Astrocyte-Mediated Synaptic Tagging via CREB-S100B-RAGE Signaling

The astrocyte-mediated synaptic tagging mechanism operates through coordinated CREB1, S100B, and RAGE (receptor for advanced glycation end products) signaling to regulate synaptic maintenance and protection. Neural activity triggers calcium waves in astrocytes through connexin-43 gap junctions and purinergic P2Y1 receptor activation, leading to calcium/calmodulin-dependent protein kinase II (CaMKII) activation. Activated CaMKII phosphorylates CREB1 at serine 133 in astrocytic nuclei, promoting transcription of S100B, a calcium-binding protein with dual neurotrophic and neuroinflammatory properties. S100B is synthesized and released from astrocytic endfeet that ensheath active synapses through vesicular exocytosis and unconventional secretory pathways. At physiological concentrations, extracellular S100B binds to neuronal RAGE receptors, activating NF-κB and PI3K/Akt survival pathways while simultaneously triggering astrocytic release of complement inhibitors C1q-binding protein and vitronectin. This creates a localized protective microenvironment around tagged synapses. The astrocytic S100B-RAGE axis also stimulates expression of neuronal CD59 (protectin) and clusterin, which prevent membrane attack complex formation. Additionally, S100B promotes astrocytic uptake of extracellular ATP and adenosine through equilibrative nucleoside transporters, reducing purinergic-mediated microglial activation. The pathway maintains synaptic phosphatidylserine asymmetry by enhancing astrocytic lactate production, which fuels neuronal ATP-dependent phospholipid flippases. This astrocyte-centric mechanism provides spatially restricted synaptic protection through coordinated metabolic support, complement regulation, and anti-inflammatory signaling, representing a non-cell-autonomous approach to activity-dependent synaptic maintenance that operates parallel to intrinsic neuronal protective mechanisms.