Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways

By Won-Suk Chung, L. Clarke, Gordon X. Wang, Benjamin K. Stafford, Alexander Sher, C. Chakraborty, Julia Joung, L. Foo, Andrew Thompson, Chinfei Chen and 2 more. Nature, 2013

1,243 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/49ae16d8a642c6ccdf19f0d707057b5705f04c38

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

1. M. Sofroniew
2. M. Pekny
3. C. Eroglu
4. M. Pekna
5. J. Burda
6. N. J. Allen
7. Maiken Nedergaard
8. Alexei Verkhratsky

In Molecular Biology

1. M. Sofroniew
2. M. Pekny
3. M. Pekna
4. Maiken Nedergaard
5. B. Barres
6. N. J. Allen
7. J. Burda
8. Irving L. Weissman

In Neurology

1. M. Sofroniew
2. M. Pekny
3. M. Pekna
4. J. Burda
5. C. Eroglu
6. N. J. Allen
7. Maiken Nedergaard
8. Alexei Verkhratsky

Citations in the corpus

• Physiology of Astroglia. (2018, positive): “That astrocytes are capable of synapse elimination in vitro and in vivo was confirmed by the same group in a later study (334), and it has been hypothesized that disruption of the ability of astrocytes and microglia to eliminate and regulate synapse formation contributes to the pathogenesis of psych”
• Transcellular degradation of axonal mitochondria (2014, background): “Recently, astrocytes have been shown to phagocytose whole synapses elsewhere in the visual pathway (11).”
• Astrocyte reactivity and reactive astrogliosis: costs and benefits. (2014, background): “Although it is currently unknown which mechanisms regulate the expression of C1q in microglia in the context of chronic neurodegeneration or in the normal aging brain (227), the involvement of reactive astrocytes is not unlikely, not least in the light of increased expression of GFAP, a hallmark of ”
• Astrocytes Control Synapse Formation, Function, and Elimination (2015, positive): “…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).”
• Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and CNS inflammation via the aryl hydrocarbon receptor (2016, neutral): “pSOCS:AhR(1) forward, 5′CCAGCTCCCTACCTGTTTGA-3′, and reverse, 5′-GGAATGGAGCGGACAGGA-3′; pSOCS2:AhR(2) forward, 5′-ATGAGTCAACACGTCCCAGA-3′, and reverse, 5′CTGCACACTCTCGTTTTGGG-3′, pSOCS2:AhR(3), forward, 5′TGGCAAAGTCTCTCGCAGA-3′, and reverse, 5′-TGCTCGGGGTTAAATGGTAC-3′.”
• Astrocytes: a central element in neurological diseases (2016, background): “This process is governed by neuronal activity, and requires expression of phagocytic receptors MEGF10 and MERTK [40].”
• Glial fibrillary acidic protein (GFAP) and the astrocyte intermediate filament system in diseases of the central nervous system. (2015, background): “They are indispensable for proper brain development [5 ,6 ,7 ,8], play fundamental roles in maintaining ion, neurotransmitter, water [9] and energy homeostasis [10], and modulate neuronal signaling [11,12].”
• Major depressive disorder: hypothesis, mechanism, prevention and treatment (2024, background): “221,222 Under physiological conditions, microglia can play a neuroprotective role by producing cytokines.”
• The Aging Astrocyte Transcriptome from Multiple Regions of the Mouse Brain (2018, background): “, 2011) and by eliminating excess synapses by phagocytosis using the receptors Mertk and Megf10 and indirectly by inducing expression of complement cascade components in neurons (Bialas and Stevens, 2013; Chung et al., 2013; Stevens et al., 2007).”
• Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse (2015, positive): “Furthermore, a phagocytic receptor required for astrocyte-mediated synapse elimination, MERTK (Chung et al., 2013), is not expressed by fetal astrocytes but later turns on and reaches peak levels around 6 months to 1 year of age.”
• iPSC-derived human microglia-like cells to study neurological diseases (2017, neutral): “As iMGLs and primary microglia express both C1q and CR3 (CD11b/CD18 dimer), we used iMGLs to assess whether synaptic pruning in human microglia primarily involves this pathway as seen in mice (Chung et al., 2013).”