Lectures 9 & 11 Flashcards
What does Long-Lasting LTP depend on?
Translation and Transcription (locally and genomically)
Are there multiple signaling pathways from an LTP signaling event or just one?
Many
What happens if you block any of the signaling cascades from an LTP signaling event?
Memory will be affected somehow
What is the goal of synapse to nucleus signaling pathways? (Think a particular protein)
Phosphorylation of CREB which leads to transcription
What are the three main sources of synapse to nucleus signaling?
- G-protein coupled receptors
- NMDA mediated Ca2+ influx
- BDNF-Trk B signaling cascade
What is BDNF important for when it comes to synapses?
Synaptic plasticity
How many waves of protein synthesis are there during an LTP event?
Two waves
What mediates the two waves of protein synthesis?
Calcium stores
Where does the first wave of protein synthesis occur?
In the dendrites
Describe the second wave of protein synthesis
It occurs when protein is synthesized from the new mRNA produced by the genomic signaling cascade
What is the initial and second messenger that begins the signaling cascade?
Ca2+ is both
What are the two places that source the calcium necessary for protein translation?
Extracellular (fluid) and intracellular (ER)
What are the two extracellular source of calcium and how are they different?
- NMDAR: often source for smaller stimulations and enters through dendritic spines
- vdCC: often source for LARGER stimulations and enters through the soma
What are the two sources of calcium from the intracellular ER and how do they differ?
- RyRs: stores Ca2+ when it binds to it in the spine
- IP3R: stores Ca2+ when IP3 binds to IP3Rs in the dendrite
What are the three compartments of a neuron?
- spine compartment
- dendritic compartment
- soma compartment
What are the two mechanisms Metabotropic receptors use to influence postsynaptic response to stimulation?
- alter the opening of a G-protein-gated ion channel
- stimulate an effector enzyme that either synthesizes or breaks down a second messenger
What do IP3Rs respond to?
Ca2+ and IP3
When is IP3 synthesized?
When glutamate binds to mGluR1
What are the 3 forms of LTP?
LTP1, LTP2, and LTP3
How is LTP1 induced?
Glutamate produced by a weak stim binds to NMDA which leads to an influx of Ca2+ into the spine.
What does LTP1 cause?
Ca2+ influx from the spine binds to the RyRs and causes the ER to release additional Ca2+ into the spine
What induces LTP2?
Glutamate from a strong stim binding to NMDA and to the mGluR1s
What does LTP2 cause?
Local protein synthesis
What produces LTP3?
Strong stimulation opens the vdCCs and Ca2+ in the soma increases to the point it can translocate to the nucleus
What does LTP3 cause?
Ca2+ in the soma translocates to the nucleus and initiatives transcription of genes necessary for the expression of LTP3
What problems does local protein synthesis solve?
- specificity to the spine level
- it creates a protein on demand system
How do mRNAs arrive at specific dendritic locations?
RNA binding proteins attach them to cytoskeleton motor proteins
Once transported to the dendritic spine region, what does mRNA do?
The mRNA cycles between nearby spines
What uncages glutamate?
Photon stimulation
What does uncaging glutamate do?
There is rapid changes in the spatial distribution of mRNA & polyribosome complexes form to translate mRNA into new protein that is captured by the spines
What are some of the proteins that will be synthesized from the mRNA from local protein synthesis?
PSD-95, Arc, GluA1, CaMKII, AMPA, more
What is required to assemble Ribosomal Complexes?
Basic Ribosomal Unit/mRNAs known as TOPS
What are TOPS in regards to translation?
Translation factors
What does translation of TOPS depend on?
Activity dependent
What does BDNF bind to?
TrkB
What are TrkB receptors colocalized with?
NMDA and AMPA
What does BDNF binding to TrkB do?
Activates complex kinase mTOR (mammalian target of rapamycin)
What does mTOR do?
Inhibits TOP protein 4E-BP
What does 4E-BP do?
Block translation of other TOPS such as EFs (Elongation factors) & IFs (initiation factors)
What does the inhibition of 4E-BP allow small ribosomal units to do?
Combine with other TOPS like EFs and IFs to form functional polyribosomal complexes to translate mRNA
What happens to LTP if a TrkB inhibitor is introduced shortly after induction?
LTP can be generated but it cannot endure
What happens to LTP if you introduce a TrkB inhibitor at 80 minutes after induction?
No effect
What is TrkB activity required for?
Local protein synthesis and it is required in less than 80 minutes
What are the two things the consolidation of memory is involved in?
Degradation of existing proteins and protein synthesis
How are proteins that regulate/suppress translation dealt with to allow for synaptic plasticity? What activates what?
Ubiquitin Proteasome Systems are activated by glutamate and CaMKII recruits proteasome molecules to the spines
What is Arc?
A protein derived from the immediate early gene Arc
Arc stands for activity regulated cytoskeleton-associated protein
What is the antisense technique?
A technique that prevents translation of specific proteins by introduced a synthesized strand of nucleic acid that will bind to specific mRNAs
What is Arcs role in the consolidation of LTP? (Less the actual function and more so how long until its removal has an effect)
Arc antisense at 160 minutes after induction reverses LTP, but not after 280 minutes
Therefore, after 280 minutes synaptic changes have been consolidated
What are the current thoughts on what Arc does and why do we think that?
Arc may regulate the regulation of Actin dynamics by phosphorylating cofilin for several hours, this is based on Arc absence leading to large reductions in phosphorylated cofilin and a corresponding loss of new actin filaments
What does memory reflect?
The changes in synaptic connections within the neuronal ensemble, activated by the experience
What is important to retrieving a memory?
Presynaptic neuron depolarizing downstream neurons sufficiently to produce APs that will activate the whole engram (something that cant be done by a changing synaptic strength in a single spine)
What is the Clustered Plasticity Model?
The idea that the dendritic branch becomes the fundamental storage unit when we think of memory. The clustered potentiated synapses are more effective than distributed ones and they can share new proteins among the spines
