Early‐Life Manganese Overexposure Activates Microglial Phagocytosis through the YY1/TREM2 Axis Leading to Hippocampal Synaptic Remodeling in Mice

Abstract

ABSTRACT The early‐stage hippocampal development depends on precise synaptic remodeling, processes where microglia play indispensable roles. Disruption of this event reshape hippocampal neural circuit architecture and heighten the risk for long‐term 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‐life Mn exposure impaired learning, long‐term memory, and behavioral performance in young adulthood male mice, accompanied by microglia excessive‐phagocytosis and aberrant hippocampal synaptic remodeling. Single‐nucleus transcriptomics, CUT&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‐related genes, thereby driving excessive microglial phagocytosis. This heightened engulfment capacity led to over‐phagocytosis ultimately resulting in abnormal synaptic remodeling during critical developmental windows. Mechanistically, Mn‐induced YY1 accumulation may result from enhanced HIF1α‐mediated transcription and disrupted SMURF2‐dependent ubiquitin degradation. Together, our findings identified YY1/TREM2 as an axis through which early‐life 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.