live further from the equator or live in urban vs. rural settings. These environments result in less exposure to sunlight, thereby reducing the initial steps in the production of vitamin D. Rodent models have been developed to characterize the behavioral and developmental effects of DVD deficiency. This review focuses on these animal models and discusses the current knowledge of the role of DVD deficiency in altering behavior and neurobiology relevant to schizophrenia.

Vitamin D regulates tyrosine hydroxylase expression: N-cadherin a possible mediator.

Vitamin D is a neuroactive steroid. Its genomic actions are mediated via the active form of vitamin D, 1,25(OH)2D3, binding to the vitamin D receptor (VDR). The VDR emerges in the rat mesencephalon at embryonic day 12, representing the peak period of dopaminergic cell birth. Our prior studies reveal that developmental vitamin D (DVD)-deficiency alters the ontogeny of dopaminergic neurons in the developing mesencephalon. There is also consistent evidence from others that 1,25(OH)2D3 promotes the survival of dopaminergic neurons in models of dopaminergic toxicity. In both developmental and toxicological studies it has been proposed that 1,25(OH)2D3 may modulate the differentiation and maturation of dopaminergic neurons; however, to date there is lack of direct evidence. The aim of the current study is to investigate this both in vitro using a human SH-SY5Y cell line transfected with rodent VDR and in vivo using a DVD-deficient model. Here we show that in VDR-expressing SH-SY5Y cells, 1,25(OH)2D3 significantly increased production of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis. This effect was dose- and time-dependent, but was not due to an increase in TH-positive cell number, nor was it due to the production of trophic survival factors for dopamine neurons such as glial-derived neurotrophic factor (GDNF). In accordance with 1,25(OH)2D3's anti-proliferative actions in the brain, 1,25(OH)2D3 reduced the percentage of dividing cells from approximately 15-10%. Given the recently reported role of N-cadherin in the direct differentiation of dopaminergic neurons, we examined here whether it may be elevated by 1,25(OH)2D3. We confirmed this in vitro and more importantly, we showed DVD-deficiency decreases N-cadherin expression in the embryonic mesencephalon. In summary, in our in vitro model we have shown 1,25(OH)2D3 increases TH expression, decreases proliferation and elevates N-cadherin, a potential factor that mediates these processes. Accordingly all of these findings are reversed in the developing brain in our DVD-deficiency model. Remarkably our findings in the DVD-deficiency model phenocopy those found in a recent model where N-cadherin was regionally ablated from the mesencephalon. This study has, for the first time, shown that vitamin D directly modulates TH expression and strongly suggests N-cadherin may be a plausible mediator of this process both in vitro and in vivo. Our findings may help to explain epidemiological data linking DVD deficiency with schizophrenia.

The effect of developmental vitamin D deficiency in male and female Sprague–Dawley rats on decision-making using a rodent gambling task

Developmental vitamin D (DVD) deficiency is a plausible risk factor for schizophrenia that has been associated with behavioural alterations including disruptions in latent inhibition and response inhibition. The rodent gambling task (rGT) assesses risk-based decision-making, which is a key cognitive deficit observed in schizophrenia patients. The primary aim of this study was to examine risk-based decision-making in DVD-deficient and control rats on the rGT. We also evaluated the performance of female Sprague–Dawley rats on the rGT for the first time. Adult male and female Sprague–Dawley rats from control and vitamin D deficient dams were trained to perform the rGT in standard operant chambers and their performance and choice-preferences were assessed. Female rats were significantly faster to reach rGT training criteria compared with male rats and DVD-deficient rats were faster to reach training criteria than control animals. After reaching stable performance on the rGT DVD-deficient and control rats showed a significant preference for the optimal choice-option in the rGT, but there were no significant effects of sex or diet on these responses. DVD deficiency did not alter the decision-making processes on the rGT because no significant changes in choice-preferences were evident. This is the first study to demonstrate that once established, the performance of females is comparable to male Sprague–Dawley rats on the rGT.

Developmentally vitamin D-deficient rats show enhanced prepulse inhibition after acute Δ9-tetrahydrocannabinol.

