血浆外泌体携带非编码RNA影响精神分裂症小鼠叶皮层锥体神经元突触活动的作用机制  

Mechanism of action of plasma exosomes carrying non-coding RNAs affecting synaptic activity of pyramidal neurons in the lobar cortex of mice with schizophrenia

作　　者：王志超 吴桐[2] 孙正海[2] 王宇晨 李平[2] 崔光成[2] WANG Zhichao;WU Tong;SUN Zhenghai;WANG Yuchen;LI Ping;CUI Guangcheng(Departments of Academic Research,Qiqihar Medical University,Qiqihar 161000,China;School of Medical Health,Qiqihar Medical University,Qiqihar 161000,China)

机构地区：[1]齐齐哈尔医学院学术理论研究部,黑龙江齐齐哈尔161000 [2]齐齐哈尔医学院精神卫生学院,黑龙江齐齐哈尔161000

出　　处：《中国实用神经疾病杂志》2023年第7期891-897,共7页Chinese Journal of Practical Nervous Diseases

基　　金：齐齐哈尔医学科学院面上项目(编号:QMSI2019M-02);黑龙江省教育厅基本科研业务基础研究项目(编号:2020-KYYWF-0033);黑龙江省自然科学基金联合引导项目(编号:LH2020H130)。

摘　　要：目的通过全转录组测序技术揭示血浆外泌体miRNAs参与精神分裂症发生和发展的可能分子机制。方法获取精神分裂症小鼠和正常小鼠前额皮质组织和血浆外泌体进行全转录组测序筛选差异表达的m RNAs和miRNAs。从GEO数据库下载精神分裂症小鼠相关转录组测序数据集GSE111708、GSE108925和GSE189821,筛选差异表达的mRNAs。对差异基因进行GO功能和KEGG通路富集分析,随后对血浆外泌体中差异表达的miRNAs与小鼠前额皮质组织中差异表达的miRNAs取交集,通过TargetScan数据库检索miR-146a-5p下游靶基因,并使用Cytoscape v3.6.0软件对miRNAs-靶基因调控网络进行可视化和映射。结果全转录组测序数据差异分析共获得1549个差异基因,这些差异基因主要在突触调节相关功能和通路上富集。进一步对精神分裂症小鼠相关GEO芯片中的差异基因进行KEGG富集分析发现,精神分裂症相关基因与神经元退化相关。对精神分裂症小鼠前额皮质组织中的164个差异表达miRNAs与血浆外泌体中的5个差异表达miRNAs取交集,得到目标基因miR-146a-5p,且miR-146a-5p在前额皮质组织和血浆来源外泌体中均为高表达。最后对miR-146a-5p的161个靶基因与精神分裂症小鼠前额皮质组织中低表达的差异基因取交集发现,共11个靶基因在精神分裂症小鼠前额皮质组织中低表达,且这些基因富集在Notch信号通路上,主要参与调控神经元突触活动。结论血浆来源外泌体中的miR-146a-5p可能通过传递至叶皮层锥体神经元中靶向调控Notch1,进而抑制Notch信号通路介导的小鼠叶皮层锥体神经元突触活动,最终促进小鼠精神分裂症的发生和发展。Objective To reveal the possible molecular mechanisms of plasma exosomal miRNAs involved in the occurrence and development of schizophrenia by whole-transcriptome sequencing technology.Methods Whole-transcriptome sequencing of prefrontal cortex tissues and plasma exosomes from schizophrenic and normal mice was obtained to screen for differentially expressed mRNAs and miRNAs.GSE111708,GSE108925 and GSE189821,the relevant transcriptome sequencing datasets of schizophrenic mice,were downloaded from the Gene Expression Omnibus(GEO)database to screen for differentially expressed mRNAs.Gene Ontology(GO)function and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis were performed on the differential genes.Subsequently,the differentially expressed miRNAs in plasma exosomes were intersected with the differentially expressed miRNAs in mouse prefrontal cortex tissue,and the miR-146a-5p downstream target genes were retrieved by TargetScan database,and the miRNAs-target gene regulatory network was visualized and mapped using Cytoscape v3.6.0 software.Results Differential analysis of whole-transcriptome sequencing data yielded a total of 1549 differential genes,which were enriched mainly in synaptic regulation-related functions and pathways.Further Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis of differential genes in schizophrenia mouse-associated Gene Expression Omnibus(GEO)microarrays revealed that schizophreniaassociated genes were associated with neuronal degeneration.The 164 differentially expressed miRNAs in prefrontal cortex tissues of schizophrenic mice were intersected with 5 differentially expressed miRNAs in plasma exosomes to obtain the target gene miR-146a-5p,and miR-146a-5p was highly expressed in both prefrontal cortex tissues and plasma-derived exosomes.Finally,the 161 target genes of miR-146a-5p were intersected with differentially expressed genes in the prefrontal cortex of schizophrenic mice,and a total of 11 target genes were found to be lowly expressed in the pref

关 键 词：精神分裂症 前额皮质组织 GEO 全转录组测序 GO&KEGG miR-146a-5p NOTCH信号通路 突触活动 

分 类 号：R-332[医药卫生]