Chapt. 3 - Generating Long-Term Potentiation Flashcards
LTP occurs when synaptic activity engages processes that…
rapidly deliver more AMPA receptors into the postsynaptic density (PSD)
The LTP inducing stimulus does what two things to rapidly increase the number of AMPA receptors in the PSD
- alters the dynamics of ongoing constitutive AMPA trafficking
- modifies the actin cytoskeleton complex
What idea did Gary Lynch provide about LTP
He used hippocampal slices to study LTP which was revolutionary because it retained their physiological properties. Instead of searching for a small population of synapses in a large area, could stimulate fiber populations converging on a defined dendritic location
What are the two general possibilities of what synaptic changes take place to produce LTP
- presynaptic changes that increase the release of glutamate
- postsynaptic changes that increase the postsynaptic neuron’s sensitivity to glutamate
(cant completely deny presynaptic changes, but safe to assume that it is #2)
Changes in synaptic potentials produced in an LTP are because of ______
biochemical interactions that include processes of modifying and rearranging existing proteins contains in synapses and also generating new proteins
What are the five “other” synaptic proteins
- structural proteins - ex. actin, folds/scaffolding that provide the cell structure
- functional proteins - enzymes that catalyze reactions and modify the function of other proteins
- recycling endosomes - transport internalized receptors to and from the plasma membrane
- ribosomes - translation of new proteins
- endoplasmic reticulum - can sequester (organize) and release calcium
What neurotransmitter is the primary player for LTP and what kind of neurotransmitter is it and messenger
glutamate
excitatory neurotransmitter (cause firing)
primary first messenger (elicit response)
What kind of receptor are glutamate receptors
are ionotropic (channels open to allow ions to go straight through)
AND/OR ligand gated (needs binding of ligand (glutamate) to open the channel
What are the 3 ionotropic receptors that glutamate binds to
- AMPA receptors
- NMDA receptors
- Kainate receptor
What happens to receptors after glutamate binds to them
when glutamate binds to these receptors, channels open and positively charged ions enter (Na and Ca)
Define competitive antagonists
molecules that have the property of occupying the receptor site so that normal binding partner/ligand cannot access the site. bind at same site, doesn’t change shape of receptor
Define noncompetitive antagonist
bind to target receptors at a different site then where the ligand would bind, and causes a change in shape to inhibit binding of ligand
Define agonist
enhances receptor function after binding
Graham Collingridge discovered what about NMDA receptors on LTP
Discovered that APV (a NMDA receptor antagonist) prevents the INDUCTION of LTP but has no effect on its expression
NMDA is necessary for the induction but not the expression
AMPA receptor antagonists prevent what of LTP
induction AND expression
What are the critical binding sites of the NDMA receptors for the induction of LTP
- one site binds glutamate
- other site binds magnesium (magnesium plug)
Opening of NMDA receptors requires what two events
calcium cannot enter the cell unless magnesium is removed from the pore
1. glutamate must bind to the receptor
2. cell must depolarize which causes the magnesium plug to be removed and calcium can enter the cell
What causes the induction of LTP in regards to NMDA
when extracellular calcium enters the spine via the NMDA calcium channels
The expression of LTP depends exclusively on
increase in Na entering the spine which depends on AMPA receptors
What are the two central principles of the field for AMPA receptors and LTP
- LTP inducing stimulus can rapidly increase the number of AMPA receptors in the spine
- AMPA receptors is the fundamental outcome that support the expression of LTP
AMPA receptors traffic into and out of ______. Trafficking ___ AMPA receptors into and out of these. While they are cycled, ____ deliver new AMPA receptors
dendritic spines
cycles
synaptic activity
What is the construction of glutamate receptors made of
4/5 protein subunits that come together to form pore or potential channel
AMPA receptors are in constant and random ____ where they laterally diffuse along the ______
