The strongest spatial model is a split between substrate marking at synapses and state modulation at microglia. The synaptic arm is well grounded, but the microglial surface-signaling arm remains insufficiently demonstrated in CNS microglia and must be tested under complement-defined conditions that isolate location from ligand identity and microglial state.
Curated pathway from expert analysis
flowchart TD
A["Stressed Synapse<br/>C1q Ligand Exposed"]
B["C1q Deposition<br/>Synaptic Tagging"]
C["C3 Cleavage<br/>C3b Opsonization"]
D["CR3 Recognition<br/>Microglial Receptor"]
E["Synaptic Pruning<br/>Phagocytic Engulfment"]
F["Synapse Loss<br/>Circuit Disruption"]
G["Cognitive Decline<br/>Memory Impairment"]
A --> B
B --> C
C --> D
D --> E
E --> F
F --> G
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style G fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for C1QA,C1QB,C1QC,C4A,C4B,C3,ITGAM,ITGB2,LAIR1 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,C1QB,C1QC,C4A,C4B,C3,ITGAM,ITGB2,LAIR1.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF microglia-specific C1q is deleted using Cx3cr1-CreERT2 while neuronal/astrocyte C1q is preserved, THEN microglial activation markers (CD68, MHCII) and pro-inflammatory cytokine profiling will show | Significant reduction in CD68+ phagocytic microglia and decreased IL-1β/TNF-α transcript levels in the hippocampus of microglia-C1q KO mice compared to controls | — no observation — | pending | 0.55 |
| IF LAIR1 is selectively blocked on microglia via anti-LAIR1 Fab fragments while complement C3 is simultaneously inhibited, THEN microglial process dynamics and arbor complexity will remain altered (in | LAIR1 blockade + C3 inhibition will result in impaired microglial process velocity (>30% reduction) and reduced branch complexity (Sholl analysis) while synapti | — no observation — | pending | 0.40 |