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.

Vitamin D and schizophrenia: 20 years on.

Many epidemiological studies have highlighted the link between vitamin D deficiency and schizophrenia. In particular, two prominent studies report an association between neonatal vitamin D deficiency and an increased risk of schizophrenia. In parallel, much has been learnt about the role of vitamin D in the developing central nervous system over the last two decades. Studies in rodent models of developmental vitamin D (DVD)-deficiency describe how brain development is altered leading to a range of neurobiological and behavioral phenotypes of interest to schizophrenia. While glutamate and gamma aminobutyric acid (GABA) systems have been little investigated in these models, alterations in developing dopamine systems are frequently reported. There have been far more studies reporting patients with schizophrenia have an increased risk of vitamin D deficiency compared to well controls. Here we have conducted a systematic review and meta-analysis that basically confirms this association and extends this to first-episode psychosis. However, patients with schizophrenia also have poorer general health, poorer diets, are frequently less active and also have an increased risk of other medical conditions, all factors which reduce circulating vitamin D levels. Therefore, we would urge caution in any causal interpretation of this association. We also summarize the inconsistent results from existing vitamin D supplementation trials in patients with schizophrenia. In respect to animal models of adult vitamin D deficiency, such exposures produce subtle neurochemical alterations and effects on cognition but do not appear to produce behavioral phenotypes of relevance to schizophrenia. We conclude, the hypothesis that vitamin D deficiency during early life may increase the risk of schizophrenia remains plausible and warrants ongoing research.

Developmental vitamin D and autism spectrum disorders: findings from the Stockholm Youth Cohort.

Animal studies indicate that early life vitamin D is crucial for proper neurodevelopment. Few studies have examined whether maternal and neonatal vitamin D concentrations influence risk of autism spectrum disorders (ASD). Participants were sampled from the Stockholm Youth Cohort, a register-based cohort in Sweden. Concentrations of total 25-hydroxyvitamin D (25OHD) were assessed from maternal and neonatal biosamples using a highly sensitive liquid chromatography tandem mass spectrometry method. The maternal sample consisted of 449 ASD cases and 574 controls, the neonatal sample: 1399 ASD cases and 1607 controls; and the paired maternal-neonatal sample: 340 ASD cases and 426 controls. Maternal 25OHD was not associated with child ASD in the overall sample. However, in Nordic-born mothers, maternal 25OHD insufficiency (25 - <50 nmol/L) at ~11 weeks gestation was associated with 1.58 times higher odds of ASD (95% CI: 1.00, 2.49) as compared with 25OHD sufficiency (≥50 nmol/L). Neonatal 25OHD < 25 nmol/L was associated with 1.33 times higher odds of ASD (95% CI: 1.02, 1.75) as compared with 25OHD ≥ 50 nmol/L. Sibling-matched control analyses indicated these associations were not likely due to familial confounding. Children with both maternal 25OHD and neonatal 25OHD below the median had 1.75 (95% CI: 1.08, 2.86) times the odds of ASD compared with children with maternal and neonatal 25OHD both below the median. Our results are consistent with an increasing body of evidence suggesting that vitamin D concentrations in early life may be associated with increased risk of neurodevelopmental disorders including ASD.

Association between circulating 25-hydroxyvitamin D concentrations and hip replacement for osteoarthritis: a prospective cohort study.

