Thomas H. J. Burne

Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease

Increasingly vitamin D deficiency is being associated with a number of psychiatric conditions. In particular for disorders with a developmental basis, such as autistic spectrum disorder and schizophrenia the neurobiological plausibility of this association is strengthened by the preclinical data indicating vitamin D deficiency in early life affects neuronal differentiation, axonal connectivity, dopamine ontogeny and brain structure and function. More recently epidemiological associations have been made between low vitamin D and psychiatric disorders not typically associated with abnormalities in brain development such as depression and Alzheimers disease. Once again the preclinical findings revealing that vitamin D can regulate catecholamine levels and protect against specific Alzheimer-like pathology increase the plausibility of this link. In this review we have attempted to integrate this clinical epidemiology with potential vitamin D-mediated basic mechanisms. Throughout the review we have highlighted areas where we think future research should focus.

NEONATAL VITAMIN D STATUS AND RISK OF SCHIZOPHRENIA: A POPULATION-BASED CASE-CONTROL STUDY

CONTEXT Clues from the epidemiology of schizophrenia suggest that low levels of developmental vitamin D may be associated with increased risk of schizophrenia. OBJECTIVE To directly examine the association between neonatal vitamin D status and risk of schizophrenia. DESIGN Individually matched case-control study drawn from a population-based cohort. SETTING Danish national health registers and neonatal biobank. PARTICIPANTS A total of 424 individuals with schizophrenia and 424 controls matched for sex and date of birth. MAIN OUTCOME MEASURES The concentration of 25 hydroxyvitamin D(3) (25[OH]D3) was assessed from neonatal dried blood samples using a highly sensitive liquid chromatography tandem mass spectroscopy method. Relative risks were calculated for the matched pairs when examined for quintiles of 25(OH)D3. RESULTS Compared with neonates in the fourth quintile (with 25[OH]D3 concentrations between 40.5 and 50.9 nmol/L), those in each of the lower 3 quintiles had a significantly increased risk of schizophrenia (2-fold elevated risk). Unexpectedly, those in the highest quintile also had a significantly increased risk of schizophrenia. Based on this analysis, the population-attributable fraction associated with neonatal vitamin D status was 44%. The relationship was not explained by a wide range of potential confounding or interacting variables. CONCLUSIONS Both low and high concentrations of neonatal vitamin D are associated with increased risk of schizophrenia, and it is feasible that this exposure could contribute to a sizeable proportion of cases in Denmark. In light of the substantial public health implications of this finding, there is an urgent need to further explore the effect of vitamin D status on brain development and later mental health.

Developmental Vitamin D3 deficiency alters the adult rat brain.

There is growing evidence that Vitamin D(3) (1,25-dihydroxyvitamin D(3)) is involved in brain development. We have recently shown that the brains of newborn rats from Vitamin D(3) deficient dams were larger than controls, had increased cell proliferation, larger lateral ventricles, and reduced cortical thickness. Brains from these animals also had reduced expression of nerve growth factor (NGF) and glial cell line-derived neurotrophic factor. The aim of the current study was to examine if there were any permanent outcomes into adulthood when the offspring of Vitamin D(3) deficient dams were restored to a normal diet. The brains of adult rats were examined at 10 weeks of age after Vitamin D(3) deficiency until birth or weaning. Compared to controls animals that were exposed to transient early Vitamin D(3) deficiency had larger lateral ventricles, reduced NGF protein content, and reduced expression of a number genes involved in neuronal structure, i.e. neurofilament or MAP-2 or neurotransmission, i.e. GABA-A(alpha4). We conclude that transient early life hypovitaminosis D(3) not only disrupts brain development but leads to persistent changes in the adult brain. In light of the high incidence of hypovitaminosis D(3) in women of child-bearing age, the public health implications of these findings warrant attention.

A sensitive LC/MS/MS assay of 25OH vitamin D3 and 25OH vitamin D2 in dried blood spots.

