Chapt. 6 - Consolidating LTP: Specific Mechanisms Flashcards
strength of the received signals to a neuron can be regulated at the level of _______
what are these two ways?
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
protein on-demand system
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
to arrive at specific dendritic locations, mRNAs depend on ____ which do what?
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
once mRNA is transported to dendritic spine regions, what occurs and what does uncaging of glutamate cause the mRNA to do
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
spines stimulated by glutamate ____ and ___ mRNA and ribosomes that translate the mRNA into protein
enlarge and capture
TOP mRNA
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
The synthesis of TOP mRNAs is regulated by a kinase called what
mTOR
What activates the mTOR-TOP pathway
BNDF, a protein
produces increased amounts of BNDF when synaptic activity generates lasting LTP
activation of mTOR-TOP pathway is critical for _____ to support the ____ of LTP
synaptic changes
enduring
(without it, experiment shows it effects the late stages of LTP)
two types of evidence suggest that BNDF plays a critical role in activating the ____ pathway
mTOR-TOP
1. BNDF is critical for development of LTP
2. interfering with BDNF signaling prevents translation of TOP mRNA
BNDF is mediated by a subset of _____ receptors
tyrosine kinase receptors (TrkB)
the co-release of BDNF with glutamate helps to generate a sustained source of _____
internal calcium
inhibiting TrkB receptor response to BNDF result in what
preventing late phase LTP but do not prevent induction or stabilization
local protein synthesis pathway
BNDF -> TrkB -> mTOR -> TOP
explain the local protein synthesis process
- 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
in the local protein synthesis process, what is the target of BDNF
4E-BP
Interfering with TrkB in local protein synthesis pathway
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
how does rapamycin impact local protein translation process
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
what new functional-structural protein does this now active translation machinery synthesize
ARC (activity-regulated, cytoskeleton-associated protein) is one important protein
ARC
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
antisense methodology
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
How is antisense methodology used to investigate role of ARC in LTP
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)
BDNF -TrkB consolidation depends on _____
Why?
ARC
in the absence of ARC protein there are two outcomes
- large reduction in phosphorylated cofilin
- corresponding large less of new actin filaments
THEREFORE ARC contributes to regulation of actin polymerization
memories are mediated by changes in the _____ among the members of neuronal ensembles activated by the experience
synaptic changes
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
sending
depolarize
receiving
strengthening of individual synapses should enhance the ability of sending neurons to depolarize receiving neurons thereby…
increasing the probability of generating action potentials and thus activating the ensemble of neurons
clustered plasticity model
prevailing view that the dendritic branch rather than individual spines is the fundamental storage unit (for depolarize and propagate the signal)
3 ideas that create the foundation of this model
- fewer synaptic inputs are required to initiate an action potential when spines are clustered than when they are distributed on multiple dendritic branches
- dendrite is a functional unit that contains all machinery required to supply synapses for local protein synthesis
- 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)
