Microglia mediate forgetting via complement-dependent synaptic elimination

• Published in: Science (American Association for the Advancement of Science) Vol. 367; no. 6478; pp. 688 - 694
• Main Authors: Wang, Chao, Yue, Huimin, Hu, Zhechun, Shen, Yuwen, Ma, Jiao, Li, Jie, Wang, Xiao-Dong, Wang, Liang, Sun, Binggui, Shi, Peng, Wang, Lang, Gu, Yan
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 07.02.2020
• Subjects: Animals; Brain; CD55 Antigens; Circuits; Complement; Complement System Proteins - genetics; Complement System Proteins - physiology; Degradation; Depletion; Hippocampus; Hippocampus - physiology; Memory; Memory Disorders - immunology; Memory Disorders - physiopathology; Memory, Long-Term - physiology; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Microglia; Microglia - immunology; Microglia - physiology; Neurogenesis; Neurons; Phagocytosis; Retention, Psychology - physiology; Rewiring; Substrates; Synapse elimination; Synapses; Synapses - physiology
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aaz2288

Synapses between engram cells are believed to be substrates for memory storage, and the weakening or loss of these synapses leads to the forgetting of related memories. We found engulfment of synaptic components by microglia in the hippocampi of healthy adult mice. Depletion of microglia or inhibition of microglial phagocytosis prevented forgetting and the dissociation of engram cells. By introducing CD55 to inhibit complement pathways, specifically in engram cells, we further demonstrated that microglia regulated forgetting in a complement- and activity-dependent manner. Additionally, microglia were involved in both neurogenesis-related and neurogenesis-unrelated memory degradation. Together, our findings revealed complement-dependent synapse elimination by microglia as a mechanism underlying the forgetting of remote memories.