A TMEM119-tankyrase axis restrains microglial phagocytosis to maintain memory and enables pharmacological forgetting.

Abstract

The persistence or loss of memory depends on the stability of synaptic connections. Microglia regulate this stability in part by phagocytic elimination of synapses, while the molecular mechanism that sets their intrinsic phagocytic capacity at homeostasis remains unknown. Here, we show that TMEM119, a microglia-specific transmembrane protein, functions as a constitutive cell-intrinsic brake on microglial surveillance dynamics and phagocytosis. Mechanistically, TMEM119 sequesters tankyrase, preventing axin degradation, thereby limiting the pool of free adenomatous polyposis coli protein available to nucleate actin assembly and drive phagocytosis. In adult mice, acute ablation of TMEM119 from microglia exaggerates synapse elimination and destabilizes established fear memories. These effects are recapitulated by a membrane-permeable peptide that enters microglia in the brain after intravenous delivery to competitively disrupt TMEM119-tankyrase association. Our results identify the TMEM119-tankyrase-axin axis as a pharmacologically accessible rheostat of microglial phagocytosis and establish a new framework for memory manipulation.