Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
The Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia.
Mol Neurobiol. 2018 Mar;55(3):2443-2453. doi: 10.1007/s12035-017-0497-3. Epub 2017 Apr 1.
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.
发育性维生素 D（DVD）缺乏被认为是精神分裂症的一个重要危险因素。我们之前使用 Sprague Dawley 大鼠的研究发现，DVD 缺乏通过降低多巴胺细胞关键分化因子核受体相关 1 蛋白（Nurr1）的 mRNA 水平，破坏中脑多巴胺神经元的发生。然而，目前尚不清楚这是否反映了多巴胺细胞数量的减少，还是 Nurr1 表达的减少。也不清楚中脑发育中的多巴胺神经元中是否存在任何特定的亚群受到选择性影响。在这项研究中，我们采用了优化的旋转盘共聚焦显微镜技术，用于组织切片的成像和 3D 分割，以评估胚胎第 15 天大鼠中脑的单个有丝分裂后多巴胺细胞。我们的结果表明，DVD 缺乏并未改变有丝分裂后多巴胺细胞的数量、形态或定位。然而，与腹侧被盖区（VTA）相比，DVD 缺乏胚胎的黑质致密部（SNc）中 Nurr1+TH+细胞的比例增加。此外，在 DVD 缺乏组中，VTA 中未成熟多巴胺细胞和成熟多巴胺神经元中的 Nurr1 表达减少。酪氨酸羟化酶在 DVD 缺乏的中脑 SNc 中选择性减少。我们得出结论，DVD 缺乏诱导的中脑多巴胺发育早期改变可能部分解释了该模型中发现的异常多巴胺相关行为。我们的发现可能对某些精神分裂症环境风险因素如何塑造多巴胺能系统的发生以及推断增加精神分裂症的风险具有更广泛的意义。
