Week 3 Topic 1 - Action potentials and synaptic transmission

Question 1

Part 2

Answer 1

So in the last section, we discussed how the neurons are able to set up their resting membrane
potential. Now in this section, now that they have established a resting membrane potential, we’re
going to look at how they can integrate signals from, for example, a presynaptic neuron, on the left
here, and how that would integrate the response to the postsynaptic neuron. Now of course, here
we’re going to discuss a one-to-one relationship

Question 2

Part 3

Answer 2

In the last section, we discussed how these neurons can integrate information from their
presynaptic partners or from the surrounding, and we spoke about how this can be very divergent
with up to 400 inputs.

Now after the signal is transmitted through the dendrites and the cell body to the axon initial
segment, this is where it can then trigger an action potential, and that’s what we’re going to focus
on today. We’re going to focus on how that action potential generation works here at the axon initial
segment, this highly specialised component in the start of the axon.

Question 3

Part 4

Answer 3

In this section, we’re now going to look at how the action potential is conducted along the axon. So we
started now with understanding how the signal is integrated the dendrites and the cell body, how this
then has triggered the action potential at the axon initial segment. And now we’re going to look a thow
both myelinated and unmyelinated fibres transmit this action potential along the length of their axon
to the terminal field, where it can then have an effect on the postsynaptic neuron in this case or, for
example, on muscle tissue to engage movement.

Question 4

Part 5

Answer 4

We’ve seen in our previous sections now how the dendrites in the cell body aim to create the
incoming signals, how the action potential is generated at the axon initial segment, and how this is
transmitted along the length of the axon. And in this section, we’re going to focus now on how this
signal, then, is transmitted between axon to axon. We’re going to focus on neurotransmitter release,
so chemical synapses in this section, but it’s important to note that electrical synapses also exist, and
you can read further in those if you wish.

We’re going to focus now on this very small region here between the two neurons, known as the
synaptic cleft, and to do this, we have a presynaptic zone here in blue in the top.

Question 5

What is the membrane surrounding all cells (including neurons) called?

Answer 5

All cells, including neurons, have this membrane surrounding them, and that’s this phospholipid
bilayer. This is a hydrophobic layer, so it allows the separation of aqueous ions between the
extracellular space and the intracellular space, allowing us to set up these ionic gradients that we’re
going to discuss.

Question 6

What are the two ways ions can move across a neuron’s membrane?

Answer 6

1. proteins in the form of pumps, such as the sodium-potassium ATPase
2. ion channels, such as the sodium channels and the potassium channels here in grey and purple.

Question 7

What are the three types of ion channels?

Answer 7

1. leak channels. That is, they’re open, and they allow ions to passively flux up and down their concentration gradients.
2. voltage - gated ion channels which are closed at the resting condition and can respond to an external stimuli like electricity and allowing these channels to flux ions across the membrane.
3. ligand-gated channel which are closed at the resting condition and responds to a neurotransmitter, causing this gate to open and allowing these channels to flux ions across the membrane.

Question 8

Which type of ion channels are most typical in neurons?

Answer 8

Most membranes and neurons have a higher concentration of
potassium leak channels, and this is important for setting up the resting membrane potential, ( ratio is 3 to 1 ) but this is just representative.

Question 9

How do the

anions,
Ca +
K+
Cl-

potassium leak channels
sodium leak channels
sodium-potassium ATP pumps

set up the ionic gradient across the membrane at resting potential?

Answer 9

Inside the cell, we have these large, organic anions and these are negatively charged ions
on large proteins.

These are locked within the cell, so they can’t cross the membrane.

And as you can
see, this puts a negative charge inside the cell in the intracellular space.

This has the effect of drawing
positively charged sodium and potassium ions, sodium in the blue and potassium in the green here,
towards the extracellular space and repelling slightly negatively charged ions such as chloride ions
2.
. And that sets up a net positive charge along the extracellular space.
And as we mentioned, there are more potassium leak channels in the membrane. In response to this
electrostatic charge, this want for the positive charged ions to be attracted towards the negative ions
inside the cell, more potassium will enter the cell, making a higher concentration of potassium inside
the cell.
Now of course, some sodium will also enter the cell, but because there are less sodium leak
channels, this is relatively fewer than the potassium. And we also have a low concentration of
chloride ions within the cell, setting up this ionic gradient across the membrane.

