Alternatively, other complement-dependent and/or -independent mechanisms may be involved. For example, C3 could bind all synapses and only those synapses that are “stronger” or more active are selectively protected by membrane-bound complement regulatory molecules

(Kim and Song, 2006 and Song, 2006). In contrast, selective, activity-dependent elimination of synapses could be driven by a complement-independent mechanism which subsequently results in complement binding and/or microglia-mediated engulfment. For example, MHC class I molecules, another class of immune molecules demonstrated to play a critical role in retinogeniculate pruning, have been Ivacaftor chemical structure shown to be activity dependent, localized to synapses, and colocalized with C1q leaving the possibility that MHC class I molecules may play an upstream role in microglia-mediated pruning of synapses (Corriveau et al., 1998, Datwani et al., 2009, Goddard et al., 2007 and Huh et al., 2000). While our data demonstrate that CR3/C3 signaling specific to microglia http://www.selleckchem.com/products/OSI-906.html is involved in the pruning of developing circuits and suggest that engulfment is the underlying mechanism, CR3 and C3 may be acting through other pathways independent of phagocytosis or may be downstream of other

signaling pathways to mediate pruning. In addition, engulfment deficits in CR3 and C3 KO mice were reduced to approximately 50% of WT littermate control values, suggesting that other complement receptor-dependent (e.g., CR4, CRig, etc.) and independent phagocytic mechanisms may also be involved. Future studies will aim to address whether and how specific synapses are eliminated by complement and other microglia-dependent mechanisms and how neural activity plays a role in this process. Our data raise the question as to whether complement and/or microglia-dependent engulfment of synaptic inputs represents either a more global mechanism underlying CNS neural circuit plasticity. While in at

least one other developing system local axonal retraction and synapse elimination appear to occur independent of microglia (Cheng et al., 2010), recent work describes a role for microglia at developing hippocampal synapses (Paolicelli et al., 2011). In addition, in vivo imaging studies in the cortex revealed that microglia dynamics and interactions with neuronal compartments change in response to neural activity and experience (Davalos et al., 2005, Nimmerjahn et al., 2005, Tremblay et al., 2010a and Wake et al., 2009). While these studies describe microglia dynamics at synapses, a precise function and molecular mechanism(s) underlying microglia-synapse interactions in these brain regions was unknown. Our study provides mechanistic insight into the dynamic between microglia and developing synapses and provides complement-dependent signaling as a potential mechanism in other brain regions.