Presynaptic Plasticity

Question 1

Short term plasticity is related to LTP/LTD (true or false)

Answer 1

False
Ltp and ltd are long term processes
Short term plasticity refers to the process by which signals are potentiated or depressed in the short term

Question 2

How is short term plasticity induced?

Answer 2

Paired pulse stimulation - 2 stimulations received within milliseconds (50ms) of each other where the first alters the postsynaptic cell response to the second stimulus

Question 3

There are two types of paired pulse responses…what are they?

Answer 3

Paired pulse facilitation - where the second stimulation increases current
Paired pulse depression - where second stimulation associated with a decrease in current

Question 4

How long does this facilitation or depression last?

Answer 4

10’s or 100’s of miliseconds

Question 5

Why might PP depression occur?

Answer 5

High release probability of synapse means there is depletion of vesicles
On second stimulation there are no vesicles to be released the free response is depressed in postsynaptic cell

Question 6

Why might PP facilitation occur?

Answer 6

Low release probability therefore many vesicles left in reserved pool

On second stimulation residual calcium from first stimulation will increase release probability of neuron to the second stimulation

Question 7

What happens to continual stimulation to parallel fibres in the cerebellum with a extracellaul conc of calcium of 2.5mM compared to 1mM?

Answer 7

Both show facilitation but facilitation is more gradual in the lower extracellular concentrations
Calcium therefore governs facilitation

Question 8

Lower probability synapses undergo more potentiation because…

Answer 8

Calcium builds up
Gradual increase in vesicle release
Higher probability release

Question 9

Vesicle release is proportional to what?

Answer 9

[Ca2+]e ^4

Therefore small change in calcium = bigger change in vesicle release

Question 10

What is the concentration of residual calcium left in a neuron following neurotransmitter release?

Answer 10

Approx 500nm

Question 11

Why does residual calcium decay at slow rate?

Answer 11

Slow buffers e.g. Parvalbumin

Question 12

What does residual calcium modulate?

Answer 12

It modules asynchronous neurotransmitter release

Question 13

How does residual calcium modulate NT release?

Answer 13

It binds to high affinity calcium sensors (these are important in PPF)

Question 14

What modulates synchronous neurotransmitter release?

Answer 14

Low affinity calcium sensors e.g. Synaptotagmin

Question 15

The relationship between intracellular calcium and NT Release rate shows a sigmoidal relationship. Why could this be?

Answer 15

Allosteric cooperativity and a 5 site model
I.e. As more calcium binds to synaptotagmin it gains affinity for calcium
OR
Calcium releases is first spontaneous then asynchronous (responds to low conc is calcium) and moves to synchronous with high calcium concentrations

Question 16

What is the problem with the 5 site model?

Answer 16

Binding to synaptotagmin does not show cooperativity but is linear
does not account for the huge range of calcium which modulates transmitter release
KO of synaptotagmin does not attenuate asynchronous release (actually enhances it)

Question 17

Since KO of synaptotagmin does not prevent asynchronous NT release what does this mean?

Answer 17

There may be two calcium sensors
1 which mediates fast ‘classical’ NT release
1 which modulates asynchronous release - unknown protein

Question 18

Why might paired pulse depression occur?

Answer 18

Vesicle depletion
Inactivation of release sites
Decreased calcium influx

Question 19

Number fo vesicles released depends on?

Answer 19

Release probability

Number of readily releasable vesicles

Question 20

What is meant by inactivation of release sites?

Answer 20

Vesicle fusion inhibited by current vesicles attached to exocytic machinery
Time taken to clear proteins involved in fusion which have been intergrated into membrane effect this

Question 21

How can depression be caused by a decrease in calcium influx?

Answer 21

Calcium may modulate calcium influx
E.g. Calmodulin can mediate calcium channel function
Depleting calmodulin binding site in p-type calcium channels prevents calmodulin dependant depression. Therefore, decreasing calcium in a cell decreases calcium calmodulin and thus calcium calmodulin complex cannot inhibit p type channel

Question 22

What receptors are important for plasticity at mossy fibres?

Answer 22

Adenosine (a1) receptors
MGluRs
Kainate receptors

Question 23

What proteins mediate recovery from PPD?

Answer 23

Proteins within tha active zone such as rim1 and bassoon

Question 24

What is special about eh synapse between mossy fibres and ca3 neurons?

Answer 24

PPF occurs here
Very large synapses
Low degree of release probability

Question 25

How does adenosine regulate release probability?

Answer 25

Tonic adenosine acts on A1 GPCR located in presynaptic membrane Decreases cAMP via Gai Which decreases release probability

Question 26

What happens to release probability on A1 GPCR KO?

Answer 26

Prevents facilitation As there is a loss of adenosine inhibition on vesicle release Vesicle pool depleted rapidly Will enhance EPSP whilst reduce potentiation

Question 27

What is the the effect of glutamate on presynaptic kainate receptors? How?

Answer 27

Enhances neurotransmitter release on second stimulation in paired pulse delivery. First pulse = glumate release Feedbacks back to kainite receptors which increases release probability On second stimulation more NT is release causing facilitation

Question 28

What proteins cause kainate mediated PPF?

Answer 28

?CaMKII ?Camp

Question 29

What mGluR subtypes are responsible for feedback to influence release probability?

Answer 29

MGluR 2+3

Question 30

How do mGluRs effect release probability?

Answer 30

They inhibit calcium channels therefore decrease frequency dependant facilitation

Question 31

Why are mGluRs only activated at high frequency firing?

Answer 31

Located at preterminal zone High levels of glutamate are required to 'over spill' to reach this area Therefore, high frequency firing required to achieve mGluR mediated negative feedback High levels may also act on neighbouring mossy fibres

Question 32

What is the problem with mGluR negative feedback?

Answer 32

mGluR agonists attenuate postsynaptic EPSPs However, they do not completely reduced presynaptic calcium levels alone. There must be another mechanism by which mGluRs modulate neurotransmitter release

Question 33

How is LTP at the mossy fibre synapse different to that between CA3-CA1 neurons?

Answer 33

It is NMDAR independent | Reflect changes in calcium with pre synaptic neuron

Question 34

What channel is believed to be responsible for mossy fibre LTP? Why?

Answer 34

R type calcium channels | Attenuation of function disrupts LTP

Question 35

Why is LTP not due to p/q or n type calcium channels?

Answer 35

Attenuation of theirt function does not disrupt LTP | Means that either one type provides sufficient calcium or that it comes from another source

Question 36

What subunit is found in r type calcium channels?

Answer 36

Alpha 1 e subunit Lowers the threshold for presynaptic LTP at low firing rates These channels have preferential access to AC1 but not release machinery

Question 37

How does R type calcium channels cause presynaptic LTP?

Answer 37

``` Calcium binds to AC1 Activates it (deletion of AC1 actuated LTP) Increase in cAMP Increase in PKA Facilitation ```

Question 38

What is the mechanism of PKA facilitation?

Answer 38

Unknown but may involved rim1(alpha) rab3a interaction as KO prevents LTP