Queensland Brain Institute, University of Queensland, Qld 4072, Australia.
School of Biomedical Sciences and Pharmacy, University of Newcastle, NSW 2308, Australia; Centre for Brain and Mental Health Research, Hunter Medical Research Institute, NSW 2305, Australia.
Brain Res. 2022 Aug 15;1789:147953. doi: 10.1016/j.brainres.2022.147953. Epub 2022 May 26.
Schizophrenia is a neurodevelopmental disorder associated with abnormal dopamine (DA) signalling and disruptions in early brain development. We have shown that developmental vitamin D-deficiency (DVD-deficiency) increases the risk of schizophrenia in offspring and impairs various aspects of brain development in rodents, particularly that of DA neurons, however the molecular basis of these impairments remains unclear. Here, we explore whether small non-coding microRNAs (miRNAs) are involved. miRNAs regulate gene expression post-transcriptionally via translational repression and destabilisation of mRNA. While dysregulation of multiple miRNAs has been reported in post-mortem brain of patients with schizophrenia, the biological pathways affected by these small RNAs are not clear. Here we identified differential expression of 18 miRNAs in DA neurons isolated from DVD-deficient embryos. Three miRNAs were selected for further functional studies of dopaminergic neuron differentiation based on their interactions with transcripts involved in neuronal maturation. In particular, we show upregulation of miR-181c-5p suppresses neurite outgrowth of dopaminergic neurons. These findings provide further evidence that an environmental risk factor for schizophrenia - DVD-deficiency - disrupts the development of DA neurons and suggests increased miRNA expression may be one possible mechanism. This disruption potentially underlies the long-term alterations in DA mediated brain function in DVD-deficient offspring, and by inference in schizophrenia.
精神分裂症是一种神经发育障碍，与多巴胺（DA）信号异常和早期大脑发育中断有关。我们已经表明，发育性维生素 D 缺乏（DVD 缺乏）会增加后代患精神分裂症的风险，并损害啮齿动物大脑的各个方面的发育，尤其是 DA 神经元，但这些损伤的分子基础仍不清楚。在这里，我们探讨了小分子非编码 microRNAs（miRNAs）是否参与其中。miRNAs 通过翻译抑制和 mRNA 的不稳定性来对转录后基因表达进行调控。虽然在精神分裂症患者的死后大脑中已经报道了多种 miRNAs 的失调，但这些小 RNA 影响的生物学途径尚不清楚。在这里，我们在 DVD 缺乏胚胎中分离的 DA 神经元中鉴定到 18 个 miRNA 的差异表达。基于与神经元成熟相关的转录本的相互作用，选择了三个 miRNA 进行多巴胺能神经元分化的进一步功能研究。特别是，我们表明 miR-181c-5p 的上调抑制了多巴胺能神经元的突起生长。这些发现进一步证明了精神分裂症的一个环境风险因素——DVD 缺乏症——会破坏 DA 神经元的发育，并表明增加的 miRNA 表达可能是一种可能的机制。这种破坏可能是 DVD 缺乏后代中 DA 介导的大脑功能长期改变的基础，进而也是精神分裂症的基础。
