The developmental vitamin D (DVD) model of schizophrenia

It is now widely acknowledged that exposure to adverse environmental factors in utero may not only affect how the brain develops but have long-lasting consequences for later brain function in the adult offspring. This idea has gained particular prominence amongst researchers interested in the etiology of neurodevelopmental disorders such as schizophrenia and autism. Approximately 10 years ago we proposed that developmental vitamin D (DVD) deficiency may explain several epidemiological features of this disease, most noticeably the winter/spring season of birth effect. In 2003 we published results from our first study indicating there were structural changes in how the brain develops in these offspring. Since then we have firmly established that DVD deficiency not only affects brain cell differentiation and gross anatomy but also produces alterations in behavior in these offspring as adults. In this chapter we describe how we came to construct the model we use today. Over the past 7 years the model has proved informative producing both structural brain changes (ventriculomegaly) and behavioral alterations (hyperlocomotion in response to NMDA antagonists) that are thought to be relevant to schizophrenia

Vitamin D in synaptic plasticity, cognitive function, and neuropsychiatric illness

Over a billion people worldwide are affected by vitamin D deficiency. Although vitamin D deficiency is associated with impaired cognition, the mechanisms mediating this link are poorly understood. The extracellular matrix (ECM) has now emerged as an important participant of synaptic plasticity and a new hypothesis is that vitamin D may interact with aggregates of the ECM, perineuronal nets (PNNs), to regulate brain plasticity. Dysregulation of PNNs caused by vitamin D deficiency may contribute to the presentation of cognitive deficits. Understanding the molecular mechanisms underpinning the role of vitamin D in brain plasticity and cognition could help identify ways to treat cognitive symptoms in schizophrenia and other neuropsychiatric conditions

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 an neuro developmental 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 neuro developmental 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 analtered behavioral profilein response to DA releasing and blocking agents that are reminiscent of that see nin schizophrenia patients. Furthermore, developmental studies revealed that DVD deficiency also altered cell proliferation, apoptosis, and neurotransmission across the embryonic brain. Inparticular, 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 neuronontogeny to induce the behavior al abnormalities observed in adult offspring. The widespread evidence that both dopaminergic and structural changes are presenting people who develop schizophrenia prior to on set 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 to get here evidence from multiple risk factors and genetic vulnerabilities to form a convergent pathway in disease pathophysiology

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

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

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(3) deficiency induces alterations in immune organ morphology and function in adult offspring

Vitamin D3 deficiency and insufficiency are common in women of child-bearing age. This may be cause for concern because vitamin D3 is a well known regulator of immune function and epidemiological evidence has suggested that immune disorders, including autoimmune diseases, could have developmental origins. However, it is not known whether a developmental deficiency in vitamin D3 could lead to persistent changes in the immune system in adult offspring. Given the prominence of receptors for vitamin D3 within immune cells we hypothesised that the developmental absence of vitamin D3 may alter thymic development and thus produce associated functional changes in T cells. We have developed a model of developmental vitamin D3 (DVD) deficiency in Sprague-Dawley rats, in which the vitamin D3 deficiency is transient and restricted to gestation. First we demonstrate that DVD deficiency induced an increase in central but not peripheral immune organ size. Second when stimulated, lymphocytes from DVD-deficient rats exhibit a pro-inflammatory phenotype. This is the first study to show that a transient vitamin D3 deficiency restricted to gestation can persistently alter aspects of immune phenotype and function in the adult offspring. Given an increased incidence of vitamin D3 deficiency in women of child-bearing age these findings may be highly relevant for autoimmune disorders with a developmental basis

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

The p75 neurotrophin receptor regulates hippocampal neurogenesis and related behaviours

Although changes to neural circuitry are believed to underlie behavioural characteristics mediated by the hippocampus, the contribution of neurogenesis to this process remains controversial. This is partially because the molecular regulators of neurogenesis remain to be fully elucidated, and experiments generically preventing neurogenesis have, for the most part, depended on paradigms involving irradiation. Here we show that mice lacking the p75 neurotrophin receptor (p75(NTR-/-)) have 25% fewer neuroblasts and 50% fewer newborn neurons in the dentate gyrus, coincident with increased rates of cell death of newly born cells and a significantly smaller granular cell layer and dentate gyrus, than those of p75(NTR+/+) mice. Whereas p75(NTR-/-) mice had increased latency to feed in a novelty-suppressed feeding paradigm they had increased mobility in another test of "depression", the tail-suspension test. p75(NTR-/-) mice also had subtle behavioural impairment in Morris water maze tasks compared to wild-type animals. No difference between genotypes was found in relation to anxiety or exploration behaviour based on the elevated-plus maze, light-dark, hole-board, T-maze or forced-swim tests. Overall, this study demonstrates that p75(NTR) is an important regulator of hippocampal neurogenesis, with concomitant effects on associated behaviours. However, the behavioural attributes of the p75(NTR-/-) mice may be better explained by altered circuitry driven by the loss of p75(NTR) in the basal forebrain, rather than direct changes to neurogenesis