BACKGROUND Low levels of 25 hydroxyvitamin D (25OHD) during early development is associated with a range of adverse health outcomes. While a number of methods exist to measure 25OHD in sera, none have been specifically developed to examine dried blood spots (DBS). METHODS We describe an assay where 25 hydroxyvitamin D(3) (25OHD3) and 25 hydroxyvitamin D(2) (25OHD2) are extracted from 3.2 mm DBS punches, derivatised with 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) prior to analysis with LC/MS/MS. We assessed assay precision, relative accuracy and examined the impact of storage conditions in samples stored for up to 22 years. RESULTS The new assay had good accuracy and precision, and was highly sensitive, being capable of detecting <1 nmol/l 25OHD3 and 2 nmol/l 25OHD2. CDER sensitivity criteria were slightly higher at 7.7 nmol/l for 25OHD3 and 10.7 nmol/l for 25OHD2. The mean 25OHD3 concentration in 118 archived DBS was 20.8+/-11.4, (4.8 to 67.8 nmol/l). 25OHD2 was detected in only two of these samples. 25OHD3 concentrations were significantly higher in DBS collected in summer compared to winter (p<0.0001). CONCLUSION Both 25OHD3 and 25OHD2 can be reliably quantified in archived 3.2 mm dried blood spots. We can not be certain that the levels we measure in archived samples are exactly the same as when they were collected. However, the fact that the DBS levels reflect the well-known seasonal variation in this vitamin and when corrected for sera, values fall within the normal range for 25OHD3, means that DBS are a useful tissue repository for testing a range of hypotheses linking developmental hypovitaminosis D and adverse health outcomes.

Developmental Vitamin D Deficiency and Risk of Schizophrenia: A 10-Year Update

There is an urgent need to generate and test candidate risk factors that may explain gradients in the incidence of schizophrenia. Based on clues from epidemiology, we proposed that developmental vitamin D deficiency may contribute to the risk of developing schizophrenia. This hypothesis may explain diverse epidemiological findings including season of birth, the latitude gradients in incidence and prevalence, the increased risk in dark-skinned migrants to certain countries, and the urban-rural gradient. Animal experiments demonstrate that transient prenatal hypovitaminosis D is associated with persisting changes in brain structure and function, including convergent evidence of altered dopaminergic function. A recent case-control study based on neonatal blood samples identified a significant association between neonatal vitamin D status and risk of schizophrenia. This article provides a concise summary of the epidemiological and animal experimental research that has explored this hypothesis.

Advanced paternal age is associated with impaired neurocognitive outcomes during infancy and childhood

Background Advanced paternal age (APA) is associated with an increased risk of neurodevelopmental disorders such as autism and schizophrenia, as well as with dyslexia and reduced intelligence. The aim of this study was to examine the relationship between paternal age and performance on neurocognitive measures during infancy and childhood. Methods and Findings A sample of singleton children (n = 33,437) was drawn from the US Collaborative Perinatal Project. The outcome measures were assessed at 8 mo, 4 y, and 7 y (Bayley scales, Stanford Binet Intelligence Scale, Graham-Ernhart Block Sort Test, Wechsler Intelligence Scale for Children, Wide Range Achievement Test). The main analyses examined the relationship between neurocognitive measures and paternal or maternal age when adjusted for potential confounding factors. Advanced paternal age showed significant associations with poorer scores on all of the neurocognitive measures apart from the Bayley Motor score. The findings were broadly consistent in direction and effect size at all three ages. In contrast, advanced maternal age was generally associated with better scores on these same measures. Conclusions The offspring of older fathers show subtle impairments on tests of neurocognitive ability during infancy and childhood. In light of secular trends related to delayed fatherhood, the clinical implications and the mechanisms underlying these findings warrant closer scrutiny.

A systematic review of the association between common single nucleotide polymorphisms and 25-hydroxyvitamin D concentrations ☆

In order to appreciate the association between hypovitaminosis D and various adverse health outcomes, we require a thorough understanding of how common single nucleotide polymorphisms (SNPs) influence serum concentrations of 25-hydroxyvitamin D (25OHD). We undertook a systematic review of the literature in order to identify studies that examined 25OHD concentrations, and common SNPs. We found nine studies related to the vitamin D binding protein (group-specific component, GC), and five studies examining the vitamin D receptor (VDR). SNPs in a range of cytochrome P450 enzymes have also been examined in seven studies. Replicated findings have been found between 25OHD concentrations and (a) two SNPs in GC (rs4588, rs7041), (b) one SNP in VDR (rs10735810), and (c) one SNP in CYP27B1 (rs10877012). In light of these associations, it is feasible that optimal concentrations of 25OHD required to reduce disease outcomes may vary according to genotype. We speculate that recently identified U-shaped relationships between 25OHD concentrations and disease outcomes (i.e. increased risk at both high and low concentrations) may reflect a mixture of genotype-defined subgroups. Further research is required in order to clarify the genetic architecture underlying 25OHD serum concentrations, and to unravel the mechanisms of action responsible for these associations.

