Developmental Neurobiology

Staff

Professor John McGrath (Director) For Biography Click Here

Dr. Darryl Eyles (Laboratory Head)

Dr. Francois Feron (until 2003)

Dr. Tom Burne

Pauline Ko

Catherine Jones

PhD Students

Richard McCurdy

Greger Abrahamsen

Louise Harvey

James Kesby

Funding

This research program is funded by the Queensland Department of Health, the NHMRC, and The Stanley Foundation, U.S.A.

About Our Work:

Schizophrenia is thought to be a developmental disorder with a characteristic onset in late adolescence and early adulthood. Neurodevelopmental theories suggest that genetic and nongenetic factors that disrupt early brain development contribute the risk of developing Schizophrenia. This makes the study of developmental neurobiology important for schizophrenia research. Our current research is based in two laboratories ( School of Biomedical Science , University of Queensland ) and Griffith University (in collaboration with Professor Alan Mackay-Sim ).

The nasal olfactory mucosa, a window on the brain: more

Cellular and molecular abnormalities in schizophrenia and bipolar disorder have been studied using nervous tissue samples collected post-mortem. However, this material has limitations. Death induces rapid cellular and molecular changes. In addition, diagnostic and demographic data for these cases are often sub-optimal. Also, it is rare that material can be collected from unaffected family members, (e.g. from both members of a discordant monozygotic twin pair).

To overcome these difficulties it is possible to collect an easily accessible nervous tissue in living individuals: the olfactory mucosa located at the back of the nasal cavity. Furthermore, the olfactory neuroepithelium exhibits characteristics of great interest to neuroscience. As this tissue is permanently renewed (even in adult humans), it can serve as a model to study the factors involved in neurogenesis and gliogenesis. The olfactory mucosa is a reservoir of glial and neural stem cells that is readily accessible via biopsy. Thus, the olfactory neuroepithelium can be considered as a “window” that allows the examination of factors involved in brain development. Our group are examining gene expression in this tissue (with gene array). We have also isolated progenitor cells from this tissue, which has opened new avenues for biomedical research in schizophrenia.

Projects

1. Effect of low prenatal vitamin D on neurodevelopment

Inferences from epidemiology

Over the last eighty years, many studies have shown that those born in winter and spring have a small, but significantly increased, risk of developing schizophrenia. Even in subtropical locations such as Queensland , a winter-spring excess of schizophrenia births has been noted. The magnitude of the winter excess of schizophrenia births is positively associated with latitude (i.e. locations at higher latitudes have a great winter excess). Vitamin D levels fluctuate across the seasons (lowest in winter and spring) and across latitude (lowest at high latitudes), thus prenatal vitamin D ‘fits' a key epidemiological feature of schizophrenia. There are two other epidemiological clues that also suggest that vitamin D warrants closer scrutiny. Recent systematic reviews have shown that the incidence of schizophrenia is higher in migrants compared to native born. In particular, the meta-analysis by Cantor-Graae and Selten 11 found that migrants with darker skin were at higher risk compared to fairer-skinned migrants. Dark-skinned migrants to cold climates are prone to hypovitaminosis D, thus the vitamin D hypothesis could be one of the factors contributing to the increased risk of schizophrenia in second-generation migrants. Finally, compared to those born in rural regions, those born in the city have a significantly higher risk of developing schizophrenia. Hypovitaminosis D is more prevalent in city-dwellers. Based on these three clues, in 1999 our group proposed that low prenatal vitamin D is a parsimonious candidate risk factor for schizophrenia.

While the clues linking vitamin D to various features of the epidemiology of schizophrenia are suggestive, these were based on “ecological” data (i.e. group level data rather than individual level data). In the last few years, two studies based on analytic epidemiology have provided support for the hypothesis – one based on 30 year old banked maternal sera, and another based on maternal report of vitamin D supplementation.

In a pilot study, we directly measured maternal 25-hydroxyvitamin D 3 levels in maternal sera taken during the third trimester and banked for over three decades. This study was based on a collaboration with the Harvard School of Public Health (Steve Buka) and Johns Hopkins University (Bob Yolken). The 25-hydroxyvitamin D 3 levels in the 26 mothers whose children developed schizophrenia was lower than that of 51 control mothers, although this difference was not statistically significant. The results of the pilot study have influenced the development of the vitamin D hypothesis in three key aspects. Firstly, the results suggest that vitamin D does not operate in a continuous graded fashion, but may have a critical threshold below which adverse outcomes may follow. This type of association is often found in nutritional epidemiology. For example, very low levels of prenatal vitamin A are teratogenic, however there is no dose-response effect within the normal range Secondly, the study has confirmed that many pregnant women (including mother of individuals with schizophrenia) are prone to hypovitaminosis D – 12 of the 26 mothers of cases and 15 of the 51 mothers of controls had levels had level below 15 ng/ml, which is the mid-point of the ‘deficient' range. Finally, the pilot banked sera study demonstrated that 25-hydroxyvitamin D 3 can be measured in biological specimens over 30 years old.