BACKGROUND: To examine the association between circulating 25(OH)D concentrations and incidence of total hip replacement for osteoarthritis in a prospective cohort study. METHODS: This study examined a random sample of 2651 participants in the Melbourne Collaborative Cohort Study who had 25(OH)D concentrations measured from dried blood spots collected in 1990-1994. Participants who underwent total hip replacement for osteoarthritis between January 2001 and December 2018 were identified by linking the cohort records to the Australian Orthopaedic Association National Joint Replacement Registry. Cox proportional hazard regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) of total hip replacement for osteoarthritis in relation to 25(OH)D concentrations, adjusted for confounders. RESULTS: Eighty-six men and eighty-seven women had a total hip replacement for osteoarthritis. Compared with men in the lowest (1st) quartile of 25(OH)D concentration, the HR for total hip replacement was 2.32 (95% CI 1.05, 5.13) for those in the 2nd quartile, 2.77 (95% CI 1.28, 6.00) for those in the 3rd quartile, and 1.73 (95% CI 0.75, 4.02) for those in the highest quartile of 25(OH)D concentrations (p for trend 0.02). There was little evidence of an association in women. CONCLUSIONS: Higher circulating 25(OH)D concentrations were associated with an increased risk of total hip replacement for osteoarthritis in men but not in women. Although the underlying mechanism warrants further investigation, our findings highlight the need to determine the optimal levels of circulating 25(OH)D to reduce the risk of hip osteoarthritis.

Developmental Inhibition of Long Intergenic Non-Coding RNA, HOTAIRM1, Impairs Dopamine Neuron Differentiation and Maturation.

The dopaminergic (DA) system is important for a range of brain functions and subcortical DA development precedes many cortical maturational processes. The dysfunction of DA systems has been associated with neuropsychiatric disorders such as schizophrenia, depression, and addiction. DA neuron cell fate is controlled by a complex web of transcriptional factors that dictate DA neuron specification, differentiation, and maturation. A growing body of evidence suggests that these transcriptional factors are under the regulation of newly discovered non-coding RNAs. However, with regard to DA neuron development, little is known of the roles of non-coding RNAs. The long non-coding RNA (lncRNA) HOX-antisense intergenic RNA myeloid 1 (HOTAIRM1) is present in adult DA neurons, suggesting it may have a modulatory role in DA systems. Moreover, HOTAIRM1 is involved in the neuronal differentiation in human stem cells suggesting it may also play a role in early DA neuron development. To determine its role in early DA neuron development, we knocked down HOTAIRM1 using RNAi in vitro in a human neuroblastoma cell line, and in vivo in mouse DA progenitors using a novel in utero electroporation technique. HOTAIRM1 inhibition decreased the expression of a range of key DA neuron specification factors and impaired DA neuron differentiation and maturation. These results provide evidence of a functional role for HOTAIRM1 in DA neuron development and differentiation. Understanding of the role of lncRNAs in the development of DA systems may have broader implications for brain development and neurodevelopmental disorders such as schizophrenia.

Vitamin D regulation of GDNF/Ret signaling in dopaminergic neurons.

1,25(OH)2D3 (vitamin D) appears essential for the normal development of dopaminergic neurons. Vitamin D affects dopamine synthesis and metabolism as well as expression of glial cell line-derived neurotrophic factor (GDNF), which is crucial for the survival of dopaminergic neurons. We investigated the role of vitamin D on GDNF and its receptors protooncogene tyrosine-protein kinase receptor Ret (C-Ret) and GDNF family receptor alpha 1 (GFRα1) signaling. To this end, we used a developmental vitamin D-deficient rat model and SH-SY5Y cells transfected with vitamin D receptor (VDR). The absence of vitamin D ligand in gestation reduces C-Ret expression, but not GDNF and GFRα1, in embryo forebrains. Overexpression of VDR in SH-SY5Y in the absence of ligand (mimicking in vivo developmental vitamin D deficiency) also suppressed C-Ret mRNA levels. In the presence of vitamin D, C-Ret mRNA and protein expression were increased. The chromatin immunoprecipitation results suggested that C-Ret is directly regulated by vitamin D via VDR. GDNF was also increased by vitamin D in these cells. Our small interfering RNA studies showed that knocking down VDR leads to an increase in C-Ret in the absence of ligand. Finally, we confirmed the inverse relationship between GFRα1 and C-Ret, as knocking down C-Ret led to increases in GFRα1 expression. These data extend our knowledge of the diverse and important roles played by vitamin D in dopamine physiology.-Pertile, R. A. N., Cui, X., Hammond, L., Eyles, D. W. Vitamin D regulation of GDNF/Ret signaling in dopaminergic neurons.

