Chapt. 6 - Consolidating LTP: Specific Mechanisms

Question 1

strength of the received signals to a neuron can be regulated at the level of _______
what are these two ways?

Answer 1

single spines
1. spines responding to glutamate released by LTP inducing stimulus undergo rapid enlargement of actin cytoskeleton
2. proteins can be translated locally in the dendritic spine

Question 2

protein on-demand system

Answer 2

all components of neurons depend on steady supply of mRNAs that must be translated into needed proteins. used to think all protein translation occurs in somatic space, but now know that occurs locally in specific compartments and then after transcription, mRNAs are transported and localized to compartments where the have respond to specific signals and be translated as needed. EFFICIENT AND FLEXIBLE

Question 3

to arrive at specific dendritic locations, mRNAs depend on ____ which do what?

Answer 3

RNA-binding proteins (RNA-BPs)
they bind to elements within the mRNA and attach to those elements to cytoskeleton motor proteins to move the mRNAs to specific dendritic locations

Question 4

once mRNA is transported to dendritic spine regions, what occurs and what does uncaging of glutamate cause the mRNA to do

Answer 4

mRNA continues to cycle between nearby spines.
uncaging of glutamate causes spine to capture mRNA and polyribosome complexes (made of functional ribosomes) that translate mRNA into new proteins locally

Question 5

spines stimulated by glutamate ____ and ___ mRNA and ribosomes that translate the mRNA into protein

Answer 5

enlarge and capture

Question 6

TOP mRNA

Answer 6

encode for proteins such as ribosomal proteins and elongation factors that are part of the translation machinery. these encoded proteins by TOP are part of the translation machinery needed to synthesize other proteins that play a more specific role in translation and synaptic functions
synthesized TOP mRNAS enhance translation capacity in the region where translated

Question 7

The synthesis of TOP mRNAs is regulated by a kinase called what

Answer 7

mTOR

Question 8

What activates the mTOR-TOP pathway

Answer 8

BNDF, a protein
produces increased amounts of BNDF when synaptic activity generates lasting LTP

Question 9

activation of mTOR-TOP pathway is critical for _____ to support the ____ of LTP

Answer 9

synaptic changes
enduring
(without it, experiment shows it effects the late stages of LTP)

Question 10

two types of evidence suggest that BNDF plays a critical role in activating the ____ pathway

Answer 10

mTOR-TOP
1. BNDF is critical for development of LTP
2. interfering with BDNF signaling prevents translation of TOP mRNA

Question 11

BNDF is mediated by a subset of _____ receptors

Answer 11

tyrosine kinase receptors (TrkB)

Question 12

the co-release of BDNF with glutamate helps to generate a sustained source of _____

Answer 12

internal calcium

Question 13

inhibiting TrkB receptor response to BNDF result in what

Answer 13

preventing late phase LTP but do not prevent induction or stabilization

Question 14

local protein synthesis pathway

Answer 14

BNDF -> TrkB -> mTOR -> TOP

Question 15

explain the local protein synthesis process

Answer 15

1. BNDF binds to TrkB receptors that are colocalized with NMDA and AMPA receptors 2. causes activation of kinase complexes called mTOR 3. results in removal of the inhibitory influence of TOP protein (4E-BP) -> allows small ribosomal subunits to combine with TOPS (ex. elongation and initiation factors) to produce functional polyribosomal complexes that translate mRNA into proteins

Question 16

in the local protein synthesis process, what is the target of BDNF

Answer 16

4E-BP

Question 17

Interfering with TrkB in local protein synthesis pathway

Answer 17

interfering with it right after induction of LTP has no effect on generation of LTP BUT prevents enduring of LTP. interfering with LTP after 80 mins of LTP has no effect on generation or endurance
THEREFORE TrkB is required to initiate local protein synthesis

Question 18

how does rapamycin impact local protein translation process

Answer 18

rapamycin at the start of LTP induction, blocks activation of mTOR kinase and prevents late phase of LTP.
THEREFORE mTOR activity is required to initiate local protein synthesis

Question 19

what new functional-structural protein does this now active translation machinery synthesize

Answer 19

ARC (activity-regulated, cytoskeleton-associated protein) is one important protein

Question 20

ARC

Answer 20

is transcribed very rapidly in response to strong synaptic activity, 15-20 mins.
ARC mRNA quickly transported from soma to dendritic regions, it becomes available in local regions at the time the local translation machinery is active

Question 21

antisense methodology

Answer 21

allows researchers to inhibit translation of a specific protein, done by applying synthesized strand of nucleic acid (antisense oligonucleotide) that binds to specific mRNA and PREVENTS translation

Question 22

How is antisense methodology used to investigate role of ARC in LTP

Answer 22

arc antisense REVERSES well established LTP when applied 160 mins after inducing stimulus but not when applied 280 (LTP was fine).
THEREFORE synaptic changes have been confidently consolidated by 280 mins
(arc protein synthesis crucial in time for LTP)

Question 23

BDNF -TrkB consolidation depends on _____
Why?

Answer 23

ARC

Question 24

in the absence of ARC protein there are two outcomes

Answer 24

1. large reduction in phosphorylated cofilin
2. corresponding large less of new actin filaments
   THEREFORE ARC contributes to regulation of actin polymerization

Question 25

memories are mediated by changes in the _____ among the members of neuronal ensembles activated by the experience

Answer 25

synaptic changes

Question 26

retrieving a memory depends on the ability of the _____ neurons to ____ the ____ neurons sufficiently to produce action potentials that will propagate the signal within the ensemble

Answer 26

sending
depolarize
receiving

Question 27

strengthening of individual synapses should enhance the ability of sending neurons to depolarize receiving neurons thereby…

Answer 27

increasing the probability of generating action potentials and thus activating the ensemble of neurons

Question 28

clustered plasticity model

Answer 28

prevailing view that the dendritic branch rather than individual spines is the fundamental storage unit (for depolarize and propagate the signal)

Question 29

3 ideas that create the foundation of this model

Answer 29

1. fewer synaptic inputs are required to initiate an action potential when spines are clustered than when they are distributed on multiple dendritic branches
2. dendrite is a functional unit that contains all machinery required to supply synapses for local protein synthesis
3. when spines are stimulated they not only attract mRNA and ribosomes for translation (trap them) the new protein can be shared be among nearby spines in a cluster
   (greater activation in cluster, cluster spines cooperate to initiate local protein synthesis and capture and share the new protein)