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Astrocytes Phagocytose Synapses for Circuit Homeostasis Astrocytes phagocytose adult hippocampal synapses for circuit homeostasis Lee, et. al, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea Research Group for Neurovascular Unit, Korea Brain Research Institute (KBRI), Daegu, Republic of Korea Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Republic of Korea Research Group for Neural Circuit, Korea Brain Research Institute (KBRI), Daegu, Republic of Korea [paraphrase] In the adult hippocampus, synapses are constantly formed and eliminated. However, the exact function of synapse elimination in the adult brain, and how it is regulated, are largely unknown. Here we show that astrocytic phagocytosis3 is important for maintaining proper hippocampal synaptic connectivity and plasticity. By using fluorescent phagocytosis reporters, we find that excitatory and inhibitory synapses are eliminated by glial phagocytosis in the CA1 region of the adult mouse hippocampus. Unexpectedly, we found that astrocytes have a major role in the neuronal activity-dependent elimination of excitatory synapses. Furthermore, mice in which astrocytes lack the phagocytic receptor MEGF10 show a reduction in the elimination of excitatory synapses; as a result, excessive but functionally impaired synapses accumulate. Finally, Megf10-knockout mice show defective long-term synaptic plasticity and impaired formation of hippocampal memories. Together, our data provide strong evidence that astrocytes eliminate unnecessary excitatory synaptic connections in the adult hippocampus through MEGF10, and that this astrocytic function is crucial for maintaining circuit connectivity and thereby supporting cognitive function. Adult synapses constantly undergo synaptic turnover1,2 during experience-dependent plasticity and cognitive functions. However, it is unclear how synapses in the adult brain are eliminated and whether synapse elimination has a direct role in circuit homeostasis. Astrocytes eliminate synapses by phagocytosis during postnatal development3. By phagocytosing synapses through the MEGF10 and MERTK phagocytic receptors, astrocytes actively contribute to activity-dependent synapse pruning and developmental refinement of circuits. Moreover, contrary to the previous notion that microglia are the sole mediators of synapse elimination, astrocytes have been shown to have a major role in eliminating synapses in developing brains. On the basis of these findings, we hypothesized that synapses in the adult brains are also refined by astrocytic phagocytosis, and that such elimination is critical for maintaining circuit homeostasis. Hippocampal memory traces are thought to be stored transiently and to disappear after several weeks. Moreover, connectivity patterns in the adult CA1 undergo nearly full erasure in about 3–6 weeks, which suggests that there must be a mechanism to control such rapid synaptic turnover and re-patterning of connectivity. As we found that astrocytes, but not microglia, constantly eliminate excess synaptic connections, astrocytic phagocytosis may contribute to the rapid renewal of synaptic memory traces in the adult hippocampus. Our findings have important implications and raise interesting questions—for example, how MEGF10 eliminates unnecessary excitatory synapses, but not inhibitory ones, in response to neuronal activity; and whether the capacity of astrocytic phagocytosis changes during ageing or in neurological diseases. Brains with excessive synaptic connectivity can show disrupted synaptic plasticity and cognitive functions. Therefore, it is possible that restoring the constant refinement of synaptic connectivity by modulating MEGF10 may be a novel strategy for the treatment of brain disorders that involve synaptopathologies. [end of paraphrase]
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