We have relatively more potassium within the cell, as can be seen here in the green, and relatively
fewer on the extracellular space. Again, there’s a higher concentration of sodium on the extracellular
space compared to the intracellular space.

These sodium-potassium ATP pumps, they act to help maintain this concentration gradient.

Of
course, I should point out as well that we have a higher concentration of chloride ions outside the cell
as opposed to inside the cell.

Obviously, these ionic gradients are established, and the sodium-potassium pump acts to pump
ions against these gradients, so it’s an energy-dependent mechanism that helps to maintain the high
concentration of potassium inside the cell and the lower concentration of potassium outside the cell.

In order to do this, the pump needs energy. This is an energy-dependent mechanism, so it uses
adenosine triphosphate and changes this, obviously, to adenosine diphosphate and an organic
phosphate molecule.

And this energy allows the channel to collect three sodium channels from the
intracellular space, as you just saw, and actively pump them to the extracellular space.

In turn, two
potassium ions are gathered from the extracellular space and pumped to the intracellular space.

This has two mechanisms.

This, first of all increases the concentration of sodium in the extracellular
space and increases the concentration of potassium in the intracellular space. But also, as three
positively charged ions were pumped out of the cell and only two positively charged ions were
pumped into the cell, this helps to maintain the net negativity of the intracellular space compared to
the extracellular space.
Slide 8
This is what we can see here.

At the resting membrane potential, we have this mix of ions in the
outside, largely sodium and chloride and fewer potassium, and on the inside, we have a greater
concentration of potassium and fewer sodium and chloride ions. This sets up a gradient across the
membrane, and

Question 10

At resting potential, what are the two forces ions are under?

Answer 10

these ions are under two forces.

1. First of all, they’re under the force of the electrostatic force, and that is the charge component. The
   want for the positive ions to go towards the negative ions, for example, through the leak channels, as
   we discussed.
2. But they’re also under the force of diffusion. That is that they want to move along their concentration
   gradients from an area of high concentration to an area of low concentration. So for example, under
   these conditions for diffusion, potassium would want to leave the cell and go to the extracellular
   space.

Question 11

With an action potential, how is sodium impacted by electrostatic and diffusive forces?

Answer 11

It’s important for the action potential, that we’ll come to a later section, to see how these
electrostatic forces influence the different ions.

For sodium, as you can see here, both the
electrostatic force in red and the force of diffusion want to drive sodium into the cell, so sodium is
very potentiated and very ready to drive into the cell should these voltage-gated sodium channels
open.

Question 12

With an action potential, how is potassium impacted by electrostatic and diffusive forces?

Answer 12

Potassium, on the other hand, has divergent forces. The charge component, the electrostatic
component in red, as we discussed, brings potassium into the cell, but the force of diffusion wants
to take potassium out of the cell.

Question 13

With an action potential, how is chloride impacted by electrostatic and diffusive forces?

Answer 13

And for chloride, these are reversed where the charge component
wants to repel chloride from the cell, and the force of diffusion wants to attract chloride into the cell.

Question 14

What is the equilibrium potential?

Answer 14

We have a point called the equilibrium potential, and that is the point for any ion where this net flux
across the membrane would be zero, and that would be because the force of the electrostatically
charged component and the force of the diffusion would be equal to each other. So under resting
conditions, these ions would not move across the membrane potential.

Question 15

At resting potential, how does the charge of the intracellular space compare to the charge of the extracellular space?

Answer 15

1. Chloride and sodium are highest outside the cell,
2. potassium and organic anions here, the big A with the negative, are higher inside the cell.

And what the resting membrane potential
is, if we were to record, the electrode here on the right hand, side between the extracellular space
and the intracellular space, what we’re recording is the fact that the intracellular space, due to these
ionic gradients, is relatively more negative to the extracellular space. In this case, by around minus 60
to minus 70 millivolts.

Question 16

How many synaptic inputs can a neuron receive at a time?

Answer 16

neurons can

receive multiple inputs somewhere in the region of up to 400 presynaptic inputs to a neuron.

Question 17

How does a signal pass through a neuron, generally speaking? So how is the signal transmitted? What is this signal?

Answer 17

Now, this signal, if we think about the anatomy of a neuron, is largely integrated via the dendrites
and the cell body, as you can see here. So these signals are responding by the dendrites and the cell
body, and then they travel through the cell body, making their way towards the axon initial segment,
which we’ll discuss in relation to the generation of an action potential.

