Abstract
Microglia are highly motile glial cells that are proposed to mediate synaptic pruning during neuronal circuit formation. Disruption of signaling between microglia and neurons leads to an excess of immature synaptic connections, thought to be the result of impaired phagocytosis of synapses by microglia. However, until now the direct phagocytosis of synapses by microglia has not been reported and fundamental questions remain about the precise synaptic structures and phagocytic mechanisms involved. Here we used light sheet fluorescence microscopy to follow microglia–synapse interactions in developing organotypic hippocampal cultures, complemented by a 3D ultrastructural characterization using correlative light and electron microscopy (CLEM). Our findings define a set of dynamic microglia–synapse interactions, including the selective partial phagocytosis, or trogocytosis (trogo-: nibble), of presynaptic structures and the induction of postsynaptic spine head filopodia by microglia. These findings allow us to propose a mechanism for the facilitatory role of microglia in synaptic circuit remodeling and maturation.
Highlights
Microglia are highly motile glial cells that are proposed to mediate synaptic pruning during neuronal circuit formation
These findings indicate that the second postnatal week of mouse hippocampal development is likely to be a period of active microglia phagocytosis and suggested that this period may be most relevant to search for evidence of phagocytic elimination of synapses by microglia
Immunoreactivity for postsynaptic density 95 (PSD95) protein was found to be localized inside microglia by confocal, super-resolution, and electron microscopy[8]
Summary
Microglia are highly motile glial cells that are proposed to mediate synaptic pruning during neuronal circuit formation. Our findings define a set of dynamic microglia–synapse interactions, including the selective partial phagocytosis, or trogocytosis (trogo-: nibble), of presynaptic structures and the induction of postsynaptic spine head filopodia by microglia These findings allow us to propose a mechanism for the facilitatory role of microglia in synaptic circuit remodeling and maturation. These data, combined with the known phagocytic capacity of myeloid cells, led to the hypothesis that microglia may have a role in the phagocytic elimination of synapses as part of the widespread pruning of exuberant synaptic connections during development[6,7] This hypothesis was supported by two studies that reported the selective engulfment of synaptic structures by microglia and the appearance of excess immature synapses in mice lacking either the fractalkine[8] (Cx3cl1/Cx3cr1) or complement component[9] (C1q/C3/CR3) microglia signaling pathways. Our findings provide the first direct evidence for the elimination of synaptic material by microglia in living brain tissue and suggest that microglia facilitate circuit maturation by a combination of trogocytosis of the axonal compartment and the remodeling of postsynaptic sites
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