Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways

Department of Neurobiology, Stanford University, School of Medicine, Stanford, California 94305, USA.
Nature (Impact Factor: 41.46). 11/2013; 504(7480). DOI: 10.1038/nature12776
Source: PubMed


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.

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    • "Astrocytes also promote synapse formation, influence synapse stability, and help refine neural connectivity. Astrocytes participate during development in the formation of synaptic networks by regulating synaptogenesis (Molofsky et al., 2012; Allen et al., 2012; Eroglu et al., 2009) and by pruning synaptic spines (Chung et al., 2013). Very little information is available on the important question of how these activities are carried out in a region-restricted manner by astrocyte heterogeneity. "
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    Neuron 04/2015; 86(2):374-386. DOI:10.1016/j.neuron.2015.01.014 · 15.05 Impact Factor
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    • "Previous studies have shown that eye-specific segregation in the dLGN is regulated by spontaneous retinal waves, which are bursts of action potentials that spread across large regions of the RGC layer and occur before eye opening (Penn et al. 1998; Huberman et al. 2002; Stellwagen and Shatz 2002; Feller 2009). Interestingly, synapse-elimination processes by astrocytes are strongly dependent on neural activity , because blocking spontaneous retinal waves in both eyes significantly reduces astrocyte-mediated phagocytosis of bilateral synaptic inputs, whereas selective blocking of activity in only one eye induces preferential engulfment of the silenced synapses by astrocytes (Chung et al. 2013). Therefore, astrocytes actively contribute to neural activity – dependent synapse pruning and elimination that mediates neural circuit refinement by phagocytosing unwanted synapses through MEGF10 and MERTK path- ways. "
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    Cold Spring Harbor perspectives in biology 02/2015; 7(9). DOI:10.1101/cshperspect.a020370 · 8.68 Impact Factor
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    • "This phagocytosis of synapses is dependent on neuronal activity and is mediated via the Mertk and Megf10 pathways. Thus, astrocytes actively contribute to activity-dependent synapse elimination and CNS remodeling (Chung et al., 2013). Next to the phagocytosis of synapses, activated astrocytes are able to phagocytize amyloid β deposits in vitro and in situ (Wyss-Coray et al., 2003). "
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