Developmental vitamin D (DVD) deficiency has been proposed as a risk factor for schizophrenia. DVD-deficient rats show selective cognitive deficits and novelty-induced hyperlocomotion and enhanced locomotor responses from acute treatment with psychomimetic drugs, such as amphetamine and MK-801. Here we aimed to examine the effect of a drug from a different class of psychomimetic/psychoactive compounds, Δ9-tetrahydrocannabinol (THC), on tasks of relevance to the cognitive and positive symptoms of schizophrenia. The aim of this study was to investigate whether DVD deficiency modulates the behavioural effects of THC on tests of delay-dependent memory, sensorimotor gating and locomotion. Adult control and DVD-deficient rats were injected with THC (0, 0.3, 0.6, 1.25, 2.5 mg/kg) 15 min before a delay match to sample (DMTS) task using variable delays (0-24 s). A separate group of rats was injected with either 2.5 mg/kg THC or vehicle before tests of either prepulse inhibition (PPI) of the acoustic startle response or in the open field. Control and DVD-deficient rats showed a similar dose-dependent impairment in performance on the DMTS. The greatest impairment was observed at 2.5 mg/kg for all delays (0-24 s). DVD-deficient rats showed THC-induced enhancement of PPI, which was not observed in control rats. There was no effect of maternal diet on acoustic startle response or locomotor responses in the open field. This study reports the novel findings that DVD-deficient rats were more sensitive to the acute effects of THC on PPI. It appears that prenatal vitamin D deficiency has long-term effects on sensitivity to the behavioural effects of cannabinoids.

Altered dopamine ontogeny in the developmentally vitamin D deficient rat and its relevance to schizophrenia.

Schizophrenia is a heterogeneous group of disorders with unknown etiology. Although abnormalities in multiple neurotransmitter systems have been linked to schizophrenia, alterations in dopamine (DA) neurotransmission remain central to the treatment of this disorder. Given that schizophrenia is considered a neurodevelopmental disorder we have hypothesized that abnormal DA signaling in the adult patient may result from altered DA signaling during fetal brain development. Environmental and genetic risk factors can be modeled in rodents to allow for the investigation of early neurodevelopmental pathogenesis that may lead to clues into the etiology of schizophrenia. To address this we created an animal model of one such risk factor, developmental vitamin D (DVD) deficiency. DVD-deficient adult rats display an altered behavioral profile in response to DA releasing and blocking agents that are reminiscent of that seen in schizophrenia patients. Furthermore, developmental studies revealed that DVD deficiency also altered cell proliferation, apoptosis, and neurotransmission across the embryonic brain. In particular, DVD deficiency reduces the expression of crucial dopaminergic specification factors and alters DA metabolism in the developing brain. We speculate such alterations in fetal brain development may change the trajectory of DA neuron ontogeny to induce the behavioral abnormalities observed in adult offspring. The widespread evidence that both dopaminergic and structural changes are present in people who develop schizophrenia prior to onset also suggest that early alterations in development are central to the disease. Taken together, early alterations in DA ontogeny may represent a core feature in the pathology of schizophrenia. Such a mechanism could bring together evidence from multiple risk factors and genetic vulnerabilities to form a convergent pathway in disease pathophysiology.

Attentional Processing in C57BL/6J Mice Exposed to Developmental Vitamin D Deficiency

Epidemiological evidence suggests that Developmental Vitamin D (DVD) deficiency is associated with an increased risk of schizophrenia. DVD deficiency in mice is associated with altered behaviour, however there has been no detailed investigation of cognitive behaviours in DVD-deficient mice. The aim of this study was to determine the effect of DVD deficiency on a range of cognitive tasks assessing attentional processing in C57BL/6J mice. DVD deficiency was established by feeding female C57BL/6J mice a vitamin D-deficient diet from four weeks of age. After six weeks on the diet, vitamin D-deficient and control females were mated with vitamin D-normal males and upon birth of the pups, all dams were returned to a diet containing vitamin D. The adult offspring were tested on a range of cognitive behavioural tests, including the five-choice serial reaction task (5C-SRT) and five-choice continuous performance test (5C-CPT), as well as latent inhibition using a fear conditioning paradigm. DVD deficiency was not associated with altered attentional performance on the 5C-SRT. In the 5C-CPT DVD-deficient male mice exhibited an impairment in inhibiting repetitive responses by making more perseverative responses, with no changes in premature or false alarm responding. DVD deficiency did not affect the acquisition or retention of cued fear conditioning, nor did it affect the expression of latent inhibition using a fear conditioning paradigm. DVD-deficient mice exhibited no major impairments in any of the cognitive domains tested. However, impairments in perseverative responding in DVD-deficient mice may indicate that these animals have specific alterations in systems governing compulsive or reward-seeking behaviour.

