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 remodeling. Recently microglial cells have been shown to be responsible for a portion of synaptic remodeling, but the remaining mechanisms remain mysterious. Here we report a new role for astrocytes in actively engulfing CNS 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 normally refine their retinogeniculate connections and retain excess functional synapses. Lastly, 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 players in the synapse remodeling underlying neural circuit refinement, and have important implications for understanding learning and memory as well as neurological disease processes.

Activity-Dependent Structural Plasticity of Perisynaptic Astrocytic Domains Promotes Excitatory Synapse Stability

“…Thus, a low PAP motility favors spine persistence. Interestingly, it was recently found that increased synaptic activity could promote engulfment and elimination of excitatory synapses by astrocytic processes [20]. Although PAP motility was not specifically assessed in these experiments, this suggests that astrocytic processes, depending on their level of activation and interaction with synapses, could contribute either to spine pruning and elimination or to long-term spine persistence.…”

“…However, other studies have also proposed different mechanisms to account for a contribution of astrocytes to plasticity and memory [17,18]. Additionally, recent studies also suggest that astrocytes could participate, during development, in the formation of synaptic networks by regulating synaptogenesis [19] and spine pruning [20]. Altogether, these data indicate an important functional role of astrocytes in their interactions with synapses, despite a lack of clear mechanistic insight.…”

Phagocytic clearance of presynaptic dystrophies by reactive astrocytes in Alzheimer's disease

“…Furthermore, our finding of reactive astrocytes actively enwrapping, internalizing and further degrading presynaptic dystrophies in the APP/PS1 mouse brain is an extension of the capacity of astrocytes to phagocytose synapses as a normal process that mediates the refinement of neural circuits in the developing (Chung, Allen, & Eroglu, 2015) and in the adult CNS (Chung et al, 2013), thus suggesting a major role of astrocytes in synaptic pruning in health and disease. Supporting a phagocytic role for reactive astrocytes in AD, it has been suggested that they could mediate Aβ clearance (Osborn et al, 2016) and limit amyloid deposits (Xiao et al, 2014) since these glial cells express many potential phagocytic receptors that bind Aβ (Jones, Minogue, Connor, & Lynch, 2013; Sokolowski & Mandell, 2011).…”

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

“…Recently, direct evidence implicating CXCL12/SDF1 in preclinical models of anxiety and other neuropsychiatric disorders have been published (Guyon, 2014;Yang et al, 2016). Astrocytes have recently been implicated to have a role in synaptic elimination during brain development in a manner similar to the role played by the microglia in developmental pruning (Chung et al, 2013).…”