Half the Genetic Variance in Vitamin D Concentration is Shared with Skin Colour and Sun Exposure Genes.

This study assessed the heritability of 25 hydroxyvitamin D3 (25(OH)D3) in a large twin cohort and the shared effect of sun exposure and skin colour on 25(OH)D3 variance. Study participants included 1604 twin pairs and their siblings (n = 4020). Twin correlations for 25(OH)D3 concentration were rMZ=0.79 (584 pairs) and rDZ = 0.52 (1020 pairs) consistent with an average h2 = 0.50 throughout the year. Significant phenotypic and genetic seasonal fluctuation was observed in 25(OH)D3 concentrations with heritability decreasing during the winter (h2 = 0.37) compared to summer (h2 = 0.62). Skin colour (measured both ordinally and quantitatively) and self-reported sun exposure were found to significantly affect 25(OH)D3 concentration. Twins with olive/dark skin had significantly lower 25(OH)D3 concentrations than those with fair/pale skin and multivariate genetic analysis showed that approximately half of the total additive genetic variation in 25(OH)D3 results from genes whose primary influence is on skin colour and sun exposure. Additionally, 37% of the total variance was attributed to shared environmental effects on vitamin D, skin colour and sun exposure measures. These results support a moderate estimate of vitamin D heritability and suggest significant influence of season, skin colour and sun exposure on the genetic variance.

Functional and molecular changes in the nucleus accumbens of MK-801-sensitized rats.

Behavioural sensitization is a putative mechanism in the pathophysiology of drug addiction and neuropsychiatric disorders such as schizophrenia. In rodents, drug-induced behavioural sensitization has been described for several different drug classes. The N-methyl-D-aspartate receptor antagonist MK-801 can inhibit sensitization to other drugs of abuse. However, MK-801 also produces behavioural sensitization to its own hyperlocomotor inducing effects, suggesting that MK-801 sensitization has a distinctive mechanism of action. The aim of this study was to carry out a functional and molecular analysis of the nucleus accumbens (NAc) of adult male Sprague-Dawley rats sensitized to MK-801 (seven daily injections of 0.25 mg/kg, 5 days of withdrawal and subsequent 0.25 mg/kg challenge), or following acute MK-801 (0.25 mg/kg), or naive rats as controls. Locomotor activity was the primary measure of sensitization. Ex-vivo slice electrophysiology showed a decrease in the excitatory synaptic strength in the NAc of rats sensitized to MK-801 compared with acute MK-801 treatment or naive controls. An LC-MS/MS SWATH proteomics approach showed that proteins altered by MK-801 sensitization were predominantly related to functions including calcium and glutamate signalling, and mitochondrial dysfunction. These results shed some light on neural changes in the NAc after sensitization to MK-801. This model could prove useful for studying the role of N-methyl-D-aspartate receptors in the pathophysiology of drug addiction and schizophrenia.

Associations of maternal and fetal vitamin D status with childhood body composition and cardiovascular risk factors.

