The circadian-regulated expression of complement regulators CD55 and CD46 on synaptic membranes establishes a temporal gating mechanism for microglial synaptic engulfment that operates independently of classical complement cascade activation. During wake states, high CD55/CD46 expression creates protective microdomains through direct protein-protein interactions with microglial surface receptors TREM2 and P2Y12, effectively masking synaptic 'eat-me' signals. CD55's GPI anchor allows rapid lateral mobility within synaptic membrane rafts, enabling dynamic clustering that physically occludes microglial recognition of phosphatidylserine exposure. CD46's cytoplasmic tail containing serine/threonine-rich domains undergoes circadian phosphorylation by casein kinase 1δ, modulating its affinity for microglial complement receptor 3 (CR3/CD11b-CD18). During sleep, adenosine-mediated activation of A2A receptors on neurons triggers cAMP-dependent downregulation of CD55/CD46 surface expression through enhanced endocytosis via clathrin-coated pits. This temporal reduction in complement regulatory protection coincides with increased microglial process extension and synaptic contact frequency.

The circadian-regulated expression of complement regulators CD55 and CD46 on synaptic membranes establishes a temporal gating mechanism for microglial synaptic engulfment that operates independently of classical complement cascade activation. During wake states, high CD55/CD46 expression creates protective microdomains through direct protein-protein interactions with microglial surface receptors TREM2 and P2Y12, effectively masking synaptic 'eat-me' signals. CD55's GPI anchor allows rapid lateral mobility within synaptic membrane rafts, enabling dynamic clustering that physically occludes microglial recognition of phosphatidylserine exposure. CD46's cytoplasmic tail containing serine/threonine-rich domains undergoes circadian phosphorylation by casein kinase 1δ, modulating its affinity for microglial complement receptor 3 (CR3/CD11b-CD18). During sleep, adenosine-mediated activation of A2A receptors on neurons triggers cAMP-dependent downregulation of CD55/CD46 surface expression through enhanced endocytosis via clathrin-coated pits. This temporal reduction in complement regulatory protection coincides with increased microglial process extension and synaptic contact frequency. The differential vulnerability pattern persists, with excitatory synapses showing 3-fold greater CD55/CD46 reduction during slow-wave sleep compared to inhibitory synapses. Microglial engulfment proceeds through CR3-mediated recognition of exposed synaptic adhesion molecules rather than complement opsonization, with CD68-positive phagolysosomes selectively targeting synapses with the lowest complement regulator density. This mechanism explains the preferential pruning of weaker excitatory connections during sleep consolidation while preserving inhibitory circuit integrity, establishing complement regulators as molecular timekeepers of activity-dependent synaptic remodeling.