Chapt. 5 - Consolidating LTP: Translation and Transcription Flashcards
de novo protein synthesis hypothesis
idea that for memories to endure, the learning experience must produce new proteins, proteins that were not present at the time of the learning event
Muller and Pilzeckers
Problem with DNPS hypothesis
didn’t specify what does the building of the needed new proteins are what gets built (because LTP wasn’t discovered yet)
What is the fundamental consolidation event
the construction of an enlarged stable actin cytoskeleton that is linked to the extracellular matric and presynaptic partner.
THEREFORE this requires no new proteins and disagrees with DNPS hypothesis
Evidence that synaptic events that produce enduring LTP initiate _______ and ______ of _______ into new proteins that can be important for synaptic changes to endure
transcription
translation
messenger RNA (mRNA)
The initial generation and stabilization of synaptic basis of LTP depends on what to do what?
While the enduring of LTP involves what to do what?
Generation and Stabilization = post-translation processes that modify and arrange existing proteins
Enduring = if synaptic changes resist the pressure to return to their original potentiated state, inducing stimulus must also initiate translation processes to generate new proteins
Evidence using a protein synthesis inhibitor shows that S-LTP produced by the weak stimulus depends only on ____. While the consolidation of synaptic changes supports that L-LTP requires _____
post translation modifications and rearrangements of pre-existing proteins
requires new proteins
Transcription
process of converting genetic material from DNA to messenger RNA, happens when signaling molecules enter the nucleus and activate transcription factors which are proteins that interact with DNA to produce mRNA
Translation
process by which mRNA is converted to protein (protein synthesis occurs)
mRNA is translated as it passes through a membrane system that surrounds the nucleus but also translation machinery and relevant mRNA are distributed where?
within the dendrite and soma
means possibility they are translated locally from already existing mRNA
New proteins can be derived from ____ or be the result of ______
derived by local translation of mRNAs already present in the dendrite spine region
OR
result from synaptic activity signaling the genome to transcribe new mRNA
L-LTP depends on parallel effects of the LTP inducing stimulus. It initiates both _____ and _____
local translation
genomic signaling cascades
genomic signaling cascades
transcribe new mRNA that can be translated
(synapse to nucleus and soma to nucleus)
Local protein synthesis
mRNA and protein translation machinery (ER and ribosomes) are present locally in the dendritic spine and is all that you need to produce a new protein. FAST AND SPECIFIC. Machinery is activated during synaptic activity or experience
Experiments that provide evidence for local translation/protein synthesis
- invitro - separate dendrites from somas, making it impossible for proteins that have newly synthesized in the soma from a genomic cascade to influence synaptic strength. stimulation delivered to the schaffer collateral fibers (on dendrite part) can produce LTP therefore protein had to of been translated locally in dendrites
- can produce L-LTP on dendrites in both apical and basal region. when emetine (protein synthesis inhibitor) applied to all, prevented L-LTP in both. when applied to one, other place could still produce L-LPT. when applied to soma, did not block in either region –> therefore proteins were translated in the dendrites
mRNAs that are not produced locally can become generate by a genomic signaling cascade that result in ___ of new mRNA because of ____ and ____
transcription
synaptic activity
neuronal depolarization
for genomic signaling cascades, the signaling molecules enter the nucleus to phosphorylate _____ which interact with DNA to produce ____. This results in production of mRNA that gets _____ into a new protein
transcription factors
mRNA
translated
Synapse to nucleus (1 way to signal the nucleus)
synaptic activity initiates a cascade that produce signaling molecules that eventually move to the nucleus to initiate transcription
Soma to nucleus (other way to signal nucleus)
result of action potentials produced by synaptic activity, calcium enters the soma through voltage dependent calcium channels which it can more directly initiate transcription
Which way of signaling to the nucleus is more likely
soma to nucleus because it is faster and more efficient, 15 mins compared to hours
what support present to support that L-LTP depends on transcription
- inhibitors of transcription blocked development of L-LTP but did not interfere with initial development and stabilization
- transcription factor CREB protein was implicated in both synaptic plasticity and long term memory and memory and L-LTP was prevented if no CREB
CREB when activated vs inactivated
called a ______ switch
inactivated = unphosphorylated state and has little effect on gene transcription
activated = phosphorylated and initiates production of mRNAs and transcribe mRNA that are critical for production of long lasting changes in synaptic strength. mRNAs called plasticity products
called a molecular memory switch
Two general models of how signals reach the nucleus/ activate CREB
- synapse to nucleus signaling
- soma to nucleus signaling
synapse to nucleus signaling
stimulate post synaptic site which activates second messenger system –> activate protein kinases –> secondary messenger or kinase move into nucleus where they phosphorylate CREB protein –> transcription is initiated
In synapse to nucleus signaling there are multiple pathways that can phosphorylate CREB
- Protein Kinase A activated by second messenger system cAMP –> PKA move to nucleus to phosphorylate CREB and initiate transcription (without PKA, block L-LTP and reduces genes controlled by CREB)
- Extracellular regulated kinase-mitogen-activated protein kinase (ERK-MAPK) initiated by neurotrophic factors which binds to tyrosine kinase (Trk) receptors, move to nucleus and initiate transcription factors.
