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Nature. 2013 Dec 19;504(7480):394-400. doi: 10.1038/nature12776. Epub 2013 Nov 24.

Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways.

Author information

1
Department of Neurobiology, Stanford University, School of Medicine, Stanford, CA 94305, USA.
2
Department of Molecular and Cellular Physiology, Stanford University, School of Medicine, Stanford, CA 94305, USA.
3
Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI 48105, USA.
4
Santa Cruz Institute of Particle Physic and Department of Physics, University of California, Santa Cruz, CA 95064.
5
Institute of Molecular and Cell Biology, AStar, 61 Biopolis Drive, Proteos Building, Singapore 138673.
6
Children's Hospital, Harvard Medical School, 300 Longwood Ave., CLS12250, Boston, MA 02115.
#
Contributed equally

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.

PMID:
24270812
PMCID:
PMC3969024
DOI:
10.1038/nature12776
[Indexed for MEDLINE]
Free PMC Article
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