LTP And LTD Flashcards
What does the hebbian synapse model say
This models says that the coordinated activity (so if you stimulate both the pre and post synaptic neurones) of a presynaptic terminal and a post synaptic terminal neurone STRENGTHENS the synaptic connections between them
What happens if you stimulate a neurone that synapses onto another neurone? And what did hebbs suggest about synapse stimulation?
So if you have two neurones which synapse onto each other, if you stimulate one neurone and record the other neurone, you see an excitatory post synaptic potential EPSP
What did Hebb suggest?
- if you stimulate both of these neurones at the same time then the EPSP increase and so does the amplitude of spikes.
What does the hippocampus do? What processes happen here>
The hippocampus can store spatial memory
Long term potentiation and long term depression can happen here. LTP and LTD
Where does alzheimer’s disease affect?
The hippocampus
Where does the main input from the hippocampus come from and go to?
The main input comes from the entorhinal (found in the temporal LOBE) and this sends signals to the dentate gyrus In the hippocampus
The dentate gyrus is then linked to the CA3 neurone
The CA3 neurone then synpases onto the CA1 neurone
How to measure a CA1 neurone (a neurone in hippocampus) and stimulate it without ca3?
Patch clamp technique
Stimulate this with an electrode.
What happens if you stimulate a CA1 neurone? What happens to the amplitude if you stimulate this multiple times? What happens if you stimulate the CA3 neurone at the same time?
If you stimulate the CA1 neurone (remember this is stimulated by the CA3 neurone and you stimulate it with an electrode) , this causes it to depolarise and you get a post synaptic EPSP
Stimulating this neurone many times causes a EPSP with the same amplitude each time. This amplitude becomes normalised
If you stimulate the CA3 with a high frequency stimulus at the same time for a short period of time, this causes long term potentiation. This causes following EPSPs amplitudes to increase in the CA1 neurone.
This can last up to days
So summary of CA1 and CA3 LPT
Stimulating ca1 with a general stimulation causes a relatively normal amplitude of EPSP. Remember this is second in the pathway from ca3 to ca1 and in this test you stimulate with an electrode.
Stimulating ca3 with a high frequency stimulation (and stimulating the CA1 with another electrode) causes the amplitude of the EPSP to increase in the CA1 neurone. This is long term potentiation and can last days.
This means if you stimulate the CA1 neurone again with JUST the CA3 neurone a stronger EPSP remains due to the LTP lasting a while
Remember the CA3 synpases onto the CA1!!! Not the other way around!!
Note which CA neurone synpases onto the other?
The CA3 synpases onto the CA1!!!!!
Where does LTP occur? And what is important to note when there is two inputs to a neurone?
It occurs somewhere between the synpases of neurones
When you have two inputs to a neurone (such as one neurone and a electrode) then the EPSP can be recorded for each individual neurone.
So in terms of the hippocampal neurones CA3 and CA1, what is the conditioned pathway and the unconditioned pathway? And why does the conditioned pathway work better after the unconditioned pathway has done its job?
The conditioned pathway is the normal pathway from CA3 to 1
The conditioned pathway is when the CA1 neurone is stimulated directly by an electrode
If these two pathways work together, then the conditioned stimulus triggers the activation of the CA1 neurone much better.
So remember this causes an LTP - which means the amplitude of the EPSP is greater.
How do LTPs occur?
They have post not pre synaptic origins
There is probably a critical role from calcium
Where does the idea that calcium has a crucial role in causing LTPs?
And remember these basically increase the the amplitudes of action potentials!
In post synapses there a glutamate receptors. Remember they have the role of opening and allowing calcium in
Glutamate diffuses across the synaptic cleft from the CA3 neurones which can be detected from AMPA and NMDA receptors. This can allow calcium to enter causing a EPSP
Why do NMDA receptors need a certain HIGH frequency threshold stimulation to work?
These receptors which detect glutamate are often blocked by magnesium ions
When the membrane of the receptor / synpase in general is hyperpolarised, the magnesium is often bound to the pore of the NMDA receptor. So calcium can’t go through.
Remember calcium entry into the post synapse isnt what causes an action potential. It’s the movement of sodium!
To open this receptor the cell needs glutamate but also needs to be depolarised!
So the membrane of the post synapse needs a HIGH enough frequency stimulation for depolarisation to occur and thus for calcium to enter.
This calcium entry only happens at high enough stimulation! (Note depolarisation of the post synapse could still happen without its entry) and when it does enter this may cause an LTP
What are the two phases of LTP?
Early phase - this happens early and doesn’t require protein synthesis. This is often called LTP induction
Late phase - this requires later and requires protein synthesis. This is often called LTP expression
Early phase of LTP?
NMDA receptor is activated (due to depolarisation of the CA1 neurone) - which mediates calcium entry
The receptor also auto phosphorylates itself and it has multiple catalytic sub units. In this way more calcium may enter after the initial long term potentiation, allowing for the LTP to continue
The calcium in the post synapse then activates a protein called calmodulin kinase 2
(This is ONLY seen in 5% of pre synapses) its more common in post synapses
What does calmodulin kinase 2 do?
One of the targets is the AMPA receptor - it can phosphorylate this and help it to open
The calmodulin kinase 2 can phosphorylate itself hence why a LTP can last.
How does the action of the calmodulin kinase 2 phosphorylate AMPA receptors affect glutamate current and LTP?
It causes glutamate current to increase through the membrane allowing a LTP
What are we unsure about?
If protein kinase C works in LTP too
What happens to AMPA vesicles in the post synapse when there is the early LTP?
Note the movement of calcium into the POST synapse should give you a clue
There is a pool of post synaptic vesicles with the AMPA receptors
When an LTP occurs (as in when calcium moves inside)
This causes the AMPA vesicles to fuse to the post synaptic membrane during LTP induction.
