Autophagy in DG engrams mediates Rac1-dependent forgetting during aging via microglia-mediated synapse elimination

Abstract

AbstractEngrams are considered to be substrates for memory storage, and the functional dysregulation of the engrams leads to cognition impairment. However, the pathological changes of the engrams leading to forgetting, which typically involves a failure in memory retrieval, remains unclear. Here we found that the expression of autophagy protein 7 (Atg7) in dentate gyrus (DG) engrams was dramatically increased in aged mice, leading to the activation of surrounding microglia and impair retrieval of conditioned fear memory. Using transcriptomic and fluorescence in situ hybridization analyses, we demonstrated Toll-like receptor (TLR) pathway were upregulated in DG microglia by overexpressing ATG7 in DG engrams. TLR2/4 in the microglia mediates the excessive synapse elimination and impaired retrieval of fear memory induced by ATG7-depedent autophagy in DG engrams. The expression of Rac1, a Rho-GTPases which mediates active forgetting, was upregulated in aged engrams. Optogenetic activation of Rac1 in DG engrams promoted the expression of ATG7 and autophagy in the engrams, the activation of microglia, and thus impaired the retrieval of fear memory. Interference of the Atg7 expression in the engram and microglia activation prevented the impairment of fear memory retrieval induced by activation of Rac1 in DG engrams. Together, our findings revealed autophagy-dependent remodeling of DG engrams by microglia as a novel interference mechanism of memory retrieval.