Maternal vitamin D deficiency during pregnancy may have persistent adverse effects on childhood growth and development. We examined whether 25-hydroxyvitamin D (25(OH)D) concentrations during pregnancy and at cord blood were associated with childhood body composition and cardiovascular outcomes. This study was embedded in a population-based prospective cohort in Rotterdam, The Netherlands, among 4,903 mothers and their offspring. We measured 25(OH)D concentrations at a median gestational age of 20.4 weeks (95% range 18.5-23.4 weeks) and at birth (40.1 weeks [95% range 35.8-42.3 weeks]). 25(OH)D concentrations were categorized into severely deficient (<25.0 nmol/L); deficient (25.0 to 49.9 nmol/L); sufficient (50.0 to 74.9 nmol/L) and optimal (≥75.0 nmol/L). At 6 years, we measured childhood body mass index; fat and lean mass by Dual-energy X-ray Absorptiometry; blood pressure; and serum cholesterol, triglycerides, and insulin concentrations. Compared with children from mothers with optimal 25(OH)D concentrations (≥75.0 nmol/L), those of severely deficient vitamin D (<25.0 nmol/L) mothers had a 0.12 standard deviation score (SDS); (95% Confidence Interval (CI) [0.03, 0.21]) higher fat mass percentage and a 0.13 SDS (95% CI [-0.22, -0.04]) lower lean mass percentage. These associations remained after adjustment for current child vitamin D status. Maternal and cord blood 25(OH)D concentrations were not associated with cardiovascular risk factors in childhood. In conclusion, severe maternal 25(OH)D deficiency (<25.0 nmol/L) during pregnancy is associated with an adverse childhood body composition profile, but we did not observe evidence for an association with childhood cardiovascular risk factors. Further studies are needed to replicate our findings, to examine the underlying mechanisms, the causality of the associations, and the potential for public health interventions.

Short- and long-term effects of risperidone on catalepsy sensitisation and acquisition of conditioned avoidance response: Adolescent vs adult rats.

The effects of antipsychotic drugs (APDs) on the adolescent brain are poorly understood despite a dramatic increase in prescription of these drugs in adolescents over the past twenty years. Neuronal systems continue to be remodeled during adolescence. Therefore, when given in adolescence, antipsychotic drugs (APDs) have the potential to affect this remodeling. In this study we investigated the effects of chronic 22-day risperidone treatment (1.3mg/kg/day) in both adolescent and adult rats. We examined short- and long-term changes in behaviour (catalepsy, locomotion and conditioned avoidance response (CAR)), and dopaminergic and serotonergic neurochemistry in the striatum and the nucleus accumbens. Here, we report that, both during chronic treatment and after a lengthy drug-free interval, risperidone induced a sensitised cataleptic response regardless of the age of exposure. Selectively in adolescents, risperidone-induced catalepsy was inversely correlated with striatal dopamine turnover immediately after chronic treatment. After a drug-free interval, a significant proportion of rats with prior adolescent risperidone treatment also failed to acquire CAR to a defined criterion. Our data provide evidence that the same chronic risperidone treatment regimen can induce contrasting short- and long-term neural outcomes in the adolescent and adult brains.

25-Hydroxyvitamin D concentration and all-cause mortality: the Melbourne Collaborative Cohort Study.

OBJECTIVE: To investigate relationships between mortality and circulating 25-hydroxyvitamin D (25(OH)D), 25-hydroxycholecalciferol (25(OH)D3) and 25-hydroxyergocalciferol (25(OH)D2). DESIGN: Case-cohort study within the Melbourne Collaborative Cohort Study (MCCS). We measured 25(OH)D2 and 25(OH)D3 in archived dried blood spots by LC-MS/MS. Cox regression was used to estimate mortality hazard ratios (HR), with adjustment for confounders. SETTING: General community. SUBJECTS: The MCCS included 29 206 participants, who at recruitment in 1990-1994 were aged 40-69 years, had dried blood spots collected and no history of cancer. For the present study we selected participants who died by 31 December 2007 (n 2410) and a random sample (sub-cohort, n 2996). RESULTS: The HR per 25 nmol/l increment in concentration of 25(OH)D and 25(OH)D3 were 0·86 (95 % CI 0·78, 0·96; P=0·007) and 0·85 (95 % CI 0·77, 0·95; P=0·003), respectively. Of 5108 participants, sixty-three (1·2 %) had detectable 25(OH)D2; their mean 25(OH)D concentration was 11·9 (95 % CI 7·3, 16·6) nmol/l higher (P<0·001). The HR for detectable 25(OH)D2 was 1·80 (95 % CI 1·09, 2·97; P=0·023); for those with detectable 25(OH)D2, the HR per 25 nmol/l increment in 25(OH)D was 1·06 (95 % CI 0·87, 1·29; P interaction=0·02). HR were similar for participants who reported being in good, very good or excellent health four years after recruitment. CONCLUSIONS: Total 25(OH)D and 25(OH)D3 concentrations were inversely associated with mortality. The finding that the inverse association for 25(OH)D was restricted to those with no detectable 25(OH)D2 requires confirmation in populations with higher exposure to ergocalciferol.

