山西医科大学学报2025，Vol.56Issue(11)：1268-1278,11.DOI:10.13753/j.issn.1007-6611.2025.11.009
精神分裂症模型小鼠肠道代谢紊乱和海马基因表达谱改变的关键分子靶点及通路
Key molecular targets and pathways of gut metabolic disorder and gene expression profile in hippocampus of schizophrenia model mice
摘要
Abstract
Objective To elucidate the key molecular mechanisms of the endogenous pathology of schizophrenia(SZ)-driven gut metabolic dysregulation,and identify the core hippocampal pathways and molecular targets in the hippocampus that mediate this process.Methods Twenty male C57BL/6J mice were randomly assigned into SZ model group and control group(n=10 each group).The mice in SZ model group were intraperitoneally treated with MK-801(0.6 mg/kg)once a day,whereas the mice in control group received an equivalent volume of saline(vehicle)for 14 consecutive days.The behavioral phenotypes were evaluated through open-field test and Morris water maze test,and then ultra-high performance liquid chromatography-quadrupole-orbitrap mass spectrometry and RNA sequencing technology were used to perform non-targeted metabolomics and transcriptomics analysis on fecal samples and hippocampal tissues from the two groups for identifying key differentially expressed genes and related signaling pathways.Results Compared with control group,the mice in SZ model group showed significant behavioral abnormalities,including a significant decrease in spontaneous activity in open-field test and impaired spatial memory ability in Morris water maze(P<0.001).Metabolomics analysis showed that there was significant metabolic disturbance in the gut of model mice,and 82 differential metabolites were identified and mainly enriched in amino acid and lipid metabolism,among which,tryptophan metabolism dysregulation was particularly promi-nent,showing an up-regulated kynurenine pathway and a down-regulated indole pathway.Transcriptomic analysis of the hippocampus identified ten key differentially expressed genes,namely Arc,Nr4a1,Fos,1700016P03Rik,Egr2,Gm37310,Gm44199,Dnd1,Gm16310,and Anxa8.Functional enrichment analysis revealed that these genes were primarily associated with the MAPK signaling pathway.Conclusion The gut metabolic disturbance in schizophrenia model mice,especially the changes in tryptophan and lipid metabolism,is closely related to the activation of MAPK signaling pathway in the hippocampus and the up-regulated expressions of key genes(such as Nr4a1,Fos).关键词
精神分裂症/代谢紊乱/非靶向代谢组学/转录组学/信号通路/分子靶点Key words
schizophrenia/metabolic dysregulation/untargeted metabolomics/transcriptomics/signaling pathway/mo-lecular target分类
医药卫生引用本文复制引用
JIANG Shijie,XU Ziyi,PENG Zhenlei,GUO Jun,AN Zhiguo,YI Qizhong..精神分裂症模型小鼠肠道代谢紊乱和海马基因表达谱改变的关键分子靶点及通路[J].山西医科大学学报,2025,56(11):1268-1278,11.基金项目
国家自然科学基金资助项目(81960258) （81960258）
新疆维吾尔自治区研究生科研创新项目(XJ2025G145) （XJ2025G145）
新疆维吾尔自治区自然科学基金项目(2022D01D64,2025D01C173) （2022D01D64,2025D01C173）
