Galectin-3 in microglia mediates neuroinflammation-induced cognitive dysfunction via selective elimination of excitatory synapses in hippocampal CA1.

Microglia-mediated neuroinflammation is increasingly recognized as a contributor to neurodegenerative disease progression. However, how microglia contribute to neuroinflammation-induced cognitive dysfunction remains unclear. Galectin-3 (Gal-3) is a microglia-enriched lectin that regulates inflammatory signaling and phagocytosis, a plausible mediator linking neuroinflammation to cognitive dysfunction. In a lipopolysaccharide (LPS)-induced mouse model of neuroinflammation (0.5 mg/kg for 7 consecutive days), cognitive function was evaluated using the open field, Y-maze, and novel object recognition tests. In vivo CA1 extracellular electrophysiological recordings were used to analyze local field potentials (LFPs) and single-unit spiking activity. Dendritic morphology was evaluated by Golgi staining, and synaptic markers were quantified by immunofluorescence. In hippocampal CA1, microglia exhibited increased Gal-3 expression, enhanced phagocytic activity, and selectively increased engulfment of excitatory synapses. Systemic pharmacologic inhibition with TD139 and microglia-targeted Lgals3 knockdown (AAV-shLgals3 in Cx3cr1-CreERT2 mice) preserved excitatory synapses, restored CA1 gamma power, and improved cognitive performance in the neuroinflammation model. These results identify Gal-3-dependent microglial phagocytosis as a key mechanism linking neuroinflammation to cognitive dysfunction.