Prevalence and correlates of suboptimal vitamin D status in people living with psychotic disorders: Data from the Australian Survey of High Impact Psychosis.

OBJECTIVE: Having sufficient sera concentrations of 25-hydroxyvitamin D is important for a range of health outcomes including cardiometabolic diseases. Clinical studies in people with psychotic disorders suggest that a sizable proportion has suboptimal vitamin D status (i.e. vitamin D deficiency or insufficiency). Individuals with psychosis also have many of the risk factors associated with suboptimal vitamin D status such as smoking, obesity, and reduced physical activity. The aim of this study was to examine the prevalence and socio-demographic and clinical correlates of vitamin D status using a large, population-based sample of adults with psychotic disorders. METHODS: Data were collected as part of the Survey of High Impact Psychosis, a population-based survey of Australians aged 18-64 years with a psychotic disorder. 25-Hydroxyvitamin D concentration was measured in 463 participants. 25-Hydroxyvitamin D concentration was dichotomised into optimal (above 50 nmol/L) and suboptimal (below 50 nmol/L). The influence of a range of socio-demographic and clinical variables on vitamin D status was examined using logistic regression. RESULTS: Nearly half (43.6%) of the participants had suboptimal vitamin D status. Those with (a) increased physical activity or (b) positive symptoms had significantly reduced odds of having suboptimal vitamin D status. However, there were no significant associations between suboptimal vitamin D status and other psychiatric symptom measures or cardiometabolic risk factors. CONCLUSION: Many people with psychotic disorders have suboptimal vitamin D status. As part of the routine assessment of physical health status, clinicians should remain mindful of vitamin D status in this vulnerable population and encourage the use of appropriate vitamin D supplements.

Minimizing Matrix Effects for the Accurate Quantification of 25-Hydroxyvitamin D Metabolites in Dried Blood Spots by LC-MS/MS.

BACKGROUND: The noncalcemic actions of vitamin D in multiple organs are now widely recognized. Vitamin D status has been linked with a wide variety of conditions, which has led to an increasing demand for vitamin D screening. In particular, there is intense interest in the impact of vitamin D on a variety of developmental conditions. The most readily accessible pediatric samples are dried blood spots, and health organizations are increasingly archiving such samples for later assessment of the antecedents of disease. METHODS: In 2009, we developed a method to quantify the major circulatory form of vitamin D, 25-hydroxyvitamin D, in archived dried blood spots. Over the last 6 years, we have made substantial alterations to the published method to enhance throughput, sensitivity, and assay robustness. RESULTS: With the alterations, the assay was 3 times faster than the previously published assay and had a >10-fold increase in signal strength. Intraassay imprecision decreased from 13.4% to 6.9%, and there was a 5-fold reduction in interfering phospholipids. In actual use over 2 years, the assay showed an interassay imprecision of 11.6%. CONCLUSIONS: This assay has performed reliably over the past 6 years. The practical changes we have made should allow clinical chemists to successfully adapt this method.

Associations of maternal and fetal 25-hydroxyvitamin D levels with childhood eczema: The Generation R Study.

