P371 Ch07

What is the molecular turnover problem?

AMPARs constantly degrade and get endocytosed — yet memories persist.

How can memories survive despite molecular turnover?

Through self-sustaining molecular processes that replace degraded parts without changing the overall structure.

What does it mean if blocking a molecule later causes LTP to return to baseline?

That molecule was maintaining the memory, not creating it.

What makes PKMζ special compared to regular PKC?

It lacks the inhibitory domain → it’s constitutively active (always on).

3 requirements for a molecule to be classified as a “maintenance molecule”?

1. Not making or starting LTP

2. Keep LTP strong after it already formed (maintenacne after consolidation)

3. Blocking the molecule later = erases LTP

Where is PKMζ mRNA found?

Locally in dendritic spines.

Why isn’t PKMζ always made?

A translation repressor protein normally blocks its mRNA.

What triggers PKMζ synthesis?

Synaptic activity lifts the repressor block via kinase and actin signaling.

How does PKMζ maintain itself once made?

It removes the repressor from its own mRNA → positive feedback loop.

What is ZIP and what does it do?

A peptide that mimics the missing inhibitory domain → shuts off PKMζ activity.

What happens if ZIP is added before LTP induction?

Nothing — PKMζ isn’t active yet.

What happens if ZIP is added 2–5 hours after LTP?

It reverses late-phase LTP → shows PKMζ is required for maintenance.

What does PKMζ require to keep working over time?

A continuous supply of PKMζ mRNA for ongoing local translation.

What happens to AMPARs under normal Trk signaling?

GluA2 is phosphorylated → detaches from PSD → moves to endocytotic zone → binds PICK1 + NSF for recycling.

What does PKMζ do in this AMPAR cycle?

It disrupts the PICK1–NSF complex → releases trapped GluA2s → sends them back to PSD. “Stop taking these out — put them back in and keep them there!”

How does PKMζ affect PSD-95?

Promotes PSD-95 clustering → locks AMPARs into place → strengthens the spine.

What kinase can compensate when PKMζ is absent?

PKCι/λ.

When does PKCι/λ take over?

Only when PKMζ is missing — it stays silent if PKMζ is active. Shows brian has redundancy!

What happens in PKMζ knockout mice?

LTP is still maintained, though not perfectly → PKCι/λ compensates.

What happens if both PKMζ and PKCι/λ are blocked?

LTP fails completely — no maintenance possible.

What does ZIP’s timing effect prove about PKMζ?

It’s needed for maintaining LTP, not for starting it.