motion
plasma membrane
____ AMPA receptors are more mobile than those in the ____.
extrasynaptic (not in the PSD)
PSD (better positioned to respond to glutamate)
(receptors cycling through the PSD might be captured and packaged for recycling)
AMPA receptors are composed of subunits, what are they called
GluA1 and GluA2 are the ones we are interested in and the amount of each kind of subunits present, switch depending on if its before or after LTP
Under normal/basal conditions the synapse contain what kind of subunits
GluA2
during initial induction of LTP there is an increase in what kind of subunits and why
GluA1 because they have phosphorylation sites that help the AMPA receptors get up to the PSD and remain up their
AMPA receptors (GluA1) have serine sites that when phosphorylated by different _____ make different contributions to receptor trafficking and conductance. What are the different ___ and what are their contributions
kinases
kinases
1. protein kinase A (PKA) phosphorylates serine site 845, to traffic the receptor to the extrasynaptic region
2. protein kinase C (PKC) phosphorylates site 818 to help anchor the receptor to the PSD
3. CaMKII phosphorylates site 831 and changes the channel to allow influx of calcium and sodium
TARPS
transmembrane AMPA receptor regulatory proteins that co-assemble with AMPA receptors to release or trap the receptors in the PSD
Calmodulin
a protein that serves as a surrogate for calcium (the second messenger) and undergoes a conformational change once it binds with Ca. The new shape allows it to bind with other proteins.
CaMKII cannot be activated by just Ca on its own, it needs Caand calmodulin
Explain the two domains of the CaMKII subunit
- autoinhibitory-regulatory domain which contains a phosphorylation site Thr286
- catalytic domain
Thr286, when is it exposed and not exposed
in the regulatory domain of CaMKII and is not exposed when the kinase (itself) is in an inactive state.
It is exposed when Ca-calmodulin serves as a second messenger and activates the kinase. This exposes both the Thr286 and the catalytic domain.
What does phosphorylation of the Thr286 site result in
will keep the kinase in an active state even when the second messenger (Ca-calmodulin) dissociates from the regulatory domain
Subunits of the CaMKII kinase assemble into what kind of complex and what does this allow
Holoenzyme - ring-like complex
allows for a subunit to phosphorylate its neighbour (autophosphorylation) - enables subunits to remain active even when Ca-calmodulin is no longer present, can remain in active state
How does LTP inducing stimulus increase the number of AMPA receptors trapped or immobilized in the PSD (two ways)
- lateral diffusion
- recycling endosomes
Trapping of AMPA receptors in the PSD requires interactions of what 3 molecules
- Ca-calmodulin dependent kinase II (CaMKII)
- a TARP called Stargazin
- PSD-95 Scaffolding proteins (part of cytoskeleton)
Explain lateral diffusion and how it traps AMPA receptors in the PSD
- become trapped in PSD when influx of Ca into the spine via NMDA receptors –> the calcium binds and activates CaMKII –> CaMKII phosphorylates serine residues on the terminal of the TARP Stargazin –> this releases terminal from the membrane (the whole receptor) –> then PSD95 bind/trap Stargazin and therefore trap the receptor in the PSD
The stability of the trap of the AMPA receptor increases when
CaMKII phosphorylates more of the Stargazin serine residues
Explain recycling endosomes and how it delivers AMPA receptors to the PSD
neuronal activation of NMDA lead to influx of Ca into dendritic spines –> influx induces conformational change of the motor protein, myosin Vb –> the unfolding of myosin Vb exposes a cargo-binding domain that mediates and allows Rab11 effector complex (which is connected ot the recycling endosome) to grab onto the myosin –> the activated myosin delivers AMPA receptors to the PSD –> leads to localized increase in AMPA receptor density characteristic of LTP
AMPA receptors are available to increase AMPA receptors in the PSD in two pools:
1; preexisiting surface pool
2. an intracellular pool
When LTP is induced, what are the two ____ processes that deliver AMPA receptors to the PSD (under normal conditions)
Independent (this is a sequence of events)
1. initiates lateral diffusion of receptors in the surface pool into PSD
2. then delivers receptors from intracellular pool by motor proteins
can produce LTP that last for 30 minutes at least
If lateral diffusion occurs, what happens to LTP
initial delivery of AMPA receptors is prevented and rapid generation of LTP does not occur, after some time LTP gradually merges as the AMPA receptors from the intracellular pool are delivered
If exocytosis is inhibited what happens to LTP
inhibiting intracellular pool, rapid reduction of LTP occurs and returns to baseline in about 10 mins. Great induction of lateral diffusion at the start, but then decline because no AMPA coming from intracellular pool
What occurs to LTP if both lateral diffusion and exocytosis are inhibited
LTP will not be generated
The last step of generating LTP is what and explain the process
Disassembling the actin cytoskeleton:
originally F-actin is crosslinked and connected by spectrins to reinforce and strengthen the structure for the postsynaptic site.
Ca influx through NMDA –> activates calpain –> calpain degrades the spectrin and facilitates dissembling of actin –> this weakening allows the rapid insertion of additional AMPA receptors into the PSD, makes way for them!
