L1: Synaptic plasticity

How are synapses dynamic

• With repeated use→ show short-term or long term changes

Synaptic plasticity

What does synaptic plasticity allow

• allows nuerons to store information

• in response to different degrees of experience

• Changes can either

  • increase synaptic efficacy →potentiation

  • Decrease synaptic efficacy→ depression

Short term vs long term plasticity

Short term

• timescale of ms→ several mins

• contribute to computations in neural circuits

Long term

• mins→ hours→ years

• hypothesised to be the basis of learning and memory

What happens when a presynaptic neuron is stimulated experimentally/physiolgically

1. action potential travels the length of the axon

2. until it reaches the presynaptic terminal

3. Ca enters via voltage-gated calcium channels

4. leads to local increase in Ca concentrations

5. Release Neurotransmitters in synaptic cleft

   1. glutamate in excitatory

6. binds to AMPA ionotropic receptor

7. entry of Na+ into postsynaptic neuron

8. generates current→ EPSC

The mean amplitude/size (m) of the EPSC of the postsynaptic cell is equal to

p*n*q

p→ probability of release

q→ quantal size→ i.e postsynaptic receptor response to single discrete (one quantal) of vesicle transmitter release

n→ number of release sites→ readily releasable vesciles

SYNAPTIC TRANSMISSION→ WITHOUT PLASTICITY

Due to no plasticity yet…

• after some time another AP arrives at the presynaptic terminal

• BUT

• we get the SAME mean amplitude/size (m) of EPSC

However, there is residual Ca ions left at presynaptic terminal

Why are there residual Ca ions left at the presynaptic terminal

• result of the arrival of an AP

When does residual go back to baseline?

• after 200 ms

What happens if another AP arrives within the 200ms?

1. leads to greater Ca concentration increase in presynaptic neuron

   1. as levels build up on the residual level already left over

2. increases probability of release (p) of glutamate

3. → amplitude (m) of the second EPSC

→ PAIRED PULSE FACILITATION

What does the interval between the two stimuli determine?

• the extent of increase of the second EPSC

• The longer the interval between the two stimuli→ the lower the amplitude of the second EPSC generated 

  • because there will be less residual calcium available for the arrival of the second AP at the presynaptic terminal

Paired pulse depression

• arrival of the second AP to be shortly after the first AP

however

• the second stimulus results in a smaller EPSC amplitude in the postsynaptic neuron

Why is there smaller EPSC amplitude in the postsynaptic neurone?

• decrease in readily available vesicle pool

• i.e number of release sites (n)

The longer the interval between the two stimuli…

• the less the size of the attenuated second EPSC

Why sometimes we get depression due to arrival of a paired pulse and another time facilitation?

1. if the first synaptic transmission results in larger response (bigger EPSC)

• → the direction of the change/plasticity will be towards decrease

  • PAIRED PULSE DEPRESSION

2. If the first synaptic trasmission gives a smaller response

   • there is a tendency to facilitate that synapse to become stronger

   • therefore: direction of plasticity will depend on the strngth of the synpatic transmission prior tot he second pulse arriving

Facilitation and depression coexist?

• can co-exist at the same synapses

• with history of activity influencing the direction of plasticity

High release probability favours (p)…

depression

• i.e is there was originally alot of release from before

• it is less likely that in the second time around there will be enough NT to release

• if there hasn’t been enough time to get NT vesicles back?

Low (p) favours

Facilitation

Therefore this shows an example of plasticity

• the strength of the synaptic transmission can be dynamically altered

Computations and short term synaptic plasticity

• short term plastisicty takes place over period of milliseconds to seconds

• not long lasting

→ they take part in synaptic computations

Example of this: High pass and low pass filtering

High pass filtering

• presynaptic neurone stimulated at a high frequency 

• then this frequency is not filtered

• its is passed to the post synaptic neuron

  • → post synaptic neuron also fires at the same frequency

This is due to the mechanism of…

Paired pulse facilitation:

1. As presynaptic neurone fires action potentials at a high frequency

2. the EPSC on post synaptic neurone increases in size

3. results in higher chance of action potential generation as the membrane depolarises to its threshold for firing

4. allows the postsynaptic neurone to fire at the sam frequency as the presynapatic neuron

What happens if the presynaptic neuron is activated at a lower frequency

• EPSCs do not increase

• → no facilitation

• → less chance of action potential generation/firing of the post synaptic neurone

  • i.e lower frequencies are filtered out

What does this help to make sure?

• only the presynaptic neurone (and hence synapases) that are very active pass on the info

• to a post-synaptic neurone

• → the less active synapses to be filted out

OVERALL: high pass filtering

Low pass filtering

→ Converse situation

due to paired pulse depression

Because the cell has a high probability → so a low frequency stimulation will excite but a high frequency will cause low filter to pass and the high frequency to stop.

