ID: h-6a6f132a50e9
Hypothesis
Activity-dependent MAP6 scaffolding at synapses
MAP6 may scaffold signaling complexes at synapses in an activity-dependent manner, linking NMDA receptor activation to cytoskeletal remodeling via its multiple functional domains.
EvidenceModerate (55%)📖 6 cit🗣 1 debates✓ 6 support✗ 2 oppose
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🧪 Overview
MAP6 may scaffold signaling complexes at synapses in an activity-dependent manner, linking NMDA receptor activation to cytoskeletal remodeling via its multiple functional domains
Prediction: MAP6 will physically associate with synaptic signaling proteins in a phosphorylation-dependent manner, and LTP-inducing stimulation will recruit MAP6 to dendritic spines
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
flowchart TD
A["MAP6 Occupancy on Microtubules<br/>Cold-Stable Cytoskeletal Support"]
B["Tau/MAPT Lattice Competition<br/>Dynamic Binding Balance"]
C["Synaptic Remodeling Signals<br/>NMDA-Linked Cytoskeletal Plasticity"]
D["Axonal Transport and Branching<br/>Circuit Adaptation"]
E["MAP6-Tau Imbalance<br/>Rigid or Unstable Cytoskeleton"]
A --> B
B --> C
C --> D
E -.->|"disrupts"| B
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style D fill:#1b5e20,stroke:#81c784,color:#81c784
style E fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a⚖️ Evidence
⚖️ Evidence Matrix6 supports2 contradicts
Supports
MAP6 may scaffold signaling complexes at synapses in an activity-dependent manner, linking NMDA receptor activation to cytoskeletal remodeling via its multiple functional domains
Supports
Cerebellin-neurexin complexes instructing synapse properties.
Supports
Sensory neurons drive pancreatic cancer progression through glutamatergic neuron-cancer pseudo-synapses.
Supports
mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists.
Supports
Distinct neurexin-cerebellin complexes control AMPA- and NMDA-receptor responses in a circuit-dependent manner.
Supports
Beyond NMDA Receptors: Homeostasis at the Glutamate Tripartite Synapse and Its Contributions to Cognitive Dysfunction in Schizophrenia.
Contradicts
Tau/MAP6 antagonism is shown in neuronal development models, but this does not establish that the same balance drives adult neurodegeneration progression or treatment response.
Contradicts
A microtubule-stabilizing peptide strategy failed to show clinical benefit in progressive supranuclear palsy, cautioning against simple cytoskeletal-stabilization translation in tauopathy.
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — MAP6
No curated PDB or AlphaFold mapping for MAP6 yet. Search RCSB →
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for MAP6 from GTEx v10.
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 MAP6.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
🏆 Arenas / Elo
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📊 Market Indicators
7d Trend
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Stable
7d Momentum
▼ 0.2%
Volatility
High
0.0587
Events (7d)
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Price History
▼1.5%💾 Resource Usage
No resource usage or linked notebooks recorded for this hypothesis yet.
🔮 Predictions
🔎 Predictions vs Observations2 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF neuronal activity is selectively increased via chemogenetic activation of excitatory neurons in cultured hippocampal networks, THEN MAP6 protein will show a significant increase in synaptic spine l | Increased MAP6 accumulation at dendritic spines as measured by live-cell imaging of MAP6-GFP expressing neurons | — no observation — | pending | 0.65 |
| IF MAP6 phosphorylation-deficient knockin mice (S→A mutations at predicted activity-regulated sites) are subjected to theta-burst LTP induction, THEN the maintenance phase of LTP (60-120 min post-indu | Reduced LTP maintenance magnitude (≤150% of baseline) at Schaffer collateral-CA1 synapses in knockin vs wild-type mice | — no observation — | pending | 0.58 |
🔮 Falsifiable Predictions (2)
pendingconf 65%
IF neuronal activity is selectively increased via chemogenetic activation of excitatory neurons in cultured hippocampal networks, THEN MAP6 protein will show a significant increase in synaptic spine localization (≥40% increase in spine/cytoplasm ratio) within 60 minutes post-stimulation.
Predicted outcome: Increased MAP6 accumulation at dendritic spines as measured by live-cell imaging of MAP6-GFP expressing neurons
Falsification: MAP6 spine/cytoplasm ratio changes by <20% or shows no change despite robust neuronal activity increase (c-Fos upregulation ≥3-fold confirms activation)
pendingconf 58%
IF MAP6 phosphorylation-deficient knockin mice (S→A mutations at predicted activity-regulated sites) are subjected to theta-burst LTP induction, THEN the maintenance phase of LTP (60-120 min post-induction) will show significantly reduced potentiation compared to wild-type littermates.
Predicted outcome: Reduced LTP maintenance magnitude (≤150% of baseline) at Schaffer collateral-CA1 synapses in knockin vs wild-type mice
Falsification: LTP maintenance in knockin mice remains within 10% of wild-type magnitude (both ≥160% baseline), indicating MAP6 phosphorylation is not required for LTP
▸Metadatasource: v1_phase_c_backfill · origin_type: gap_debate
| source | v1_phase_c_backfill |
| origin_type | gap_debate |
| _schema_version | 1 |
📊 Evidence Profile
Evidence Balance
+0%
Certainty
0%
Debates
0
Incoming
0
Outgoing
0
0 supporting
0 contradicting
0 neutral
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