Chp 7 - Maintaining memory (PKMz)

Question 1

What is the molecular turnover problem

Answer 1

that the synaptic molecules that support memory traces are short-lived in comparison to the duration of our memories, so how can the strengthened synapses that support memories outlive the molecules from which they are made?

Question 2

What are the forces that work to degrade the synaptic basis of memory? (what pressures occur to cause the potentiated synapses to return to the basal unpotentiated state)

Answer 2

1. degradation (breaking down) of AMPA receptors
2. receptor endocytosis, that operates to cycle AMPA receptors out of the synaptic region

Question 3

What did Francis Crick suggest about how to answer the molecular turnover problem?

Answer 3

That the molecules in synapses interact so they can be replaced with new material, one at a time, without altering the overall structure.

Question 4

To understand how consolidated synapses are maintained, requires knowing what two things

Answer 4

1. how GluA2s replace GluA1s
2. then how they are maintained in the synapses

Question 5

What did John Lisman question and suggest about the molecular turnover problem

Answer 5

questioned how unstable molecules can store information stably
suggested that stability could result from a kinase that is activated by phosphorylation and capable of intermolecular autophosphorylation (a kinase activated, then able to continue phosphorylating itself)

Question 6

What did Mary Kennedy believe in regards to maintenance molecules

Answer 6

their lab discovered CaMKII, but believed there is no ONE memory molecule, but that the synapses are regulated by mutual interactions of the whole network or proteins present, but still think there are specific and key molecules needed to maintain the synapses that support memory

Question 7

How can a maintenance molecule be identified

Answer 7

the molecule should not be required to generate and initially stabilize/ consolidate LTP, but should be required for the duration of LTP

so interfering with this molecule after consolidation phase, should return the strengthened synapse back to their baseline state (bad - not maintain)

erasure criteria - inhibiting the maintenance molecule would have no impact on normal neuronal transmission (generation, stabilization, and consolidation)

Question 8

Todd Sacktor proposed what molecule was the maintenance molecule

Answer 8

PKMZ (zeta)

Question 9

How is PKMZ different from PKC

Answer 9

PKC kinases have an inhibitory - regulatory domain and a catalytic domain, so the second messenger is required to remove the inhibitory domain and expose the catalytic domain. Whereas the PKMZ does not have an inhibitory domain and does not require a second messenger, it is constantly active

Question 10

What are the unique properties of PKMZ to allow it to be a candidate for being a maintenance molecule

Answer 10

1. no inhibitory domain
2. PKMZ mRNA is found in regions of dendritic spines and locally translated in the dendritic spine region.
3. once translated, PKMZ self-perpetuates, which is important given that all proteins degrade
4. when inhibiting it reduces late phase of LTP, but does not affect early induction

Question 11

How is PKMz translated

Answer 11

it is present in the dendritic spine and requires synaptic activity of several kinases (mTOR, PKA, MAPk, CaMKII, and P13) and active filament to translate it into PKMz mRNA.
once translated, PKMz self-perpetuates be interacting with other proteins to remove translator repressors and allows for translation of PKMz mRNA again.

Question 12

ZIP peptide

Answer 12

functions as an inhibitory domain for PKMz and inactivates it because it doesn’t naturally have one.

Question 13

What is the effect of applying ZIP prior to inducing stimulus and following induction

Answer 13

prior = does not affect early induction of LTP, but prevents later phase of LTP
following = almost immediately reverses late-phase LTP and decreases LTP (which is a property of memory maintenance molecule)

Question 14

How does PKMz contribute to the replacement of GluA1s to GluA2s

Answer 14

they traffic AMPA receptors into the PSD. there is a pool of GluA2s maintained outside of the synapse by binding to a protein, PICK1. The release of this pool relies on NSF, a trafficking protein enzyme. PKMz interacts with the NSF-PICK1 complex which release the GluA2s for entry into the PSD

Question 15

How does PKMz stop the continue pressure of endocytic processes to remove GluA2 receptors and return the synapse to the unpotentiated state?

Answer 15

Normally the activation of Trk (tyrosine kinase) receptors phosphorylate tyrosine on the GluA2 receptors which cause them to be released from the PSD into the endocytotic zone where they bind with NSF-PICK1 complex for recycling
However, with PKMz, it creates a complex with NSF-PICK1 and keep the GluA2 receptors trapped in the PSD and cannot return to unpotentiated state

Question 16

What are the three main roles of PKMz

Answer 16

1. releases pools of GluA2s to replace GluA1s
2. inhibits GluA2 endocytosis
3. clusters PSD-95 in the PSD

Question 17

What can occur if the gene for PKMz is deleted and what evidence supports this

Answer 17

compensation processes can occur to maintain LTP. the PKC I/lamba kinase can compensate. ICAP is the inhibitor of PKC I/lamba, which inhibits LTP maintenance in rats without PKMz but doesn’t not inhibit when PKMz is present.
So PKC I/lamba compensates when PKMz is absent but not when PKMz is present

Question 18

The duration of synaptic changes needed to support memory still much exceed the half life of PKMz, what is suggested to support how PKMz continuously supplies relevant mRNA

Answer 18

part of a positive feedback loop to ensure levels of PKMz are available to maintain potentiated stynapses

Question 19

What are the structural contributions for maintenance of memories

Answer 19

inducing stimulus for LTP initiates actin management processes that enlarge and stabilize the actin cytoskeleton in the spine. enlarged spine allows for capturing of replacement proteins and are able to self-perpetuate.