Science  07 Feb 2020: Vol. 367, Issue 6478, pp. 688-694 Microglia mediate forgetting via complement-dependent synaptic elimination Chao Wang, et.al. Institute of Neuroscience and Department of Neurology of the Second Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China. Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China. Department of Neurology of the First Affiliated Hospital, Interdisciplinary Institute of Neuroscience and Technology, Zhejiang University School of Medicine, Hangzhou 310029, China. Department of Neurobiology, Institute of Neuroscience, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China. Department of Psychiatry, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China. Institute of Neuroscience and Department of Neurology of the Second Affiliated Hospital, Mental Health Center, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China. Center for Neuroscience and Department of Neurology of the First Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China. Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China. Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, Hangzhou 310058, China. [paraphrase] 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. Memory is coded and allocated to engrams within related brain regions. Reactivation of engram cells is essential for memory recall, whereas failure in reactivation of engram cells leads to the forgetting of related memories. Synaptic connections between engram cells are believed to be substrates for memory storage. Circuit rewiring and synaptic reorganization may lead to loss or weakening of synaptic connections between engram cells, resulting in the forgetting of previously existing memories. For example, massive synaptic reorganization takes place in the dentate gyrus (DG) as continuously generated newborn neurons    integrate into the hippocampal neural circuit, which leads to the forgetting of hippocampus-dependent memories. Even in mature neurons, experience- and learning-dependent, dynamic remodeling of synapses occurs constantly throughout life, providing a potential mechanism for the erasure of stored memories in the synaptic connections of these cells. Microglia are not only important for pruning excessive synapses during postnatal brain development but are also involved in the dynamics of synapses in the adult brain. Because they survey the brain and play crucial roles in monitoring synapses and determining the wiring of the brain, microglia may affect the stability of synaptic connections within the neural circuits where memories are allocated. During postnatal development, microglia are involved in synaptic reorganization and circuitry refinement by synaptic pruning. In the hippocampal DG,    newborn neurons are continuously generated and integrate into the hippocampal neural circuits. This leads to drastic synaptic reorganization and circuit rewiring and the forgetting of hippocampus-dependent memories, especially during infanthood when massive neurogenesis is occurring within the DG. Synaptic connections in the brain are highly dynamic and variable in strength and connectivity. Our study shows that microglia eliminate synaptic components in the adult hippocampus, whereas depleting microglia or inhibiting phagocytosis of microglia prevents forgetting. This suggests that synapse elimination by microglia leads to dissociation of engrams and the forgetting of previously learned contextual fear memory. In the developing brain,    microglial engulfment of synapses  depends on the classical complement cascade. Disruption of the microglia-specific phagocytic pathway by knocking out complement components, such as C1q, C3, or CR3, results in sustained deficits in synaptic connectivity. C1q levels in the brain increase during aging, whereas C1q-deficient mice exhibit enhanced synaptic plasticity and less cognitive and memory decline when aged. Notably, our study showed that the C1q-dependent complement pathway is actively involved in synapse elimination by microglia in the healthy adult hippocampus. CD55 is a known inhibitor of complement pathways in the immune system and is expressed in neurons in response to chronic inflammation. We overexpressed CD55 to inhibit the complement pathways, specifically in engram cells, without affecting microglia or other neurons in the circuits, and we found that forgetting was prevented. This indicates that the elimination of synaptic structures by microglia in the DG of the healthy adult brain occurs in a complement-dependent manner. Moreover, inhibiting the activity of engram cells facilitates the forgetting of related memory, which could be blocked by depleting microglia or inhibiting complement pathways in engram cells. This indicates that synapse elimination by microglia is also activity-dependent, following similar rules in the developing brain, thus resulting in the erasure of less- active memories. Besides eliminating synapses, microglia have also been reported to be able to trigger long-term synaptic depression via AMPA receptor internalization, through activation of CR3, which may also contribute to forgetting. New neurons are continuously generated in the DG, providing a substrate for massive synaptic reorganization and circuit rewiring in this region. Newborn dentate granule neurons integrate into hippocampal neural circuits by competitively replacing existing synaptic connections formed by mature granule neurons, thus leading to the forgetting of hippocampal-dependent contextual fear memory. Our study shows that MEM-induced enhanced neurogenesis leads to increased synaptic engulfment by microglia, whereas depletion of microglia blocks facilitated memory forgetting induced by enhanced neurogenesis, suggesting that microglia contribute to neurogenesis-induced synaptic reorganization. Besides the rewiring of neural circuits caused by the continuous integration of newborn neurons, mature neurons  are also able to reorganize their connectivity. We found that depletion of microglia in the DG without neurogenesis or inhibition of complement pathways in CA1 engram cells prevents forgetting. This indicates that microglia-mediated synaptic reorganization is also happening in mature hippocampal neurons, thus leading to weakening or loss of connections between engram cells and the forgetting of encoded memories. This also suggests that, in species lacking adult neurogenesis, or in non-neurogenic brain regions such as the cortex,    microglia could be one major force contributing to synapse loss and forgetting. [end of paraphrase]