This hypothesis proposes that the CREB1-BDNF-TrkB activity-dependent transcriptional machinery directly controls the spatial expression patterns of complement regulators CD55 and CD46, creating synaptic vulnerability maps that determine which synapses are targeted for complement-mediated pruning. The mechanism operates through activity-dependent CREB1 phosphorylation at serine 133, which initiates transcription of both BDNF and complement regulator genes containing CRE sites. High-activity synapses with robust CREB activation maintain elevated CD55/CD46 expression, protecting them from complement attack through accelerated C3/C5 convertase decay and factor I-mediated C3b/C4b cleavage. Conversely, low-activity synapses exhibit reduced CREB-mediated transcription, leading to diminished CD55/CD46 surface density and increased complement vulnerability. This creates a molecular tagging system where synaptic activity history directly determines complement susceptibility. The BDNF-TrkB autocrine loop amplifies this effect through PI3K/Akt and Ras/MAPK pathways that enhance CREB-mediated complement regulator expression.

This hypothesis proposes that the CREB1-BDNF-TrkB activity-dependent transcriptional machinery directly controls the spatial expression patterns of complement regulators CD55 and CD46, creating synaptic vulnerability maps that determine which synapses are targeted for complement-mediated pruning. The mechanism operates through activity-dependent CREB1 phosphorylation at serine 133, which initiates transcription of both BDNF and complement regulator genes containing CRE sites. High-activity synapses with robust CREB activation maintain elevated CD55/CD46 expression, protecting them from complement attack through accelerated C3/C5 convertase decay and factor I-mediated C3b/C4b cleavage. Conversely, low-activity synapses exhibit reduced CREB-mediated transcription, leading to diminished CD55/CD46 surface density and increased complement vulnerability. This creates a molecular tagging system where synaptic activity history directly determines complement susceptibility. The BDNF-TrkB autocrine loop amplifies this effect through PI3K/Akt and Ras/MAPK pathways that enhance CREB-mediated complement regulator expression. Excitatory glutamatergic synapses on distal dendrites, which typically show lower basal activity and weaker CREB activation, become preferentially vulnerable due to insufficient CD55/CD46 protection. This mechanism explains the observed 70-80% reduction in complement regulator density at these synapses and provides a direct molecular link between neural activity patterns and selective synaptic elimination during development and plasticity.