This hypothesis proposes that activity-dependent CREB signaling creates spatially distinct complement vulnerability maps by differentially regulating CD55 and CD46 expression across synaptic populations. Low-activity synapses maintain high CREB1 phosphorylation through sustained calcium influx, driving transcription of CD55 and CD46 complement regulators via CRE-binding sites in their promoters. This creates complement-protected synaptic microenvironments where CD55 accelerates C3/C5 convertase decay and CD46 cofactors C3b/C4b cleavage, effectively blocking complement-mediated pruning. Conversely, high-activity synapses undergo CREB dephosphorylation through activity-dependent phosphatase cascades, leading to transcriptional downregulation of complement regulators. These complement-vulnerable synapses become preferential targets for C1q opsonization and microglial engulfment. The mechanism explains how synaptic activity history directly controls pruning susceptibility: weakly active excitatory synapses on distal dendrites lose complement protection through CREB inactivation, while strongly active perisomatic synapses maintain CREB-driven regulator expression.

This hypothesis proposes that activity-dependent CREB signaling creates spatially distinct complement vulnerability maps by differentially regulating CD55 and CD46 expression across synaptic populations. Low-activity synapses maintain high CREB1 phosphorylation through sustained calcium influx, driving transcription of CD55 and CD46 complement regulators via CRE-binding sites in their promoters. This creates complement-protected synaptic microenvironments where CD55 accelerates C3/C5 convertase decay and CD46 cofactors C3b/C4b cleavage, effectively blocking complement-mediated pruning. Conversely, high-activity synapses undergo CREB dephosphorylation through activity-dependent phosphatase cascades, leading to transcriptional downregulation of complement regulators. These complement-vulnerable synapses become preferential targets for C1q opsonization and microglial engulfment. The mechanism explains how synaptic activity history directly controls pruning susceptibility: weakly active excitatory synapses on distal dendrites lose complement protection through CREB inactivation, while strongly active perisomatic synapses maintain CREB-driven regulator expression. This creates an inverse relationship between synaptic strength and complement vulnerability, enabling activity-dependent circuit refinement. The system operates through competitive transcriptional programs where CREB occupancy at CD55/CD46 promoters determines local complement regulation, transforming neural activity patterns into molecular pruning maps that preserve functional connectivity while eliminating redundant synapses.