Developmental Vitamin D Deficiency Alters MK 801-Induced Hyperlocomotion in the Adult Rat: An Animal Model of Schizophrenia

BACKGROUND Developmental vitamin D (DVD) deficiency has been proposed as a risk factor for schizophrenia. The behavioral phenotype of adult rats subjected to transient low prenatal vitamin D is characterized by spontaneous hyperlocomotion but normal prepulse inhibition of acoustic startle (PPI). The aim of this study was to examine the impact of selected psychotropic agents and one well-known antipsychotic agent on the behavioral phenotype of DVD deplete rats. METHODS Control versus DVD deplete adult rats were assessed on holeboard, open field and PPI. In the open field, animals were given MK-801 and/or haloperidol. For PPI, the animals were given apomorphine or MK-801. RESULTS DVD deplete rats had increased baseline locomotion on the holeboard task and increased locomotion in response to MK-801 compared to control rats. At low doses, haloperidol antagonized the MK-801 hyperactivity of DVD deplete rats preferentially and, at a high dose, resulted in a more pronounced reduction in spontaneous locomotion in DVD deplete rats. DVD depletion did not affect either baseline or drug-mediated PPI response. CONCLUSIONS These results suggest that DVD deficiency is associated with a persistent alteration in neuronal systems associated with motor function but not those associated with sensory motor gating. In light of the putative association between low prenatal vitamin D and schizophrenia, the discrete behavioral differences associated with the DVD model may help elucidate the neurobiological correlates of schizophrenia.

Behavioural characterization of Vitamin D receptor knockout mice

Vitamin D (calcitriol) is a nuclear transcription regulator acting via a nuclear hormone receptor (VDR). In addition to its role in the regulation of calcium and phosphate homeostasis and in bone formation, Vitamin D is also thought to be involved in brain function. The aim of this study was to behaviourally phenotype VDR knockout mice. We characterized the behaviour of VDR null mutant mice and wildtype littermate controls by subjecting them to a range of tests including a primary behavioural screen (using the SHIRPA protocol), rotarod, gait analysis, Y-maze, marble burying test, bedding test, holeboard test, elevated plus maze, open field test and prepulse inhibition of the acoustic startle response. There were no effects of genotype on most of the scores from the SHIRPA protocol except that VDR -/- mice had alopecia, were shorter and weighed less than VDR +/+ mice. VDR -/- mice had a shorter gait as well as impairments on the rotarod, in the bedding test and impaired habituation in both the open field and on the acoustic startle response. The VDR -/- mice had normal acoustic startle responses but had impaired PPI at long (256 ms) but not short (64 ms) prepulse to pulse intervals. The VDR -/- mice were less active in the open field and buried fewer marbles in the marble burying test. However, there were no differences in the time spent on the open arms of the elevated plus maze or in working memory as assessed by repeat arm entries on the Y-maze. Therefore, it appears that VDR -/- mice have muscular and motor impairments that significantly affects locomotor behaviour but seemingly no impairments in cognition as indicated by exploration, working memory or anxiety.

Olfactory Mucosa Is a Potential Source for Autologous Stem Cell Therapy for Parkinson's Disease

Parkinsons disease is a complex disorder characterized by degeneration of dopaminergic neurons in the substantia nigra in the brain. Stem cell transplantation is aimed at replacing dopaminergic neurons because the most successful drug therapies affect these neurons and their synaptic targets. We show here that neural progenitors can be grown from the olfactory organ of humans, including those with Parkinsons disease. These neural progenitors proliferated and generated dopaminergic cells in vitro. They also generated dopaminergic cells when transplanted into the brain and reduced the behavioral asymmetry induced by ablation of the dopaminergic neurons in the rat model of Parkinsons disease. Our results indicate that Parkinsons patients could provide their own source of neuronal progenitors for cell transplantation therapies and for direct investigation of the biology and treatments of Parkinsons disease.