Well, it’s known as a graded potential.

Question 18

What is a graded potential?

Answer 18

Ion channels in the membrane can flux
specific ions, in this case, sodium, as you can see here on the left. Now, this presynaptic neuron has
caused the opening of a ligand-gated channel on the postsynaptic cell. When this is opened, sodium
has fluxed in, causing a positive change. And it’s this change in potential of the membrane around the
ion channel that’s known as our graded potential.
And this can be both positive or negative. So for example, potassium and sodium ions are positively
charged. So they will depolarise the postsynaptic cell, and that is, they will move it towards the
triggering threshold for an action potential. Whereas chloride ions, being negatively charged, if they
were fluxed, would move the resting membrane potential away from the triggering threshold and
would result in an inhibition of the likelihood of firing.

Now, these graded potentials are best described by the analogy of dropping a stone into water, and
you see there’s a diffusion of the wave in all directions.

Now that’s what happens with this charge.
It
diffuses in all directions. But as it does so, it rapidly decays. So therefore, one or two inputs to a cell
will rapidly decay and not have an effect on the cell itself.

We need the summation of different effects
to get over this quickly diminishing response that we see in graded potentials.

Question 19

What is required for an action potential?

Answer 19

Now, to actually result in the triggering of an action potential, as we mentioned, the presynaptic
neuron here on the left has to respond.

This will result, for example, in neurotransmitter release.

This
neurotransmitter release will activate a graded potential on the postsynaptic neuron, and the arrows
here denote the size of this graded potential.
As this graded potential moves through the cell body, it diminishes rapidly, as we mentioned, this
electrotonic transmission.

It reaches then, at the start of the axon, this region called the axon initial
segment, here denoted as AIS, and as it reaches that axon initial segment, there’s a threshold, in this
case, minus 55 millivolts.

Now, this threshold is the triggering point above which the all or nothing event of an action potential
will be initiated.

If this graded potential, such as on the left here, reaches the axon initial segment and
it’s below this threshold, then no action potential is generated.

The graded potential decays, and the
cell returns to its resting membrane state.

However, if this graded potential is just above or succeeds
the, in this case, minus 55 millivolt triggering potential, then we get this rapid flux of sodium ions in
this very robust depolarisation and hyperpolarisation phase that we will discuss in the next lecture,
known as the action potential.

Question 20

What are the two ways to trigger an action potential?

Answer 20

Now, as I mentioned, any single response is likely, or won’t be enough, to trigger this response, so
there are a couple of ways by which the postsynaptic neuron can integrate signals from multiple
responses.

1. The first one is known as spatial summation, and that is where, in this case here, if a single channel
   was to respond, that graded potential may not be above the threshold and would not reach the AIS
   and trigger an action potential.
   However, if, for example three inputs– I’m only using three in this case, but we mentioned before,
   there can be up to 400– three inputs were to fire simultaneously, their responses would be summed
   in the cell body. So now in the red here, you can see we have a much larger graded potential, which
   can travel to the axon initial segment above the threshold for triggering, and generate the action
   potential. So this is spatial summation. This is based on the localisation of inputs around the dendrites
   and the cell body.
2. The other method is temporal summation, and this is based on the timing of triggering, either by a
   single presynaptic input or by multiple inputs. And in this case, if a single action potential was to fire
   and it wasn’t appropriate, that wouldn’t happen. And then a second one fires, and you can see that
   both of these graded potentials don’t pass the threshold, so no action potential is generated.

However, if the first and second graded potentials and postsynaptic neuron were to fire quickly,
causing this graded potential in the cell body, these responses would be summed. As you can see
on the right, they would sum on top of each other and potentially allow the triggering of an action
potential. So by this mechanism, both the spatial localisation of inputs firing and the temporal, that is
the speed, of the firing, and the speed in relation to one another, can significantly impact the action
potential propagation.

Question 21

What are the ways in which a postsynaptic cell can respond to a potential?

Answer 21

Now, the postsynaptic cell responds in a multitude of ways.

1. We have what we call excitatory
   postsynaptic potentials, and these are those potential changes that happen in response to the
   positively charged ions, such as sodium and potassium. They will move the membrane potential
   towards the triggering threshold for an action potential - and here it would be depicted here in green.
2. But we also have inhibitory postsynaptic potentials, and if you remember, I mentioned chloride ions.
   Because these are negatively charged, if chloride ions flux into the postsynaptic cell, they will move
   the resting membrane potential towards a hyperpolarised state, that as, more negative, and further
   away from this triggering threshold, which we had at minus 55 millivolts.

