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In the present study, we established a rat model of repeated subanesthetic intraperitoneal propofol administration and demonstrated that propofol induced robust conditioned place preference, indicating rewarding properties. Propofol-exposed rats exhibited significant impairments in hippocampus-dependent cognitive tasks. Transcriptomic analysis revealed marked transcriptional alterations enriched in pathways related to synaptic organization and plasticity following repeated propofol exposure. Consistently, Western blotting, transmission electron microscopy, and Golgi staining demonstrated pronounced reductions in dendritic spine density and synaptic integrity within the hippocampus. Moreover, aberrant microglial activation was observed in the hippocampus and was closely associated with synaptic degeneration and cognitive deficits. Importantly, pharmacological inhibition of microglial activation with minocycline effectively ameliorated propofol-induced cognitive impairment and synaptic degeneration. Collectively, these findings suggest that microglial activation is associated with hippocampal synaptic degeneration and cognitive deficits following repeated propofol exposure and may contribute to these pathological changes.<\/jats:p>","DOI":"10.3390\/ijms27146293","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T06:49:36Z","timestamp":1784184576000},"page":"6293","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Microglial Activation Is Associated with Hippocampal Synaptic Degeneration and Cognitive Deficits Following Repeated Propofol Exposure"],"prefix":"10.3390","volume":"27","author":[{"given":"Liyun","family":"Deng","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, China"},{"name":"Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Center of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7514-6528","authenticated-orcid":false,"given":"Mengchan","family":"Su","sequence":"additional","affiliation":[{"name":"Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Center of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, China"},{"name":"Department of Pain Management, West China Hospital, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, China"},{"name":"Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Center of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahui","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, China"},{"name":"Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Center of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3674-7947","authenticated-orcid":false,"given":"Guo","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, China"},{"name":"Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Center of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5322-6802","authenticated-orcid":false,"given":"Ruotian","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, China"},{"name":"Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Center of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5823-8247","authenticated-orcid":false,"given":"Chan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, China"},{"name":"Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Center of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1007\/s10877-021-00738-5","article-title":"Propofol detection for monitoring of intravenous anaesthesia: A review","volume":"36","author":"Ferrier","year":"2022","journal-title":"J. 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