CREB-Mediated Differential CD55/CD46 Expression Creates Activity-Dependent Complement Vulnerability Maps for Synaptic Pruning
🧪 Overview
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.
...🧬 Mechanism
Curated pathway from expert analysis
flowchart TD
A["CD55 DAF, CD46 MCP<br/>Hypothesis Target"]
B["Complement<br/>Cited Mechanism"]
C["Cellular Response<br/>Stress or Clearance Change"]
D["Neural Circuit Effect<br/>Synapse/Glia Vulnerability"]
E["Neurodegeneration<br/>Disease-Relevant Outcome"]
A --> B
B --> C
C --> D
D --> E
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style B fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style E fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a⚖️ Evidence
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — CD55
No curated PDB or AlphaFold mapping for CD55 yet. Search RCSB →
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for CD55, CD46, CREB1 from GTEx v10.
💉 Clinical Trials
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 CD55, CD46, CREB1.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
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💾 Resource Usage
▸Metadatasource: v1_phase_c_backfill · origin_type: debate_synthesizer
| source | v1_phase_c_backfill |
| origin_type | debate_synthesizer |
| _schema_version | 1 |