Remember calcium causes vesicular fusion!
This increases the number of AMPA receptors in the membrane = AMPafication
When does the late phase of LTP occur?
1 hour after initiation of the early phase
What happens in the late phase of LTP?
How are these proteins made?
So in this phase proteins are expressed which help LTP continue
How are these proteins made?
- cAMP causes the expression of genes that have a CRE promoter
- this sequence binds to specific transcription factors
- CREB -2 transcription factors are substituted for CREB 1 transcription factors.
- these are the phosphorylated by protein kinases that depend of cyclic AMP
- these transcription factors make certain genes express proteins which ensure LTPS can continue.
So the steps for when glutamate binds to the post synaptic membrane?
AMPA receptors depolarise the membrane
These receptors have its magnesium removed due to the change in membrane potential
Calcium enters
This activates calmodulin and calmodulin kinase 2
This leads to phosphorylation of AMPA receptors
Adenylyl cyclase is then activated which activates protein kinase A
This then is translocated to the nucleus. This trigger gene expression.
What is the link between LTP and memory? What is the morris water maze exp? And what happens if you insert mutations into the calmodulin kinase 2 enzyme
So LTP has been linked to some memory formation
- inhibiting LTP inhibits some memory formation
Experiment: put a mouse in water - it has to find a hidden platform.
- next time the mouse goes in the water, the mouse finds the right platform
However in transgenic mice?
- if you affect the calmodulin kinase 2 enzyme which is important in AMPA receptor phosphorylation then the ability to remember where the platform is is affected
How can zebrafish be used to in two experiments to show synaptic plasticity and vesicular binding?
Reporters can be measured to study synaptic plasticity
This can be used to define brain areas in which memory is formed
How can we see vesicular formation ?
A form of GFP called phluorin GluR2 can be used which is sensitive to pH
In most vesicles pH is low
This causes GFP to be not as bright
When binding to the membrane pH increases and GFP colour also does
What is important to note about LTP and what is it linked to?
LTP is only necessary for some memory formation - not all
LTP is a phenomenon which is linked to long term depression
LDP?
-
leads to a decrease in sensitivity to the same amount of neurotrasmitter
This is also related to memory
Where can LTD occur?
Hippocampus and cerebellum
What causes LTDs?
Prolonged stimulation
Causing a decrease in a EPSPs amplitude
What are the three neural cell types in the cerebellum?
Purkinje cells:
- have very large and dense dendritic trees
This is only in one plane
It has lots of synpases
Climbing fibres
- grows around the purkinje cell
It has alot of synpases around the purkinje cells
Parallel fibres:
The fibres synapses with many different purkinje cells - only once
Stimulation of neuronal cerebellum cells?
Stimulation by climbing cells causes mass depolarisation of purkinje cells
Stimulation by parallel fibres causes smaller depolarisation of purkinje cells
Stimulating both parallel and climbing fibres in the cerebellum?
Decreases the EPSP amplitude in the purkinje cells
To stimulate LTD?
Stimulate much longer with a smaller frequency
You thus get a lesser EPSP in time.
Similarity between LTP and LDP
There both show input specificity
Both localised at the synapse
Two types of LTD?
Depotentation:
- this happens after an LTP
- may be related to wiping out of memory
LTD de novo:
- there is no relation to previous potentiation
This affects memory formation
What is meant by LTD having the ability to be hebbian and non hebbian?
- so it may only involve one synapse like LTP
Or if it is non hebbian it may involve two synapses
General features of what cause LTD? Not exclusive to the cerebellum
NMDA receptors are often involved (note this doesnt say AMPA)
And low frequency stimulation
It often involves calcium influx and activation of different serine / theronine phosphates
It is often involved in glutamate but also diffuses via transmitters like 5 - HT
Endocannabinoids like anandamide are related to inhibited presynaptic transmitter release. Which would cause low frequency stimulation
What causes LTD in the purkinje cells?
- if you stimulate both climbing and parallel fibres
You have a decrease in EPSP caused by stimulation of parallel fibres
LTD is caused by metabotropic and AMPA receptors. Not NMDA receptors
What. Happens when you stimulate climbing fibres without prukinje fibres?
You dont get an LTD
AMPA receptors are stimulated
This causes depolarisation of the membrane. This further causes voltage gated calcium channels to be activated
What happens if you stimulate both parallel and climbing fibres?
Keep in mind climbing fibres help bring calcium
Stimulating parallel fibres causes the activation of metabotropic glutamte receptors
These activate the phospholipase C
This stimulates DAG to make kinase C activate)
Calcium makes kinase C activated!!
Kinase C phosphorylates AMPRa receptors but also causes them to be endocytosed, which leads to LTD. as an AMPA current is no reduced for the future
What can endocytosis inhibitors do?
Prevent LTD
Similarities of LTP and LTD?
There is phosphorylation of receptors but it happens at different places
Hippocampal LTD
Happens in synpases between CA3 and CA1 neurones. This occurs due to long frequency stimulation at low frequencies
This is calcium dependent
How active an NMDA receptor is dictates whether LTD / LTP occurs:
So how does the influx of calcium affect this?
And what do you see more of in LTD’s? What do you see more of in LPTS?
Small increases in calcium from NMDA. Receptors trigger more phosphatase action and reduce AMPA receptor efficay - so this is low frequency stimulation. So you have an LTD
Large increases in calcium activate more protein kinases so you have a LTP.. high freq stimulation
So for LTD you have more phosphatases and LPT you have more kinases
Where are the two places that LTDs occur?
At the synpase of purkinje cells
And in the hippocampus between CA3 and Ca1
Does LTP and LTD help memory formation?
No. Isnt completely sufficient for memory formation