Neuroanatomy and psychomimetic-induced locomotion in C57BL/6J and 129/X1SvJ mice exposed to developmental vitamin D deficiency

Evidence from epidemiology suggests that developmental vitamin D (DVD) deficiency is associated with an increased risk of schizophrenia. DVD deficiency in rats is associated with altered brain morphology and enhanced hyperlocomotion in response to MK-801 and amphetamine. The aim of this study was to determine if similar phenotypes were associated with DVD deficiency in two strains of mice (C57BL/6J, 129/X1SvJ). Brains from neonatal (P0) and adult (P70) mice were imaged using MRI and the volumes of the cerebrum, hippocampus, striatum, septum, cortex and ventricles measured, as well as the widths of white matter tracts. Locomotor sensitivity to 5mg/kg d-amphetamine, 0.5mg/kg MK-801 or saline was examined in a separate group of mice in an open field. DVD deficiency altered brain morphology in C57BL6/J mice, such that C57BL/6J female DVD-deficient neonatal mice had a smaller hippocampus compared to female controls. In addition, adult C57BL/6J male DVD-deficient mice had smaller lateral ventricles compared to controls, which may have been compressed by the enlarged striatum seen in these DVD-deficient mice. However, in contrast to the behavioural phenotypes found in DVD-deficient rats, there was no significant effect of maternal diet on amphetamine or MK-801-induced locomotion in either strain. These data indicate that not only species, but also strain of mouse, moderates the impact of DVD deficiency on neuroanatomical and behavioural phenotypes in rodent animal models.

Developmental vitamin D deficiency alters MK-801-induced behaviours in adult offspring

Developmental vitamin D (DVD) deficiency is a candidate risk factor for developing schizophrenia in humans. In rodents DVD deficiency induces subtle changes in the way the brain develops. This early developmental insult leads to select behavioural changes in the adult, such as an enhanced response to amphetamine-induced locomotion in female DVD-deficient rats but not in male DVD-deficient rats and an enhanced locomotor response to the N-methyl-D: -aspartate (NMDA) receptor antagonist, MK-801, in male DVD-deficient rats. However, the response to MK-801-induced locomotion in female DVD-deficient rats is unknown. Therefore, the aim of the current study was to further examine this behavioural finding in male and female rats and assess NMDA receptor density. DVD-deficient Sprague Dawley rats were assessed for locomotion, ataxia, acoustic startle response (ASR) and prepulse inhibition (PPI) of the ASR to multiple doses of MK-801. The NMDA receptor density in relevant brain regions was assessed in a drug-naive cohort. DVD deficiency increased locomotion in response to MK-801 in both sexes. DVD-deficient rats also showed an enhanced ASR compared with control rats, but PPI was normal. Moreover, DVD deficiency decreased NMDA receptor density in the caudate putamen of both sexes. These results suggest that a transient prenatal vitamin D deficiency has a long-lasting effect on NMDA-mediated signalling in the rodent brain and may be a plausible candidate risk factor for schizophrenia and other neuropsychiatric disorders.

Severity of experimental autoimmune encephalomyelitis is unexpectedly reduced in mice born to vitamin D-deficient mothers

Accumulating data indicate that vitamin D, a sun-induced hormone, plays a key role in multiple sclerosis (MS) etiology. Notably, it has been shown that there is a remarkable season of birth effect in MS. We surmised that gestational vitamin D deficiency is a risk factor for MS. To test this hypothesis, a vitamin D deficiency was induced in C57BL/6 female mice 6 weeks prior to conception and prolonged until offspring birth. Contrary to our prediction, we show here that adult offspring exposed to developmental vitamin D deficiency (DVD) developed a striking milder and delayed experimental autoimmune encephalomyelitis (EAE), when compared to control offspring. Using reverse transcription and quantitative real-time PCR, we measured the expression level of 22 candidate transcripts in the spleen, the cerebrum and the spinal cord, at Day 0 and Day 30 post-immunization. We report here that, at Day 30 post-immunization, TNF, osteopontin, H2-Eb were over-expressed and IFN was under-expressed in the spinal cord of control mice and not in DVD mice. Another discrepancy between nervous and immune systems was observed: expression of IL4 was dysregulated exclusively in the spleen. Reduced symptom severity in DVD mice can partially be explained by a nervous system-restricted over-expression of vitamin D receptor ( VDR), two heat shock proteins ( HSP90, HSPa8) and FK506 binding protein 1a ( FKBP1a), at Day 0. Our clinical test and molecular findings converge to indicate that maternal hypovitaminosis D imprints the foetus and alters the susceptibility of the offspring to EAE. We propose a new hypothesis to explain our unexpected observations.