So if the green neuron here was to fire, and we record, using a glass electrode down here, the
response of the postsynaptic cell, we see this excitatory postsynaptic potential in green. But if the
red neuron is to fire, we see this inhibitory postsynaptic potential. So the resting membrane potential
is moved away from the triggering threshold, and as you can see in both cases, this decays relatively
quickly.
Now, the postsynaptic cell, as we mentioned, has somewhere in the region of about 400 inputs. So
you could imagine that the response is dependent upon the integration of these multitude of signals,
both positive and negative. In this case, for example, if the green and the red neuron, fluxing, causing
the opening of channels fluxing in sodium and chloride ions, for example, were to fire, what the end
result for the postsynaptic neuron, of course, is a balance of both this positive and negative charge.

So, we can fine-tune the membrane potential and the likelihood for triggering of the postsynaptic
neuron.

Question 22

What are the two channels that we focus on to study action potentials and what are the concentrations of sodium and potassium at resting potential?

Answer 22

To do this, we’re really going to focus on voltage-gated sodium channels and voltage-gated potassium
channels. You see this mechanism here by which we have the usual ionic gradient that you’re now
becoming familiar with, whereby sodium is at much higher concentration outside the cell than inside
the cell. Remember that sodium is the light blue.
Therefore, if you remember back to the electrostatic and diffusion force section, sodium wants to
enter the cell because it wants to be drawn towards the negatively charged intracellular space, but
also it wants to enter the cell because it wants to go to the area of lower concentration within the
cell.
In response to an electrical stimulus, which opens this voltage-dependent gate, sodium will rapidly
flux into the cell, making the intracellular space more positive with respect to the extracellular space.
Slide 5

In the context of the voltage-gated potassium channel, which we now see here in the purple, the
opposite is true, where potassium is higher concentrated inside the cell and lower concentrated
outside the cell. If you remember that the electrostatic force, the charge component, is pulling
potassium into the cell via the leak channels, but the diffusion forces want potassium to leave the cell
because it’s a lower concentration outside the cell.
In this circumstance, the same electrical stimulus triggering the voltage-gated potassium
channel will cause potassium to leave the cell and move to the extracellular space, rendering the
intracellular space more negative, and this is the hyperpolarising response. So when we talk about
hyperpolarisation, we’re talking about the inside of the cell becoming more negative. When we talk
about depolarising, we’re talking about the inside of the cell becoming more positive with respect to
the extracellular space.

Question 23

What happens when the graded potential reaches the axon initial segment and it’s above the threshold (around minus 55 mV)? What are the stages of an AP once the threshold is reached?

Answer 23

Now, if you think back to the basic principles what we spoke about, here is the axon initial segment,
the dotted circle at the start of the axon, and we have the normal distribution, whereby the inside
of the cell is more negative with respect to the extracellular space here, denoted as a positive
response. And the incoming graded potential, if you remember we spoke about this component–
this rapidly decaying electrotonic signal. It reaches the axon initial segment, and if it’s above the
threshold, which, again, we will suggest is minus 55 millivolts in this case.

1. This triggers the opening of the voltage gated sodium channels, and sodium rapidly enters the
   neuron, depolarising the intracellular space.

Therefore, the intracellular space now becomes
more positive around this area of the membrane, and the extracellular space more negative.

If you
remember, we also said that the axon initial segment is uniquely designed for that. It has a very high
concentration of voltage gated sodium channels, for example, and voltage gated potassium channels.

So it (the axon initial segment) is uniquely excitable, in the context of the axon, to trigger these responses.

So if you imagine
it’s got a high concentration of voltage gated sodium channels, so as they trigger and open, they will
further open more sodium channels and really cause a rapid influx or rapid depolarising phase.

2. Now, as the sodium influxes into the cell, this will further depolarise the membrane in front of it.

So
we start to get the spread of the depolarisation along the membrane because it’s opening more
voltage gated-dependent channels along the membrane.

