fig4: Microglia refine circuits by complement-mediated phagocytosis of weak synapses. Schematic of retinogeniculate connectivity in wild-type (A) and complement receptor CR3 knockout (B) animals. Inputs from each eye are completely segregated in the LGNs of wild-type animals (A, separate blue and green regions). Synaptic debris from inappropriate connections is observed within local microglia (brown cells) during the pruning process. In CR3 knockout animals (B), segregation of inputs in the LGN is incomplete, resulting in regions with overlapping inputs from both eyes (blue/green regions). Significantly less synaptic debris is observed in microglia in these animals. (C) Proposed model for complement-dependent synaptic pruning by microglia. Weak synapses are tagged for elimination by recruitment of the classical complement molecule C1q. C1q can recruit and activate C3, which then serves as a ligand for the CR3 receptor (expressed exclusively by microglia) to recruit microglia to clear the synapse. How C1q and C3 are localized to and activated at weak synapses is still unknown.

Mentions: Evidence of synaptic elements contained within microglia cytoplasm combined with the known role of microglia as phagocytes, and a report implicating the classical complement cascade with synaptic pruning provided highly suggestive evidence that microglia were involved in activity-dependent synapse elimination via phagocytosis (Stevens et al., 2007; Tremblay et al., 2010; Paolicelli et al., 2011; Schafer et al., 2012). In an elegant study, Schafer et al. (2012) used the mammalian retinogeniculate system to clearly demonstrate the in vivo role for microglia in mediating activity-dependent synaptic pruning that relies on signaling from the classical complement system. This circuit undergoes a well-characterized period of robust activity-dependent synaptic elimination during postnatal development with a clear readout. RGC axons from both eyes form synapses in the lateral geniculate nucleus (LGN) of the thalamus. Due to exuberant connectivity, distinct ipsilateral and contralateral eye domains are poorly defined until approximately postnatal day 5, at which point activity-dependent synaptic pruning results in clearly segregated eye-specific domains (Fig. 4 A). Injecting unique fluorescent anterograde tracers in each eye labels RGC axons and synapses independently, allowing a clear readout of the success of activity-dependent synaptic pruning (Huberman et al., 2008). GFP-expressing microglia in the LGN were closely associated with synapses, and were often found with tracer-labeled presynaptic membrane within their processes and soma during the period (∼P5) of robust synaptic pruning, similar to previous findings in the developing cortex and hippocampus (Tremblay et al., 2010; Paolicelli et al., 2011).