The second major study involved the Northern Finnish Birth Cohort. In collaboration with colleagues from the University of Oulo (Matti Isohanni) and the University of Cambridge (Peter Jones), we found a link between the use of vitamin D supplementation during the first year of life and a reduced risk of schizophrenia in males only.

Low developmental vitamin D is a biologically plausible candidate: the evidence

Prior to 2000, it was known that the vitamin D receptor (VDR) was expressed in rat brain throughout development and into adulthood. Based mainly on in vitro studies, there were also evidence linking vitamin D to the biosynthesis of neurotrophic factors, the regulation of neurotransmitters and detoxification pathways. Important advances have been made in the last few years.

Based on post-mortem tissue, our group has (for the first time) mapped the distribution of the VDR and of the 1 hydroxylase (the final enzyme in the activation pathways) in the normal adult human brain. The findings provide further evidence that vitamin D may operate in a fashion similar to other neurosteroids. Curiously, we found that that the large (presumably) dopaminergic cells of the substantia nigra were amongst the most immunoreactive brain areas for the VDR – dopamine has long been implicated in the neurobiology of schizophrenia.

Our group has reported the temporal profile of VDR mRNA and protein expression in the developing rat brain. We have demonstrated in hippocampal cultures that vitamin D increases neurite growth in a dose-dependent fashion and increases the production of nerve growth factor (NGF). Based on fetal and neonatal rat brain tissue, we have linked the known pro-differentiating, pro-apoptotic properties of vitamin D to altered (a) rates of mitosis and cell death and (b) altered gene expression in apoptotic and mitotic pathways.

With the support of the NHMRC our group was able to develop a model to explore the impact of low vitamin D during development. In brief, compared to control pups, offspring of dams depleted of vitamin D had: (a) longer brains and larger lateral ventricles; (b) increased cell proliferation and reduced apoptosis; (c) reduced neurotrophin receptor (p75); and (d) reduced levels of the nerve growth factor (NGF) and glial cell line-derived growth factor. As adults, these animals have significantly increased ventricular volume and persisting reductions in NGF expression. We have shown that these changes are associated with altered behaviour in the adult rat exposed to transient prenatal hypovitaminosis D. For example, adult rats that had been exposed to transient prenatal hypovitaminosis D have increased spontaneous hyperlocomotion.

Prior to 2000, it was known that the vitamin D receptor (VDR) was expressed in rat brain throughout development and into adulthood. Based mainly on in vitro studies, there were also evidence linking vitamin D to the biosynthesis of neurotrophic factors, the regulation of neurotransmitters and detoxification pathways. Important advances have been made in the last few years.

Based on post-mortem tissue, our group has (for the first time) mapped the distribution of the VDR and of the 1 hydroxylase (the final enzyme in the activation pathways) in the normal adult human brain. The findings provide further evidence that vitamin D may operate in a fashion similar to other neurosteroids. Curiously, we found that that the large (presumably) dopaminergic cells of the substantia nigra were amongst the most immunoreactive brain areas for the VDR – dopamine has long been implicated in the neurobiology of schizophrenia.

Our group has reported the temporal profile of VDR mRNA and protein expression in the developing rat brain. We have demonstrated in hippocampal cultures that vitamin D increases neurite growth in a dose-dependent fashion and increases the production of nerve growth factor (NGF). Based on fetal and neonatal rat brain tissue, we have linked the known pro-differentiating, pro-apoptotic properties of vitamin D to altered (a) rates of mitosis and cell death and (b) altered gene expression in apoptotic and mitotic pathways.

With the support of the NHMRC our group was able to develop a model to explore the impact of low vitamin D during development. In brief, compared to control pups, offspring of dams depleted of vitamin D had: (a) longer brains and larger lateral ventricles; (b) increased cell proliferation and reduced apoptosis; (c) reduced neurotrophin receptor (p75); and (d) reduced levels of the nerve growth factor (NGF) and glial cell line-derived growth factor. As adults, these animals have significantly increased ventricular volume and persisting reductions in NGF expression. We have shown that these changes are associated with altered behaviour in the adult rat exposed to transient prenatal hypovitaminosis D. For example, adult rats that had been exposed to transient prenatal hypovitaminosis D have increased spontaneous hyperlocomotion.

