Scientific Understanding of Consciousness
Synapse Elimination via Astrocytes
Nature 504, 394–400 (19 December 2013)
Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways
Department of Neurobiology, Stanford University, School of Medicine, Stanford, California 94305, USA
Won-Suk Chung, Laura E. Clarke, Chandrani Chakraborty, Julia Joung & Ben A. Barres
Department of Molecular and Cellular Physiology, Stanford University, School of Medicine, Stanford, California 94305, USA
Gordon X. Wang & Stephen J. Smith
Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan 48105, USA
Benjamin K. Stafford
Santa Cruz Institute of Particle Physic and Department of Physics, University of California, Santa Cruz, California 95064, USA
Institute of Molecular and Cell Biology, A *Star, 61 Biopolis Drive, Proteos Building, 138673 Singapore
Lynette C. Foo
Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, CLS12250, Boston, Massachusetts 02115, USA
Andrew Thompson & Chinfei Chen
To achieve its precise neural connectivity, the developing mammalian nervous system undergoes extensive activity-dependent synapse remodelling. Recently, microglial cells have been shown to be responsible for a portion of synaptic pruning, but the remaining mechanisms remain unknown. Here we report a new role for astrocytes in actively engulfing central nervous system synapses. This process helps to mediate synapse elimination, requires the MEGF10 and MERTK phagocytic pathways, and is strongly dependent on neuronal activity. Developing mice deficient in both astrocyte pathways fail to refine their retinogeniculate connections normally and retain excess functional synapses. Finally, we show that in the adult mouse brain, astrocytes continuously engulf both excitatory and inhibitory synapses. These studies reveal a novel role for astrocytes in mediating synapse elimination in the developing and adult brain, identify MEGF10 and MERTK as critical proteins in the synapse remodelling underlying neural circuit refinement, and have important implications for understanding learning and memory as well as neurological disease processes.
Astrocytes constitute at least one-third of human brain cells, yet we do not completely understand their function. To understand their functions better, we previously performed gene expression analysis on purified mouse astrocytes and found that they are enriched in genes for phagocytic pathways, including two phagocytic receptors, Megf10 and Mertk. MEGF10 is an orthologue of Drosophila Draper and Caenorhabditis elegans CED-1 that help to mediate axon pruning by glia cells in flies and phagocytosis of apoptotic cells in nematodes. MEGF10 has also been shown to mediate phagocytosis in vitro and in vivo, and the function of MEGF10 requires other proteins, such as GULP1 and ABCA1. MERTK is a member of the MER/AXL/TYRO3 receptor kinase family that mediates shedding of the photoreceptor outer segment by retinal pigment epithelial cells. MERTK works with the integrin pathway to regulate CrKII/DOCK180/Rac1 modules in controlling rearrangement of the actin cytoskeleton on phagocytosis. Both MEGF10 and MERTK function as engulfment receptors by recognizing ‘eat me signals’, such as phosphatidylserine, presented in target debris. Because astrocytes highly express phagocytic receptors as well as all their other interacting proteins listed above, and one astrocyte has been shown to ensheath thousands of synapses, we reasoned that astrocytes mediate synapse elimination within the developing and adult central nervous system (CNS) through the MEGF10 and/or MERTK phagocytic pathways.
Synapses in the adult brain, especially dendritic spines, are dynamic structures that turn over rapidly during activity-dependent synaptic plasticity induced by learning and memory. Because MEGF10 and MERTK are highly localized to astrocytes in the adult CNS and not just the developing CNS, we next asked whether synapse engulfment and elimination by astrocytes persists in the adult CNS.
Our findings demonstrate that astrocytes actively contribute to the activity-dependent synapse elimination that mediates neural circuit refinement in the developing CNS by phagocytosing synapses via the MEGF10 and MERTK pathways, and that astrocytes continue to engulf synapses in the adult CNS. These findings reveal a previously unknown role for astrocytes, provide new information about the mechanisms underlying neural circuit refinement during development, and add to the growing evidence that substantial synapse turnover and remodelling occurs in the adult CNS. Astrocytes thus share with microglia the ability to actively engulf and eliminate synapses in response to neural activity, but synapse engulfment by astrocytes is independent of complement protein C1q, and uses distinct phagocytic pathways from microglia. Astrocytes in Drosophila also phagocytose synapses, indicating that the phagocytic function of astrocytes is evolutionarily conserved. These findings have important implications and raise many questions. How does neural activity control the rate of astrocyte-mediated synapse phagocytosis, do astrocytes and microglia phagocytose different synapse types or circuits, and how do astrocytes decide which synapses to engulf? Because MEGF10 and MERTK phagocytic receptors initiate the engulfment process by recognizing phosphatidylserine presented by target debris, an important question is whether the weak synapses that need to be eliminated present ‘eat me signals’ locally and if so what their identities are. Most notably, our findings suggest that the activity-dependent engulfment of synapses by astrocytes has an active role in continually remodelling the synaptic architecture of our brains. Whether such remodelling underlies learning and memory, and whether a declining rate of synapse engulfment by astrocytes throughout life could contribute to critical period plasticity during development or to synaptic senescence and neurodegeneration with ageing, are important questions for future study.
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