Abstract
BACKGROUND Engrams are considered to be substrates for memory storage, and the adaptive plasticity remolding that switch engrams to an inaccessible state cause forgetting. The normal function of engrams is ensured by the crosstalk between neurons and microglia, the major immune cells in the brain implicated in synapse remodeling and memory processing. However, the cellular processes and molecular mediators between engrams and microglia underlying forgetting are poorly understood.
METHODS We utilized doxycycline (Dox)-dependent robust activity marking (RAM) system to label and manipulate DG engrams encoding contexture fear memory in mice. Combining optogenetics, microglia-specific transcriptomics, fluorescence in situ hybridization and spine morphology analysis, we investigated the potential mechanisms of information exchange between engrams and microglia mediating memory forgetting.
RESULTS The expression of Rac1 in dentate gyrus (DG) engrams upregulated memory encoding. Increased Rac1 activity in DG engrams accelerated forgetting, upregulated autophagy influx and the expression of autophagy protein 7 (Atg7). The elevated ATG7 expression in the engrams activated of DG microglia and promoted forgetting. In addition, the Toll-like receptor (TLR) signal in DG microglia was upregulated when overexpressing ATG7 or activating Rac1 in DG engrams, and mediated the ATG7-dependent synapse remodeling and Rac1-dependent forgetting.
CONCLUSIONS In this study, we found that Rac1 increases ATG7-dependent autophagy in DG engrams, which activated microglia via TLR2/4, to promote spine remodeling and forgetting. These results unravel a novel pathway mediating memory forgetting, and provide a potential therapeutic strategy in the treatment of cognitive disorders such as Alzheimer’s disease.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
This version focus on the mechanism of autophagy in DG engrams and microglia in mediating Rac1-induced forgetting, while the previous version focus on the pathological role of autophagy and Rac1 in age-dependent forgetting. This version removed the data in aged mice, while included the specific functional verification the of engrams label by RAM system.