Paired pulse depression

If presynaptic neuron fires at a high frequency:

1. decrease in EPSC size (because not enough NT? coz it is a high p neuron?)

2. less chance of action potential firing as threshold for AP generation is not reached

3. higher frequnecies are filtered out

if presynaptic neurone is firing a a low frequency

1. no attenuation of the EPSC

2. AP can generated

   1. (the EPSC was large to begin with during paired pulse depression)

Long term plasticity: allows neurons to store information for how long?

• longer time period of hours→ days→ months→ yyears

What changes in the synapes in this plasticity

1. structurual changes

   • spines!

2. changes involving molecular mechanisms

   • → changes in neurotransmitter release

   • and/or

   • changes invovling receptors and post-synaptic levels

Long-term potentiation (LTP)

• lasting changes that result in strengthening of synaptic transmission

Long term depression (LTD)

• lasting changes that lead to weakening of synaptic transmission

There are different forms of experimentally induced LTP and LTD depending on…

• the brain region and transmitter receptors involved

Why has the hippocampus been extensively studied?

1. as well defined layers → allow experimenter to relatively easily electrically stimulate one layer whist recording from the other that receives a synapase from the stimulated layer

2. Hippocampus (and neocortex) are two structurates involved in learning and memory

How has the hippocampus been studied

LTP and LTD protocols:

• induced in different regions of the hippocampus and cortex

  • including dentate gyrus, CA1 region, visual cortex and somatosensory cortex

One form of LTP

NMDAR-dependent LTP

How is NMDAR-dependent LTP induced experimentally

• in different regions of the brain

  • CA1 or hippocampus

What does experimental stimulation cause?

1. Stimulate pre-synaptic neurones→ e.g Schaffer collaterals in the hippocampus

2. result→ arrival of AP in the presynaptic terminals of the neuron

3. Calcium enetry via voltage gated Ca Channels

4. leads to release of glutamate from presynaptic terminal

5. Glutamate bind to AMPARs of the postsynaptic membrane

6. allows Na+ influx through AMPARs

7. leads to slight depolarisation of the post-synaptic spine

How is this depolarisation recorded?

Via electrode

1. Group of CA1 neurone via an extracellular electrode

   • → field Excitatory Post Synaptic Potentials

2. From a single neurone via intracellular electrode or using whole cell patch clamp technique

How does the experimenter stimulate the pre-synaptic Schaffer collaterals

• at a constant amplitude and frequency

  • such as every 10 seconds

• → forms the baseline recording

What happens in baseline recording

1. AMPARs activated

2. synaptic efficacy remains the same→ each pre-synaptic stimulation there is the same size of AMPAR-mediated post-synaptic response

3. NMDARs→ still blocked by magnesium ions at hyperpolarised potentials

   • → NO ION FLUX through NMDARs

Experimental protocol that can have a long lasting change on synaptic efficacy

• activation of presynaptic neurone 

• at a high frequency 

• Types:

  1. 100 Hz High frequency stimulation (HFS)

  2. Theta burst stimulation (TBS)→ a non-invasive brain stimulation technique that uses short, high-frequency bursts of magnetic pulses to modulate brain activity

What does this high frequency of presynaptic neuron sttimulation lead to

1. increased Na+ flux in post-synaptic neurone

2. lead to further depolarsiation of post-synaptic spine

3. Mg blockage of NMDARs is relieved

4. NMDARs allows Na+ and Ca+ entry 

5. accumulates in the post-synaptic spine

6. Ca can act as a second messenger (the first messenger is glutamte)

7. activates specific intracellular mechanisms

What intracellular mechanisms are activated

1. Activation of calcium calmodulin (CaM)

2. activates calcium-calmodulin-dependent protein kinase II (CaMK-II)

3. kinase phsophorylate post-synaptic AMPA receptors at the GluA1 subunit and GluA2 subunit

4. increasing AMPAR conductance

CaMK-II can also be involved in…

• trafficking of more AMPA receptors to the synaptic spine

Thus, subsequent to delivery of HFS or TBS, when the freuency of presynaptic stimulation is returned to pre-induction frequency…

when back to original frequency baseline

1. the AMPAR conductatnce is larger than prior to TBS/HFS delivery.