Publications

Feron F, McCurdy R, McGrath J, Mackay-Sim A. Olfactory epithelium: A window on brain development. In Press – Cambridge University Press (2004)

McLean D, Feron F, Mackay-Sim A, McCurdy R, Hirning M, Chant D, McGrath J. Paradoxical association between smoking and olfactory identification in psychosis versus controls. Australian and New Zealand Journal of Psychiatry, 2004 38: (1-2) 81-83

McGrath J, Saari K,, Hakko H, Jokelainen J, Jones P, Jarvelin M, Chant D, Isohanni M. Vitamin D supplementation during the first year of life and risk of schizophrenia: a Finnish cohort study. Schizophrenia Research, (2004) 67: (2-3) 237-245

Mackay-Sim A, Feron F, Eyles D, Burne T, McGrath J. Disorders of synaptic plasticity, schizophrenia, vitamin D and brain development. (Book) International Review of Neurobiology, 2004 59: 351-380

McGrath J. Does 'imprinting' with low prenatal vitamin D contribute to the risk of various adult disorders? Medical Hypotheses 2001;56(3):367-371.

McGrath JJ, Kimlin MG, Saha S, Eyles DW, Parisi AV. Vitamin D insufficiency in south-east Queensland. Med J Aust 2001;174(3):150-1.

Hsu P, Yu F, Feron F, Pickles JO, Sneesby K, Mackay-Sim A. Basic fibroblast growth factor and fibroblast growth factor receptors in adult olfactory epithelium. Brain Res 2001;896(1-2):188-97.

Eyles DW, Pond SM, Van der Schyf CJ, Halliday GM. Mitochondrial ultrastructure and density in a primate model of persistent tardive dyskinesia. Life Sci 2000;66(14):1345-50.

Newman MP, Feron F, Mackay-Sim A. Growth factor regulation of neurogenesis in adult olfactory epithelium. Neuroscience 2000;99(2):343-50.

Feron F, Mackay-Sim A, Andrieu JL, Matthaei KI, Holley A, Sicard G. Stress induces neurogenesis in non-neuronal cell cultures of adult olfactory epithelium. Neuroscience 1999;88(2):571-83.

Feron F, Perry C, Hirning MH, McGrath J, Mackay-Sim A. Altered adhesion, proliferation and death in neural cultures from adults with schizophrenia. Schizophr Res 1999;40(3):211-8.

McGrath J. Hypothesis: is low prenatal vitamin D a risk-modifying factor for schizophrenia? Schizophr Res 1999;40(3):173-7.

Feron F, Perry C, McGrath JJ, Mackay-Sim A. New techniques for biopsy and culture of human olfactory epithelial neurons. Arch Otolaryngol Head Neck Surg 1998;124(8):861-6.

Coronas V, Feron F, Hen R, Sicard G, Jourdan F, Moyse E. In vitro induction of apoptosis or differentiation by dopamine in an immortalized olfactory neuronal cell line. J Neurochem 1997;69(5):1870-81.

Murrell W, Bushell GR, Livesey J, McGrath J, MacDonald KP, Bates PR, et al. Neurogenesis in adult human. Neuroreport 1996;7(6):1189-94.

Feron, R. Burne, T.H.J, Brown, J. Smith, E., McGrath, J.J., Mackay-Sim, A., Eyles, D. Developmental vitamin D3 deficiency alters the adult rat brain. Brain Research Bulletin. (Accepted 14.12.04).

Burne THJ, McGrath JJ, Eyles DW, Mackay-Sim A. Behavioural characterization of vitamin D receptor knockout mice. Behavioural Brain Research In press (accepted 1. 8.04).

Ko P, Burkert R, McGrath J, Eyles D. (2004) Maternal vitamin D3 deprivation and the regulation of apoptosis and cell cycle during rat brain development. Developmental Brain Research, 153 (1) 61-68.

Eyles DW, Smith S, Kinobe R, Hewison M, McGrath JJ. (2005) Distribution of the vitamin D receptor and 1-hydroxylase in human brain. J Chem Neuroanat: 29(1):21-30.

Burne, T. H. J., Becker, A., Brown, J., Eyles, D. W., Mackay-Sim, A. and McGrath, J. J. (2004) Transient prenatal vitamin D deficiency is associated with hyperlocomotion in adult rats. Behavioural Brain Research. ;154(2):549-55.

TH Burne, F Féron, J Brown, DW Eyles, JJ McGrath, A Mackay-Sim (2004). Combined prenatal and chronic postnatal vitamin D deficiency in rats impairs sensorimotor gating. Physiol Behav 81, 451-455.

Mackay-Sim A, Feron F, Eyles D, Burne T, McGrath J. (2004) Schizophrenia, vitamin D3, and brain development. International Review of Neurobiology; 59:351-80