3. Now, this will continue to spread. This depolarisation will spread along the axon, as you can see here.
4. So we’re now starting to move electrotonically along the axon, the signal is progressing.
5. And behind
   that, if you remember, now, the slower voltage gated potassium channels will now begin to open.
   There’s a half a millisecond delay in their response.
6. They will begin to open, and potassium will begin
   to leave the cell, making– because potassium now wants to get away from this positively charged
   environment and wants to flow down its concentration gradient.
7. Now, at the same point, if you remember, the sodium channels– this is when they become inactive. So
   because they’re inactivated now, behind this potential change, as seen in number four,
8. the charge can
   only move along in that one direction towards a terminal field and can’t propagate back towards the
   cell body. And this is important because in certain pain states, this can become abnormal, causing an
   action potential to travel in both directions.

Question 24

Describe how an AP conveys down an unmylinated fibre.

Answer 24

Now, in the context of an unmyelinated fibre, if we look at that and how that conveys, this is a
relatively slow process.

So we have this influx of sodium, which then depolarises the membrane,
moves this charge across, further opening more voltage gated sodium channels and causing further
influx of sodium as we move along the axon.

Behind this, the potassium is now starting to leave and the sodium channels are inactivated.

So we’re
starting to get a reversal of the membrane potential back to its resting state, that is, more positive on
the outside and more negative on the inside.

And this continues on the entire length of the axon.

Now,
it’s a relatively slow process because sequential voltage dependent channels have to respond along
the entire length of the axon.

So this is a slightly slower process causing this electrotonic spread each
time the cycle has to refresh itself along entire length the axon.

Question 25

Describe how an AP conveys down a mylinated fibre.

Answer 25

Now, in myelinated fibres, this is different. If you think, now-- and think that the myelinated fibres are surrounded by myelin generated by Schwann cells in the peripheral nervous system, or oligodendrocytes in the central nervous system. And this myelin is an insulating fatty layer. Much like the rubber cable around the wire in your house, it insulates that cable and prevents the current, or the conductance, the charge, from leaking across into the environment. For example, if you had a bare wire, you might get a shock from that. That’s what this is here to do. It’s here to prevent that. Now, in a myelinated fibre, the conduction is classically known as saltatory conduction, and that’s where the potential appears to jump from one node to the other node. And these nodes of Ranvier here are these little bare, uninsulated sections between the different oligodendrocytes in this case, because we’re talking about a central nervous system neuron, that are exposed to the extracellular space. And much like the axon initial segment, which we previously spoke about, these are very specialised compartments that have a high density of voltage gated sodium channels in the node and surrounding the node are high density, for example, voltage gated potassium channels. So again, they’re uniquely excitable compared to the insulated membrane along which the oligodendrocytes are ensheathing the axon. Now, in this case, the incoming signal causes influx of sodium at the axon initial segment. That causes then a depolarisation, so a more positive charge within the neuron. And this positive charge spreads electrotonically along the axon to the next node of Ranvier-- to the next bare component-- where it can then flux ions across the membrane. This then happens again at this node of Ranvier. The sodium channels are triggered, sodium fluxes into the cell, and this is propagated along to the next node of Ranvier. And the same potassium mechanism is happening behind this, where at each node of Ranvier sequentially along the axon, potassium is then leaving the cell, reestablishing the resting membrane potential of the cell. And, of course, the sodium potassium ATPase pumps, you remember, are very important here as well to reestablish these membrane potentials. Now, by this mechanism, myelin, in this case, can really increase the speed of propagation because we don’t have to have sequential activation of ion channels across the entire length of the axon. We get this apparent jumping in the saltatory conduction from one node to the next. And you can really rapidly increase the conduction velocity-- the speed at which we can transmit these signals.

Question 26

What generates myelin in the peripheral nervous system?

Answer 26

myelin generated by Schwann cells in the peripheral nervous system,

Question 27

What generates myelin in the central nervous system?

Answer 27

oligodendrocytes in the central nervous system.

Question 28

What is saltatory conduction?

Answer 28

in a myelinated fibre, the conduction is classically known as saltatory conduction, and that’s where the potential appears to jump from one node to the other node. And these nodes of Ranvier here are these little bare, uninsulated sections between the different oligodendrocytes in this case, because we’re talking about a central nervous system neuron, that are exposed to the extracellular space. apparent jumping in the saltatory conduction from one node to the next.

Question 29

What is conduction velocity?

Answer 29

the speed at which we can transmit signals down the axon (faster in myelinated axons)

Question 30

Why is myelination important?