2. So synaptic efficacy increases

3. This is a long lasting (up to an hour) in creases

4. THEREFORE is LONG TERM POTENTIATION

A larger synaptic efficacy means that

• there is higher probability of AP generation in the post-synaptic neurone

• as a result of synaptic transmission

The induction of LTP occurs

• during the short period of HFS/TBS delivery

• where NMDARs are open

As LTP induction requires activity of NMDARs

• this LTP is called NMDAR-dependent LTP

• Evidence:

  • if the experimenter blocks NMDARs during HFS/LTP protocol

  • LLTP cannot be induced

During LTP induction, NMDARs act as…

• as coincident detectors

Meaning→ they are activated only when the pre-synaptic release of glutamate is coincident with post-synaptic depolarisation

What allows them to be coincident detectors

• blockage of magnesium at resting potentials

Coincident detection can be better appreciated during

Pairing protocols

Pairing protocols

For induction of NMDAR-dependent LTP :

1. a high frequency closer to baseline levels

2. AT SAME TIME AS the post-synaptic neurone is depolarised by the experimenter

→This depolarisation is enough to relieve the magnesium block of NMDARs

Therefore what is required for LTP induction

• NOT: high freuency stimulation of presynaptic neuron is not required to gradually depolarise the post-synaptic neuron via more soduim entry AMPAR receptor

instead

• The concident of presynaptic neuron and post-synaptic neuron is again the requirement for LTP induction

What allows this coincidence of presynaptic firing and post-synpatic depolarsiaion

1. the magnesium blockage of NMDARs at hyperpolarised potentials

2. and relief→ and hence Ca2+ entry

How fast must the depolarisations be for LTP to be induced

• depolarisation of post-synaptic neuron within 10ms 

• following the EPSP generated as a result of the presynaptic release of glutamate 

  • in order for the LTP to be induced

what happens if the postsynaptic cell is depolarised much later than the EPSP generation

• the LTP is not induced

Overall, what are the unique properties of NMDARs that form the basis of the role in inducing LTP

1. high calcium permeability

2. blockage by Magnesium at resting membrane potentials

3. slower kinetics of NMDA receptors compared to AMPARs

The properties of NMDARs contribute to three features of LTP

1. Co-operativity

2. Input Specificity

3. Associativity

Cooperativitity

• if more presynaptic fibres are recruited

  • by increasing the intensity and not the frequency of the stimulation protocol

• then more glutamate will be released

• → higher chance that the postsynaptic neurone (or neurones) will be depolarised

  • hence leading to removal of magnesium blockage of NMDARs

what ensures that only pathways that are highly active induce LTP→ input specificity

• because depolarsiation of the postysynaptic neurones (the output)

• and the magneisum relief of NMDARs only occurs at the postsynaptic spines that receive the high frequency input

• →as other pathways without high frequency input and postsynpatic depolaristion do not change in synaptic efficacy

→ input specificity

Input specificicity

Associativity

• follows from input specificity and cooperativity:

1. If there are two pathways that target the same postsynaptic neurone (or neurones)

2. but pathway A cannot induce LTP by itself

3. but pathway B can induce LTP by itself

   • (pathway A has smaller intensity of stimulation than pathway B)

     • i.e recruitetes less fibres than pathway B

4. → IF high frequency stimulation is simultaenously applied to both pathways

   1. Then LTP is induced in both pathways also

Why is this?

• postsynaptic target will be depolaised sufficiently enough 

• to allow for opening  of NMDARs

• and Entry of calcium ions into the spine of pathway A

This is again the idea of coincident detection:

• presynaptic glutamate release is coincident with postsynaptic depolarisation

The induction of NMDAR-dependent LTP during TBS/HFS leads to…

• subsequent increase in AMPAR components on post-synaptic neurone

This increase is called→

• The expression of NMDAR-dependent LTP

• i.e only the induction is NMDAR dependent

Not post induction:

• if the experimenter blocks NMDARs post HFS/TBS application (after LTP induction)

• the synaptic efficacy remains high

NMDAR dependent LTP is an example of

• Hebbian plasticity

• Canadian pshycholist Donald Hebb

• When an axon of Cell Ais near enough to excite a cell B and repeatedly and persistently takes part in firing it

• some growth process or metabolic change takes pace in one or both cells suchas that A’s efficiency (as one of the cells firing B) is increased

In the case of NMDAR dependent LTP, the expression  of this cahnge is the…

• the increase in AMPARs

• on the postsynaptic membrane

Overall summary of NMDAR dependent LTP (need to check this)

1. Apply HFS/TBS 

2. NMDAR more likely to open Mg gate

3. Ca2+ into postsynaptic neuron

4. Causes kinase actiivty

5. increases no. AMPARs to membrane (expression)

6. and also more spines? thicker?

7. stronger efficacy

Order of paired protocol determines if LTP or LTD

Post synaptic second= LTP

Pre synaptic second =LTD