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.

144 Reads
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: If "the connectome" represents a complete map of anatomical and functional connectivity in the brain, it should also include glia. Glia define and regulate both the brain's anatomical and functional connectivity over a broad range of length scales, spanning the whole brain to subcellular domains of synaptic interactions. This Perspective article examines glial interactions with the neuronal connectome (including long-range networks, local circuits, and individual synaptic connections) and highlights opportunities for future research. Our understanding of the structure and function of the neuronal connectome would be incomplete without an understanding of how all types of glia contribute to neuronal connectivity and function, from single synapses to circuits. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 04/2015; 86(2):374-386. DOI:10.1016/j.neuron.2015.01.014 · 15.05 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Astrocytes, through their close associations with synapses, can monitor and alter synaptic function, thus actively controlling synaptic transmission in the adult brain. Besides their important role at adult synapses, in the last three decades a number of critical findings have highlighted the importance of astrocytes in the establishment of synaptic connectivity in the developing brain. In this article, we will review the key findings on astrocytic control of synapse formation, function, and elimination. First, we will summarize our current structural and functional understanding of astrocytes at the synapse. Then, we will discuss the cellular and molecular mechanisms through which developing and mature astrocytes instruct the formation, maturation, and refinement of synapses. Our aim is to provide an overview of astrocytes as important players in the establishment of a functional nervous system. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.
    Cold Spring Harbor perspectives in biology 02/2015; 7(9). DOI:10.1101/cshperspect.a020370 · 8.68 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The ubiquitin proteasome system (UPS) is crucial for intracellular protein homeostasis and for degradation of aberrant and damaged proteins. The accumulation of ubiquitinated proteins is a hallmark of many neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer's, Parkinson's, and Huntington's disease, leading to the hypothesis that proteasomal impairment is contributing to these diseases. So far, most research related to the UPS in neurodegenerative diseases has been focused on neurons, while glial cells have been largely disregarded in this respect. However, glial cells are essential for proper neuronal function and adopt a reactive phenotype in neurodegenerative diseases, thereby contributing to an inflammatory response. This process is called reactive gliosis, which in turn affects UPS function in glial cells. In many neurodegenerative diseases, mostly neurons show accumulation and aggregation of ubiquitinated proteins, suggesting that glial cells may be better equipped to maintain proper protein homeostasis. During an inflammatory reaction, the immunoproteasome is induced in glia, which may contribute to a more efficient degradation of disease-related proteins. Here we review the role of the UPS in glial cells in various neurodegenerative diseases, and we discuss how studying glial cell function might provide essential information in unraveling mechanisms of neurodegenerative diseases.
    Frontiers in Molecular Neuroscience 08/2014; 7:73. DOI:10.3389/fnmol.2014.00073 · 4.08 Impact Factor
Show more