Signalling: NT release

Question 1

How can synapses me modulated?

Answer 1

Short-term:
Facilitation, depression + temporary potentiation.

Long-term:
Long-term potentiation (LTP) and long-term depression.

Question 1

How is synaptic input received and responses produced?

Answer 1

Single neurones can have many thousands of inputs

Synaptic input received in integrating segment.

Responses produced in spike initiation zone.

Question 2

What is facilitation?

Answer 2

Short-term modulation of synapse.

2 or more AP’s reach pre-synaptic terminal in short period of time.

Increased NT quanta = more NT released per AP.
= leading to a stronger response in post-synaptic neurone
= more frequently used pathways become more effective!

Facilitation is enhanced by shorter intervals between APs.

Question 3

What is synaptic depression?

Answer 3

In response to a tetanic train, the first response of a synapse is depression.
= depletion of NT, results in decreased NT quanta + decreased post-synaptic response.

Question 4

What is a tetanic train?

Answer 4

Rapid succession of APs close together.

First response to a tetanic train is depression….

Question 5

What is post-tetanic potentiation?

Answer 5

Following depression, there may be changes to Ca2+ dependent processes which increase the production of synaptic NT vessicles available per incoming AP.

In addition, there may be rapid fire tetanic stimulation without depression, which can lead to enhanced NT vessicle production and ptotentiation of post-synaptic response.

= causing a SHORT-term enhancement of synaptic activity.

Which only persists temporarily… elementary form of memory!

Question 6

What determines the specificty of short term plasticity?

Answer 6

Short term plasticity is specific to individual synapses, not the neurone itself - branches from the same axon might undergo different short term plasticity.

Question 7

What is the Hebbian synapse?

Answer 7

Neurones can have many inputs, but inputs that operate similarly can work in harmony/synchrony.

Synapses of inputs that work in harmony are strengthened and the efficiency of these connections are strengthened = so pathways can respond better to particular stimuli.

Synapses associated with same kind of input are strengthened, whilst those that are not harmonious would be weakened = Stimulation from more common, repeated pathways would result in a greater synaptic response…

Reduction in threshold and strenghthening of in phase activity.

Question 8

What is long-term potentiation?

Answer 8

Responding to tetanic stimulation results in durable, enhanced synaptic activity which can persist for weeks or longer after tetanic event.

Synaptic activity enhanced by NMDA receptors, Ca2+/Calmodulin-dependent protein kinases (CAM-KII), retrograde factors…

Greater availability of Ca2+ for synapstic vessicles + enhanced receptor responses post-synaptically.

LTP associated with increased Ca2+ influx and activation of Ca2+ dependent protein kinases CAM-KII and PKC.

Question 9

What is LTD?

Answer 9

Long-term depression = reduced synaptic activity = with reduced availability of Ca2+ + synaptic receptors…

Question 10

Where has LTP been documented?

Answer 10

Hippocampus = spatial memory
Amygdala = fear memory.
Cortex = LTP-like mechanism for motor skill.

Question 11

What are the different pathways in the rodent hippocampus?

Answer 11

Perforant pathway = entry from entorhinal cortex to Dentate Gyrus.
= Stimulating Granule cells in DG.

Mossy fibers extend from Granule cells in DG to the Pyramidal cells in CA3.

Schaffer collaterals extend from pyramidal cells in the CA3 to pyramidal cells in CA1.

Question 12

How can LTP be measured in rodent hippocampus?

Answer 12

Measure input in CA3 pyramidal cells, measure input in CA1 pyramidal cells.

Apply tetanic burst to Schaffer collaterals to stimulate the CA1 pyramidal cells.

Measure EPSP before and after tetanic train - pathways with high activity, may be able to see enhanced EPSP…

with LTP - there would be a greater probability of enhanced EPSPs…

Question 13

What retrograde messengers can influence LTP?

Answer 13

NO, CO, arachidonic acid - secreted retrograde messengers can modulate pre-synaptic neurone + quantal release.

Question 14

What proteins are involved in LTP?

Answer 14

Increased AMPA function and number post-synaptically.
+ conductance (PKC and PKA phosphorylate).

CAM-KII = activated by Ca2+/Calmodulin but can be phosphorylated, such that it is active independently to Ca2+.

PKC and PKA can phosphorylate AMPA and increase conductance through channel

Question 15

How do NMDA and AMPA receptors relate to LTP?

Answer 15

Whilst AMPA receptor numbers may be limited, repeated NMDA activity during LTP and its intracellular signalling leads to the increased recruitment and activity of AMPA receptors.

= The increased senstivity of post-synaptic cell is mediated by NMDA, but expressed as greater activity and function of AMPA receptors!

= Increased pre-synaptic quantal release with potentiated response.

Question 16

How are silent synapses converted to active synapses?

Answer 16

Glutamatergic synapses all express NMDA receptors, but not all synapses express AMPA.

Repeated activation of NMDA and its signalling leads to the recruitment of AMPA receptors - via Ca2+ conductance through channel = increased CAM-KII…. fusion of AMPA receptors.

Question 17

How are NMDA receptors activated?

Answer 17

Under non-depolarised conditions, Mg2+ blocks the NMDA receptor channel.

NMDA requires glutamate to bind to orthosteric site AND glycine to bind to allosteric site in order to open channel.

= NMDA dual-gated.

BUT, even with glutamate and glycine bound, Mg2+ will continue to block channel pore if membrane remains polarised.

= Therefore, independent membrane depolarisation is required to relieve Mg2+ block and allow ion flux.

Question 18

What ions flow through NMDA?

Answer 18

Ca2+/Na+ in, K+ out. = depolarisation = EPSP.

Question 19

What are the different regulatory site of NMDA?

Answer 19

NMDA can be modulated by redox changes of thiol groups in NMDA complex.

= Reducing agents causes activation = Dithiothreitol.

Oxidising agents = reduces activation.

Endogenous polyamines modulate NMDA - low uM potentiates, high uM inhibit.

Activation of intracellular PKC enhances NMDA responses.

Question 20

What is the structure of NMDA receptors?

Answer 20

Hetero-oligomeric complexes - requiring atleast 2 copies of NR1 and 2 copies of NR2.

NR1 binds glycine, whilst NR2 binds glutamate.

Question 21

How can NMDA be blocked?

Answer 21

MK801 can block channel.