” Although it is not yet known whether or how microglia target sp

” Although it is not yet known whether or how microglia target specific “weaker” synapses, these data are consistent with previous work demonstrating that such a competition results in decreased territory of the “weaker” inputs and increased territory of “stronger” inputs within the dLGN (Del Rio and Feller, 2006, Huberman et al., 2008, McLaughlin selleck chemicals et al., 2003, Penn et al., 1998, Shatz, 1990, Shatz and Stryker, 1988, Stellwagen and Shatz, 2002, Stellwagen et al., 1999 and Torborg and Feller, 2005). In the retina, spontaneous, correlated neuronal activity from both eyes (i.e., retinal waves) drives the elimination of synapses and segregation of inputs into eye-specific

territories in the dLGN (Del Rio and Feller, 2006, ZD1839 Feller, 1999, Huberman et al., 2008, McLaughlin et al., 2003, Penn et al., 1998, Stellwagen

and Shatz, 2002 and Torborg and Feller, 2005). Interestingly, complement and complement receptor-deficient mice have similar pruning deficits to mice in which this correlated firing has been disrupted (e.g., cAMP-analog injection, β2nAChR−/− mice, etc.) ( Stevens et al., 2007), suggesting the intriguing possibility that complement cascade activation and function is regulated by neural activity. Neural activity could also directly regulate microglia function (i.e., activation, recruitment, phagocytic capacity) Astemizole through complement-independent mechanisms. Alternatively, neural activity may drive the elimination of synapses by other mechanisms which ultimately lead to complement activation and/or microglia-mediated

engulfment. Future studies will aim to address how neural activity, complement, and microglia may interact to contribute to developmental synaptic pruning ( Figure S7). Synaptic pruning likely involves several mechanisms that cooperatively interact to establish precise synaptic circuits. We suggest that microglia may be a common link and identify CR3/C3 signaling as one pathway underlying microglia-synapse interactions and microglia-dependent pruning in the developing CNS. One of the major questions raised by these findings is precisely how secreted complement proteins mediate the selective elimination of synapses by microglia. In the immune system, C3 is cleaved into an activated form, iC3b, which covalently binds to the surface of cells or debris and targets them for elimination by macrophages via specific phagocytic receptor signaling (e.g., CR3) (Lambris and Tsokos, 1986 and van Lookeren Campagne et al., 2007). Similar to the immune system, we propose that activated C3 (iC3b/C3b) could selectively “tag” weak synapses (Figure S7). Consistent with C3 “tagging” subsets of RGC terminals, previous confocal analysis revealed colocalization of C3 with pre and postsynaptic markers in the developing dLGN (Stevens et al., 2007).

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