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

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Abstract

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.

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Abbreviations

BM:

Basal medial domain of the basal plate

DA:

Dopamine

DVD deficiency:

Developmental vitamin D deficiency

E:

Embryonic day

FP:

Floor plate

IZ:

Intermediate zone

Lmx1a/b:

LIM homeobox transcription factor 1-alpha/-beta

mes:

Mesencephalon

MZ:

Mantle zone

Nurr1:

Nuclear receptor related 1 protein

ROI:

Region of interest

SD:

Sprague Dawley

SHH:

Sonic hedgehog

SNc:

Substantia nigra pars compacta

TH:

Tyrosine hydroxylase

VDR:

Vitamin D receptor

VTA:

Ventral tegmental area

VZ:

Ventricular zone

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Acknowledgements

This study was funded by the National Health and Medical Research Council of Australia (NHMRC grant number APP1042259).

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Authors and Affiliations

  1. Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia

    Wei Luan, Luke Alexander Hammond, Edmund Cotter, Geoffrey William Osborne, Virginia Nink, Xiaoying Cui & Darryl Walter Eyles

  2. The Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia

    Geoffrey William Osborne

  3. Queensland Centre for Mental Health Research, Brisbane, QLD, Australia

    Suzanne Adele Alexander & Darryl Walter Eyles

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  1. Wei Luan
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  2. Luke Alexander Hammond
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  3. Edmund Cotter
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Correspondence to Darryl Walter Eyles.

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All procedures were performed with approval from the Animal Ethics Committee of the University of Queensland (Animal Ethics Approval number: AE05580) and under the guidelines of the National Health and Medical Research Council of Australia.

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The authors declare no conflict of interest.

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Luan, W., Hammond, L.A., Cotter, E. et al. Developmental Vitamin D (DVD) Deficiency Reduces Nurr1 and TH Expression in Post-mitotic Dopamine Neurons in Rat Mesencephalon. Mol Neurobiol 55, 2443–2453 (2018). https://doi.org/10.1007/s12035-017-0497-3

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