Plasma exosomes carrying mmu-miR-146a-5p and Notch signalling pathway-mediated synaptic activity in schizophrenia.

IF 4.1 2区 医学 Q2 NEUROSCIENCES Journal of Psychiatry & Neuroscience Pub Date : 2024-08-29 Print Date: 2024-07-01 DOI:10.1503/jpn.230118
Zhichao Wang, Tong Wu, Houjia Hu, Alabed Ali A Alabed, Guangcheng Cui, Lei Sun, Zhenghai Sun, Yuchen Wang, Ping Li
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引用次数: 0

Abstract

Background: Schizophrenia is characterized by a complex interplay of genetic and environmental factors, leading to alterations in various molecular pathways that may contribute to its pathogenesis. Recent studies have shown that exosomal microRNAs could play essential roles in various brain disorders; thus, we sought to explore the potential molecular mechanisms through which microRNAs in plasma exosomes are involved in schizophrenia.

Methods: We obtained sequencing data sets (SUB12404730, SUB12422862, and SUB12421357) and transcriptome sequencing data sets (GSE111708, GSE108925, and GSE18981) from mouse models of schizophrenia using the Sequence Read Archive and the Gene Expression Omnibus databases, respectively. We performed differential expression analysis on mRNA to identify differentially expressed genes. We conducted Gene Ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses to determine differentially expressed genes. Subsequently, we determined the intersection of differentially expressed microRNAs in plasma exosomes and in prefrontal cortex tissue. We retrieved downstream target genes of mmu-miR-146a-5p from TargetScan and used Cytoscape to visualize and map the microRNA-target gene regulatory network. We conducted in vivo experiments using MK-801-induced mouse schizophrenia models and in vitro experiments using cultured mouse neurons. The role of plasma exosomal miR-146a-5p in schizophrenia was validated using a cell counting kit, detection of lactate dehydrogenase, dual-luciferase assay, quantitative reverse transcription polymerase chain reaction, and Western blot analysis.

Results: Differential genes were mainly enriched in synaptic regulation-related functions and pathways and were associated with neuronal degeneration. We found that mmu-miR-146a-5p was highly expressed in both prefrontal cortical tissue and plasma exosomes, which may be transferred to lobe cortical vertebral neurons, leading to the synergistic dysregulation of gene network functions and, therefore, promoting schizophrenia development. We found that mmu-miR-146a-5p may inhibit the Notch signalling pathway-mediated synaptic activity of mouse pyramidal neurons in the lobe cortex by targeting NOTCH1, which in turn could promote the onset and development of schizophrenia in mice.

Limitations: The study's findings are based on animal models and in vitro experiments, which may not fully replicate the complexity of human schizophrenia.

Conclusion: Our findings suggest that mmu-miR-146a-5p in plasma-derived exosomes may play an important role in the pathogenesis of schizophrenia. Our results provide new insights into the underlying molecular mechanisms of the disease.

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携带mmu-miR-146a-5p的血浆外泌体与精神分裂症患者Notch信号通路介导的突触活动
背景:精神分裂症的特点是遗传和环境因素的复杂相互作用,导致各种分子通路的改变,而这些改变可能是导致精神分裂症发病的原因。最近的研究表明,外泌体microRNA可能在各种脑部疾病中发挥重要作用;因此,我们试图探索血浆外泌体中的microRNA参与精神分裂症的潜在分子机制:我们利用序列读取档案(Sequence Read Archive)和基因表达总库(Gene Expression Omnibus)数据库分别获得了精神分裂症小鼠模型的测序数据集(SUB12404730、SUB12422862和SUB12421357)和转录组测序数据集(GSE111708、GSE108925和GSE18981)。我们对 mRNA 进行了差异表达分析,以确定差异表达基因。我们进行了基因本体(GO)功能分析和京都基因组百科全书(KEGG)通路富集分析,以确定差异表达基因。随后,我们确定了血浆外泌体和前额叶皮质组织中差异表达 microRNA 的交叉点。我们从 TargetScan 中检索了 mmu-miR-146a-5p 的下游靶基因,并使用 Cytoscape 可视化绘制了 microRNA-靶基因调控网络。我们使用 MK-801 诱导的小鼠精神分裂症模型进行了体内实验,并使用培养的小鼠神经元进行了体外实验。我们使用细胞计数试剂盒、乳酸脱氢酶检测、双荧光素酶检测、定量反转录聚合酶链反应和 Western 印迹分析验证了血浆外泌体 miR-146a-5p 在精神分裂症中的作用:结果:差异基因主要富集在突触调节相关功能和通路中,并与神经元变性有关。我们发现mmu-miR-146a-5p在前额叶皮质组织和血浆外泌体中均高表达,这些外泌体可能会转移到叶皮质椎体神经元,导致基因网络功能的协同失调,从而促进精神分裂症的发展。我们发现,mmu-miR-146a-5p可能通过靶向NOTCH1,抑制Notch信号通路介导的小鼠叶皮层锥体神经元的突触活动,进而促进小鼠精神分裂症的发病和发展:研究结果基于动物模型和体外实验,可能无法完全复制人类精神分裂症的复杂性:我们的研究结果表明,血浆外泌体中的mmu-miR-146a-5p可能在精神分裂症的发病机制中扮演重要角色。我们的研究结果为了解精神分裂症的潜在分子机制提供了新的视角。
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来源期刊
CiteScore
6.80
自引率
2.30%
发文量
51
审稿时长
2 months
期刊介绍: The Journal of Psychiatry & Neuroscience publishes papers at the intersection of psychiatry and neuroscience that advance our understanding of the neural mechanisms involved in the etiology and treatment of psychiatric disorders. This includes studies on patients with psychiatric disorders, healthy humans, and experimental animals as well as studies in vitro. Original research articles, including clinical trials with a mechanistic component, and review papers will be considered.
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