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.
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:#ef9a9aNo linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for C1QA 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 C1QA.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| 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 |