blocking PKA or ERK-MAPK pathways result in what
block the transcription of plasticity related mRNA and block development of L-LTP
Soma to nucleus signaling
action potential produced from cell depolarizing can generate a signal in the soma –> opens voltage-gated calcium channels (VGCC’s) located on the soma –> calcium enters soma –> binds to calmodulin which is already in the cell –> activates nuclear enzymes (calcium/calmodulin IV that can phosphorylate CREB)
Explain transcription in the nucleus
occurs in the nucleus, DNA is converted into RNA. transcription then is the transfer of information contained in DNA into mRNA. then many ways to signal pathways to lead to phosphorylation of CREB and new mRNA and new proteins critical for L-LTP
critical predication that _____ signaling can substitute for ____ signaling to produce L-LTP
soma to nucleus
synapse to nucleus
Evidence to support action potential model
action potentials critical event for L-LTP, should be possible to convert S-LTP to L-LTP by initiating action potentials WITHOUT strong stimulating synapses
(strong stimulus = L-LTP, weak stimulus - S-LTP) and that is what happened!
action potential were sufficient to prevent decay of LTP normally produced by weak stimulus and alone could phosphorylate ERK and CREB
testing soma to nucleus hypothesis
- weak stimulus applied to schaffer collateral fiber pathway 2. some slices followed by electrical stimulation applied to axon (antidromic stimulation) on CA1 pyramidal cells 3. produced action potentials in those neurons allowed influx of calcium into soma and nucleus
weak stimulation without antidromic stimulation only produce S-LTP, but with antidromic would be L-LTP
important conclusion = protein synthesis occurs in _____
two waves
1. first wave occurs locally in dendrites
2. second wave occurs when protein is synthesized from the new mRNA produced by genomic signaling cascade (contributing the most)
calcium levels need to be amplified in some way to produce long lasting LTP, how?
- extracellular = NMDA to dendritic spines and through VGCC to enter soma
- intracellular (is stored in ER) from RyR and IP3R (
translating protein requires _______ levels
increased calcium
___ is the internal source of calcium
endoplasmic reticulum
3 compartments of neurons
spine, dendritic, and soma compartment
intracellular calcium is stored on the ER and can be released into spines by what two ways
- calcium binds to RyRs located in spines
- released into the dendritic compartment when IP3 binds to IP3Rs in the dendrite
Explain IP3Rs releasing calcium
in the ER there are lots of IP3Rs. they respond to calcium and the second messenger IP3 which is synthesized when the first messenger glutamate binds to metabotropic receptor mGluR1
metabotropic receptors activate G proteins in plasma membrane by either
- alter opening of G-protein-gated ion channel
OR - stimulate an effector enzyme that either synthesizes or breaks down a second messenger
different sources of calcium contribute to different forms of LTP. (ONLY A THEORY)
LTP1?
induced when glutamate produced by weak stimulus (1 TBS) binds to NMDA receptor which causes increase in calcium into spine binding to RyRs and causes ER to release additional calcium into spine
LTP2?
induced when glutamate resulting from stronger stimulation (4 TBS) binds to NMDA receptors and to mGluR1s and results in local protein synthesis
LTP3?
produced when the strongest stimulus (8 TBS) repeatedly opens VGCCs and calcium into the soma increase to the point where it can move to the nucleus to initiate transcription of genes necessary for the expression of LTP3
