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Due to unclear mechanisms, effective treatments for cognitive deficits are lacking. Here, we examined if microglia\u2010mediated deficits in synaptic plasticity drive CRCI. Adult male mice were treated with the chemotherapeutic drugs 5\u2010fluorouracil and leucovorin (5\u2010Fu\/LV, intraperitoneal injection, I.P.) on Days 1, 8, and 15 at a dosage of 50\u2009mg\/kg for 5\u2010Fu and 90\u2009mg\/kg for LV for 3\u2009weeks. Cognitive function was assessed using a novel object recognition (NOR) test 4\u2009weeks after completion of 5\u2010Fu\/LV treatment. Compared with vehicle treatment, 5\u2010Fu\/LV treatment reduced the preference for exploring novel objects in the NOR test. Treatment with 5\u2010Fu\/LV increased the numbers of Iba1\u2010positive microglial and CD68\u2010positive\/Iba1\u2010positive microglia with shortened process lengths and diminished endpoints but decreased the number of phagocytotic (\u2264\u20091 FITC\u2010labeled beads) Iba1\u2010positive microglia. Furthermore, 5\u2010Fu\/LV treatment reduced the long\u2010term potentiation (LTP) recorded in the hippocampal CA1 region in response to a theta burst stimulation of the CA3\u2010CA1 pathway and decreased the evoked N\u2010methyl\u2010D\u2010aspartic acid receptor (NMDAR)\u2010excitatory postsynaptic currents (NMDAR\u2010EPSCs) in CA1 neurons. Cotreatment with the microglial inhibitor minocycline (33\u2009mg\/kg, daily for 3\u2009weeks) restored cognitive deficits and microglial ramification, decreased the number of CD68\u2010positive microglia, and reversed the reductions in LTP and the amplitude of NMDAR\u2010EPSCs in 5\u2010Fu\/LV\u2010treated mice. Our data suggest that microglial dysfunction and related synaptic dysfunction contribute to 5\u2010Fu\/LV\u2010induced cognitive impairment.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70024-fig-0007-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.70024","type":"journal-article","created":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T03:35:24Z","timestamp":1740972924000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Microglia\u2010Mediated Synaptic Dysfunction Contributes to Chemotherapy\u2010Related Cognitive Impairment"],"prefix":"10.1111","volume":"169","author":[{"given":"Jingxiong","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Medicine University of Missouri\u2010Columbia School of Medicine  Columbia Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Missouri\u2010Columbia School of Medicine  Columbia Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Augenreich","sequence":"additional","affiliation":[{"name":"Department of Medical Pharmacology and Physiology University of Missouri\u2010Columbia School of Medicine  Columbia Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Martinez\u2010Lemus A","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Missouri\u2010Columbia School of Medicine  Columbia Missouri USA"},{"name":"Department of Medical Pharmacology and Physiology University of Missouri\u2010Columbia School of Medicine  Columbia Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenguo","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Missouri\u2010Columbia School of Medicine  Columbia Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xunlei","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Missouri\u2010Columbia School of Medicine  Columbia Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, NextGen Precision Health University of Missouri\u2010Columbia School of Medicine  Columbia Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui\u2010Ming","family":"Chang","sequence":"additional","affiliation":[{"name":"Departments of Pharmacology and Internal Medicine The University of Arkansas for Medical Sciences  Little Rock Arkansas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward T. 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