BACKGROUND: Exposure to low levels of vitamin D in fetal life might affect the developing immune system, and subsequently the risk of childhood eczema. We examined whether 25-hydroxyvitamin D levels in mid-gestation and at birth were associated with the risk of eczema until the age of 4 years. METHODS: In a population-based prospective cohort study of 3019 mothers and their children, maternal blood samples in mid-gestation and umbilical cord blood samples at birth were used to determine 25-hydroxyvitamin D levels (severely deficient <25.0 nmol/l, deficient 25.0-49.9 nmol/l, sufficient 50.0-74.9 nmol/l, optimal ≥75.0 nmol/l). Eczema was prospectively assessed by annual questionnaires until the age of 4 years. Eczema patterns included never, early (age ≤1 year only), late (age >1 year only), and persistent eczema (age ≤ and >1 year). Data were assessed using the generalized estimating equations and multinomial regression models. RESULTS: Compared with the optimal 25-hydroxyvitamin D group, sufficient, deficient, and severely deficient groups of 25-hydroxyvitamin D level in mid-gestation were not associated with the risk of overall eczema (odds ratios [95% confidence interval]: 1.09 [0.82, 1.43], 1.04 [0.87, 1.25], and 0.94 [0.81, 1.10], p-values for trend >0.05), nor with eczema per year or eczema patterns in children up to the age of 4 years. Similarly, we observed no associations of 25-hydroxyvitamin D groups at birth with any eczema outcome. CONCLUSION: Our results suggest that levels of 25-hydroxyvitamin D in mid-gestation and at birth are not associated with the risk of overall eczema, eczema per year, or eczema patterns among children until the age of 4 years.

Rhinoviruses significantly affect day-to-day respiratory symptoms of children with asthma.

BACKGROUND: Viruses are frequently associated with acute exacerbations of asthma, but the extent to which they contribute to the level of day-to-day symptom control is less clear. OBJECTIVE: We sought to explore the relationship between viral infections, host and environmental factors, and respiratory symptoms in children. METHODS: Sixty-seven asthmatic children collected samples twice weekly for an average of 10 weeks. These included nasal wash fluid and exhaled breath for PCR-based detection of viral RNA, lung function measurements, and records of medication use and asthma and respiratory symptoms in the previous 3 days. Atopy, mite allergen exposure, and vitamin D levels were also measured. Mixed-model regression analyses were performed. RESULTS: Human rhinoviruses (hRVs) were detected in 25.5% of 1232 nasal samples and 11.5% of breath samples. Non-hRV viruses were detected in less than 3% of samples. hRV in nasal samples was associated with asthma symptoms (cough and phlegm: odds ratio = 2.0; 95% CI = 1.4-2.86, P = .0001; wheeze and chest tightness: odds ratio = 2.34, 95% CI = 1.55-3.52, P < .0001) and with cold symptoms, as reported concurrently with sampling and 3 to 4 days later. No differences were found between the 3 hRV genotypes (hRV-A, hRV-B, and hRV-C) in symptom risk. A history of inhaled corticosteroid use, but not atopic status, mite allergen exposure, or vitamin D levels, modified the association between viruses and asthma symptoms. CONCLUSION: The detection of nasal hRV was associated with a significantly increased risk of day-to-day asthma symptoms in children. Host, virus genotype, and environmental factors each had only a small or no effect on the relationship of viral infections to asthma symptoms.

Wolbachia Influences the Production of Octopamine and Affects Drosophila Male Aggression.

Wolbachia bacteria are endosymbionts that infect approximately 40% of all insect species and are best known for their ability to manipulate host reproductive systems. Though the effect Wolbachia infection has on somatic tissues is less well understood, when present in cells of the adult Drosophila melanogaster brain, Wolbachia exerts an influence over behaviors related to olfaction. Here, we show that a strain of Wolbachia influences male aggression in flies, which is critically important in mate competition. A specific strain of Wolbachia was observed to reduce the initiation of aggressive encounters in Drosophila males compared to the behavior of their uninfected controls. To determine how Wolbachia was able to alter aggressive behavior, we investigated the role of octopamine, a neurotransmitter known to influence male aggressive behavior in many insect species. Transcriptional analysis of the octopamine biosynthesis pathway revealed that two essential genes, the tyrosine decarboxylase and tyramine ß-hydroxylase genes, were significantly downregulated in Wolbachia-infected flies. Quantitative chemical analysis also showed that total octopamine levels were significantly reduced in the adult heads.

