title: Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways.
abstract: 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.
authors.affiliation: Department of Neurobiology, Stanford University, School of Medicine, Stanford, CA 94305, USA.
authors.forename: Won-Suk
authors.initials: WS
authors.lastname: Chung
authors.affiliation: Department of Neurobiology, Stanford University, School of Medicine, Stanford, CA 94305, USA.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Clarke
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University, School of Medicine, Stanford, CA 94305, USA.
authors.forename: Gordon X
authors.initials: GX
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI 48105, USA.
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Stafford
authors.affiliation: Santa Cruz Institute of Particle Physic and Department of Physics, University of California, Santa Cruz, CA 95064.
authors.forename: Alexander
authors.initials: A
authors.lastname: Sher
authors.affiliation: Department of Neurobiology, Stanford University, School of Medicine, Stanford, CA 94305, USA.
authors.forename: Chandrani
authors.initials: C
authors.lastname: Chakraborty
authors.affiliation: Department of Neurobiology, Stanford University, School of Medicine, Stanford, CA 94305, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Joung
authors.affiliation: Institute of Molecular and Cell Biology, AStar, 61 Biopolis Drive, Proteos Building, Singapore 138673.
authors.forename: Lynette C
authors.initials: LC
authors.lastname: Foo
authors.affiliation: Children's Hospital, Harvard Medical School, 300 Longwood Ave., CLS12250, Boston, MA 02115.
authors.forename: Andrew
authors.initials: A
authors.lastname: Thompson
authors.affiliation: Children's Hospital, Harvard Medical School, 300 Longwood Ave., CLS12250, Boston, MA 02115.
authors.forename: Chinfei
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University, School of Medicine, Stanford, CA 94305, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Smith
authors.affiliation: Department of Neurobiology, Stanford University, School of Medicine, Stanford, CA 94305, USA.
authors.forename: Ben A
authors.initials: BA
authors.lastname: Barres
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D001921:Brain / Q000166:cytology; D066298:In Vitro Techniques; D020647:Lateral Thalamic Nuclei / Q000166:cytology / Q000378:metabolism; D007858:Learning / Q000502:physiology; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009434:Neural Pathways / Q000166:cytology / Q000378:metabolism*; D010587:Phagocytosis; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000502:physiology; D013569:Synapses / Q000378:metabolism*; D000076202:c-Mer Tyrosine Kinase
chemical_list: C525222:Megf10 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; C490767:Mertk protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase