Projection-specific vulnerability to complement-mediated synaptic pruning drives distinct behavioral phenotypes
🧪 Overview
Prolonged anesthesia triggers complement activation (C1q/C3) that drives microglia-mediated synaptic elimination with projection-specific vulnerability. We hypothesize that ventral hippocampal neurons projecting to prefrontal cortex and amygdala lose synapses preferentially (mediating anxiety through disrupted top-down emotional regulation), while dorsal hippocampal neurons projecting to entorhinal cortex lose synapses preferentially (mediating cognitive deficits through impaired spatial memory encoding). This differential vulnerability is driven by region-specific synaptic molecular signatures (e.g., differential complement regulatory proteins, neuroligin/neurexin variants) that determine susceptibility to microglial C1q recognition and phagocytosis. Testable prediction: Blocking complement specifically in projection-defined circuits (e.g., vHPC→PFC) should selectively rescue anxiety while preserving cognitive deficits, and vice versa for dorsal hippocampal pathways.
🧬 Mechanism
Curated pathway from expert analysis
flowchart TD
A["C1QA Expression<br/>Complement C1q Alpha"]
B["C1Q Complex<br/>Assembly"]
C["Synaptic Complement<br/>Tagging"]
D["Projection-Specific<br/>Vulnerability"]
E["Complement-Mediated<br/>Pruning"]
F["C1QA as Projection-Specific<br/>Vulnerability Driver"]
A --> B
B --> C
C --> D
D --> E
E --> F
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style F fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a⚖️ Evidence
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — C1QA
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for C1QA 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 C1QA.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
🏆 Arenas / Elo
📊 Market Indicators
💾 Resource Usage
🔮 Predictions
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF C1q function is blocked selectively in ventral hippocampal (vHPC) projections to prefrontal cortex (PFC) via intra-vHPC injection of anti-C1q neutralizing antibody at the time of prolonged anesthes | Selective rescue of anxiety phenotype with persistence of spatial memory deficits, manifesting within 2 weeks post-anesthesia | — no observation — | pending | 0.65 |
| IF C1q function is blocked selectively in dorsal hippocampal (dHPC) projections to entorhinal cortex via intra-dHPC infusion of C1q inhibitor (C1-INH, 100U/kg, Berinert) concurrent with prolonged anes | Selective rescue of spatial memory with persistence of anxiety phenotype, manifesting within 3 weeks post-anesthesia | — no observation — | pending | 0.60 |
▸Metadatasource: v1_phase_c_backfill · origin_type: audit_hypothesis_generator
| source | v1_phase_c_backfill |
| origin_type | audit_hypothesis_generator |
| _schema_version | 1 |