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Disruption of this event reshape hippocampal neural circuit architecture and heighten the risk for long\u2010term memory, learning, and behavioral deficits. Manganese (Mn), a widespread environmental contaminant, is recognized for neurodevelopmental toxicity and reported disrupting hippocampal synaptic integrity. Here, we report that early\u2010life Mn exposure impaired learning, long\u2010term memory, and behavioral performance in young adulthood male mice, accompanied by microglia excessive\u2010phagocytosis and aberrant hippocampal synaptic remodeling. Single\u2010nucleus transcriptomics, CUT&amp;Tag profiling collectively reveal that Mn exposure elevated the transcription factor Yin Yang 1 (YY1) expression in developing microglia and directly activated transcription of triggering receptor expressed on myeloid cells 2 (TREM2) and phagolysosomal pathway\u2010related genes, thereby driving excessive microglial phagocytosis. This heightened engulfment capacity led to over\u2010phagocytosis ultimately resulting in abnormal synaptic remodeling during critical developmental windows. Mechanistically, Mn\u2010induced YY1 accumulation may result from enhanced HIF1\u03b1\u2010mediated transcription and disrupted SMURF2\u2010dependent ubiquitin degradation. Together, our findings identified YY1\/TREM2 as an axis through which early\u2010life Mn exposure perturbed microglial homeostasis and induced maladaptive synaptic remodeling. These results provide mechanistic insight into neurodevelopmental consequences of Mn exposure and highlight potential molecular targets for potential early therapeutic intervention of neurological disorders.<\/jats:p>","DOI":"10.1002\/advs.78036","type":"journal-article","created":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T16:21:11Z","timestamp":1791130871000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Early\u2010Life Manganese Overexposure Activates Microglial Phagocytosis through the YY1\/TREM2 Axis Leading to Hippocampal Synaptic Remodeling in Mice"],"prefix":"10.1002","author":[{"given":"Keyu","family":"Chen","sequence":"first","affiliation":[{"name":"Program of Environmental Physical Factors and Health School of Public Health China Medical University  Shenyang Liaoning P. R. 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