Developmental vitamin D deficiency alters dopamine-mediated behaviors and dopamine transporter function in adult female rats

Developmental vitamin D (DVD) deficiency has been proposed as a risk factor for schizophrenia. DVD deficiency in neonatal rats is associated with alterations in cellular development, dopamine metabolism, and brain morphology. DVD-deficient adult rats show novelty-induced hyperlocomotion and an enhanced locomotor response to MK-801, which can be ameliorated by pretreatment with the antipsychotic drug haloperidol. In this study, we examined locomotor responses of male and female juvenile and adult rats to a dose range of amphetamine. We also measured dopamine receptor and monoamine transporter densities in adult brain. Female DVD-deficient adult rats displayed an enhanced sensitivity to amphetamine-induced locomotion, an increased dopamine transporter density in the caudate-putamen and increased affinity in the nucleus accumbens compared with control females. By contrast, there were no differences between control and DVD-deficient male rats. Taken together, this suggests an alteration in the development of the dopamine system and on dopamine-mediated behaviors in female DVD-deficient rats, and this may be relevant to the underlying neurobiology of schizophrenia.

Developmental vitamin D deficiency alters adult behaviour in 129/SvJ and C57BL/6J mice

Developmental vitamin D (DVD) deficiency has been proposed as an environmental risk factor for a number of brain disorders. The absence of this vitamin during foetal development in the rat is known to alter behaviour in the adult, and many of these alterations are informative with respect to the clinical features of schizophrenia. Here we investigated whether DVD deficiency had a similar effect on 129/SvJ and C57BL/6J mice. Female mice were fed a diet deficient in vitamin D for 6 weeks prior to conception until birth, after which dams and their offspring were fed a normal diet (i.e. containing vitamin D). Control mice were fed a normal diet throughout the experiment. The adult offspring underwent a comprehensive behavioural test battery at 10 weeks of age. We found that DVD-deficient mice of both strains exhibited significantly higher levels of exploration, as measured by the frequency of head dipping on the hole board test. In addition, DVD-deficient 129/SvJ mice, but not C57BL/6J mice, displayed spontaneous hyperlocomotion. There was no effect of maternal diet on parameters assessed by the SHIRPA primary screen, or on tests of sensorimotor gating, social behaviour, anxiety or depression. Some of these findings resemble the rat phenotype (hyperlocomotion) but there are also novel effects of DVD deficiency on mouse behaviour (increased exploration). This study confirms that the developmental absence of this vitamin affects brain function in another species (mouse), and lends further weight to the hypothesis that DVD deficiency in humans may contribute to adverse neuropsychiatric outcomes.

Maternal vitamin D depletion alters neurogenesis in the developing rat brain

Evidence is accumulating that normal levels of vitamin D are important for brain development. Vitamin D acts as an anti-proliferative agent in a wide variety of tissues and developmental vitamin D (DVD) deficiency has been shown to alter brain structure and function. The aim of this study was to investigate the effect of DVD deficiency on neuroprogenitor formation in the neonatal brain. We show that DVD deficiency increased the number of neurospheres formed in cultures from the neonatal subventricular zone. Exogenous vitamin D added to the culture medium reduced neurosphere number in control but not DVD cultures. We show the receptor for vitamin D is concentrated in the subventricular zone and is also present in cultured neurospheres prepared from this region. These results show that vitamin D can regulate cell proliferation in the developing brain. Further studies are warranted to examine the underlying mechanisms for these findings.

Developmental vitamin D (DVD) deficiency in the rat alters adult behaviour independently of HPA function

Developmental vitamin D deficiency (DVD) has been shown to alter the orderly pattern of brain development. Even though the period of vitamin D deficiency is restricted to gestation this is sufficient to induce behavioural abnormalities in the adult offspring consistent with those seen in many animal models of schizophrenia. Given that some of these behavioural alterations could also be an indirect result of either impaired maternal hypothalamic pituitary axis (HPA) function (which in turn could influence maternal care) or the result of a permanent alteration in HPA function in the adult offspring we have examined HPA status in both maternal animals and adult offspring. In this study we have established that HPA function is normal in the maternally vitamin D deficient rat. We replicate the behavioural phenotype of hyperlocomotion whilst establishing that HPA function is also unchanged in the adult male offspring. We conclude that the behavioural alterations induced by DVD deficiency are due to some adverse event in brain development rather than via an alteration in stress response.