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.
...Curated pathway from expert analysis
flowchart TD
A["Target Gene: CREB1 BDNF NTRK2 TrkB"]
B["Molecular Mechanism<br/>Pathway Activation"]
C["Cellular Phenotype<br/>Neuronal / Glial Response"]
D["Network Effect<br/>Circuit-Level Consequence"]
E["Disease Relevance<br/>Neurodegeneration Link"]
A --> B --> C --> D --> E
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style E fill:#1b5e20,stroke:#81c784,color:#81c784No linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for CREB1 yet. Search RCSB →
Median TPM across 13 brain regions for CREB1, S100B, AGER (RAGE) from GTEx v10.
No clinical trials data linked to this hypothesis yet.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for CREB1, S100B, AGER (RAGE).
Run python3 scripts/backfill_hypothesis_depmap.py to populate.