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Microglia mediate forgetting via complement-dependent synaptic elimination

Microglia modulate memories Synaptic reorganization and circuit rewiring leads to loss or weakening of connections between neurons and may result in the erasure of previously formed memories. Microglia eliminate excessive synapses in the developing brain and regulate the dynamics of synaptic connections between neurons throughout life. However, it is still unclear whether forgetting is related to microglia activity and how microglia regulate memory erasure in the adult brain. Wang et al. discovered that microglia eliminated synaptic components in the adult hippocampus and that depleting microglia or inhibiting phagocytosis of microglia prevented forgetting. Synapse elimination by microglia may thus lead to degradation of memory engrams and forgetting of previously learned contextual fear memory. Science, this issue p. 688 Elimination of synapses in the mouse brain by microglia mediates dissociation of engram cells and forgetting of previously learned memories. 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.