Neonatal vitamin D status and risk of multiple sclerosis.

OBJECTIVE: Low vitamin D status at birth may be associated with risk of adult onset multiple sclerosis, but this link has not been studied directly. We assessed the relation between neonatal vitamin D concentrations, measured in stored blood samples, and risk of multiple sclerosis. METHODS: This was a population-based case-control study in Sweden including 459 incident cases of multiple sclerosis and 663 controls, randomly drawn from a national population registry and frequency matched on sex, age, and residential area. RESULTS: There was no association between neonatal 25-hydroxyvitamin D quintile and risk of multiple sclerosis (crude odds ratio = 1.0, 95% confidence interval = 0.68-1.44, for the highest quintile compared to the lowest). Adjusting for a number of potential confounding factors in early life (month of birth, latitude of birth, breastfeeding) and in adult life (25-hydroxyvitamin D, sun exposure, vitamin D intake from dairy products, fatty fish consumption, smoking, body mass index at 20 years of age) as well as ancestry, multiple sclerosis heredity, and socioeconomic group did not considerably affect the result. INTERPRETATION: At a broad population level, 25-hydroxyvitamin D at birth was not associated with risk of multiple sclerosis.

Heritability of Transforming Growth Factor-ß1 and Tumor Necrosis Factor-Receptor Type 1 Expression and Vitamin D Levels in Healthy Adolescent Twins.

Cytokines and vitamin D both have a role in modulating the immune system, and are also potentially useful biomarkers in mental illnesses such as major depressive disorder (MDD) and schizophrenia. Studying the variability of cytokines and vitamin D in a healthy population sample may add to understanding the association between these biomarkers and mental illness. To assess genetic and environmental contributions to variation in circulating levels of cytokines and vitamin D (25-hydroxy vitamin D: 25(OH)D3), we analyzed data from a healthy adolescent twin cohort (mean age 16.2 years; standard deviation 0.25). Plasma cytokine measures were available for 400 individuals (85 MZ, 115 DZ pairs), dried blood spot sample vitamin D measures were available for 378 individuals (70 MZ, 118 DZ pairs). Heritability estimates were moderate but significant for the cytokines transforming growth factor-ß1 (TGF-ß1), 0.57 (95% CI 0.26-0.80) and tumor necrosis factor-receptor type 1 (TNFR1), 0.50 (95% CI 0.11-0.63) respectively. Measures of 25(OH)D3 were within normal range and heritability was estimated to be high (0.86, 95% CI 0.61-0.94). Assays of other cytokines did not generate meaningful results. These potential biomarkers may be useful in mental illness, with further research warranted in larger sample sizes. They may be particularly important in adolescents with mental illness where diagnostic uncertainty poses a significant clinical challenge.

Ontogeny of small RNA in the regulation of mammalian brain development.

BACKGROUND: MicroRNAs (miRNAs) play a pivotal role in coordinating messenger RNA (mRNA) transcription and stability in almost all known biological processes, including the development of the central nervous system. Despite our broad understanding of their involvement, we still have a very sparse understanding of specifically how miRNA contribute to the strict regional and temporal regulation of brain development. Accordingly, in the current study we have examined the contribution of miRNA in the developing rat telencephalon and mesencephalon from just after neural tube closure till birth using a genome-wide microarray strategy. RESULTS: We identified temporally distinct expression patterns in both the telencephalon and mesencephalon for both miRNAs and their target genes. We demonstrate direct miRNA targeting of several genes involved with the migration, differentiation and maturation of neurons. CONCLUSIONS: Our findings suggest that miRNA have significant implications for the development of neural structure and support important mechanisms that if disrupted, may contribute to or drive neurodevelopmental disorders.

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 Alzheimer's 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.