Answer 30

And if you think of the brain, it’s very important because in some axons, for example, if you’ve got a motor neuron in your leg travelling up to the CNS, of course, or a higher spinal neuron, this can really be over a distance of metres. So we can really see quite a long process, where we have to get signals to the target zone very rapidly. And this is where a problem can arise, because myelination is such a specialised event, and it can really help with propagation.

Question 31

What are some diseases of poor myelination?

Answer 31

But in the case of disorders such as multiple sclerosis, demyelinating diseases, where we get a breakdown of this insulating sheath, the new signal, which is now conducting, can pass to this first node of Ranvier here from the axon initial segment. But if the myelin is disrupted, this charge can now leak out across the membrane potential and can now dissipate across the membrane because the membrane resistance is decreased. And in doing so, the ongoing charge that’s passed along the axon is significantly reduced. And if this potential is no longer strong enough to reach the adjacent node of Ranvier-- much like a graded potential decaying back in the cell body, if you remember that section-- then the action potential will be lost, and we will lose the ability to fire an action potential. And that is what happens in, for example, multiple sclerosis or diseases such as Guillain-Barre syndrome, where we get total loss or breakdown of the insulating myelin sheath and a loss of signal.

Question 32

What are the main components of the presynaptic zone?

Answer 32

1. In the membrane, we have voltage-gated channels, but in this case, now, we’re focusing on voltage-gated calcium channels. We should mention, much like sodium, calcium has a much higher concentration in the extracellular space than the intracellular space, so calcium wants to come into the cell. 2. We also have mitochondria here in yellow, because of course, there’s an energy-dependent component to it here. 3. We have vesicles, the circles, and within these vesicles, we have 4. neurotransmitters, the little dots, and these are stored here in the presynaptic terminal, waiting for them to be triggered and release to happen across the synaptic cleft.

Question 33

What type of synapse is one that releases a neurotransmitter?

Answer 33

chemical synapses

Question 34

What type of synapse is one that releases a neurotransmitter?

Answer 34

Chemical synapses

Question 35

What happens to the voltage-gated calcium channels of the presynaptic neuron?

Answer 35

In response to an incoming action potential that invades the terminal field, the voltage-gated calcium channels are now opened. They trigger. Calcium can flood into the cell, and via a calcium-dependent mechanism, the vesicles are now moved to the membranes, so this process called exocytosis.

Question 36

What is exocytosis?

Answer 36

In the presynaptic neuron, when the gated calcium channels open and calcium can flood into the cell, and via a calcium-dependent mechanism, the vesicles are now moved to the membranes. This is exocytosis

Question 37

Which proteins are involved when vesicles fuse to the presynaptic membrane?

Answer 37

Vesicals are moved toward the extracellular membrane of the neuron where they fuse with that membrane, and there are a number of proteins involved in this process, such as SNAP25 and SNARE,

Question 38

How does the neurotransmitter get to the postsynaptic neuron?

Answer 38

The process of the vesical fusing with the presynaptic membrane allows the membrane to fuse with the extracellular space and allows the neurotransmitter to be released into the synaptic cleft. This neurotransmitter will then diffuse across this very small gap where it can act as a ligand to trigger the ligand-gated ion channel, for example, on the postsynaptic cell. So if this was a neurotransmitter that was triggering a ligand-gated sodium channel, for example, it would open the channel, allowing sodium to flood into the postsynaptic cell. If you think back to a previous section, this would induce an excitatory postsynaptic potential, so it would excite the cell. But equally, this neurotransmitter release could cause chloride influx because there’s a chloride ion channel, and it could be inhibitory. So this is this integration component that we spoke about previously.

Question 39

Once the neurotransmitter is having an effect on the postsynaptic neuron, what controls what happens to the postsynaptic neuron?

Answer 39

The neurotransmitter, of course, has been released, and it’s having its effect on the postsynaptic cell, but there has to be a mechanism for controlling that and what happens here. This mechanism really is a stimulus-dependent system, so the postsynaptic neuron doesn’t just want to know that my presynaptic partner fired. He wants to know what’s the relative intensity of the signal. That’s important for how the signal was transmitted.

Question 40

What happens in the scenario where the graded potential is minus 40 mV, which is above the 55 mV threshold?

Answer 40

Experimentally, if we record-- so these arrows are recording electrodes, shall we say, and we’re recording the graded potential that’s coming into the cell body. We’re recording what’s happening at the axon initial segment triggering zone, and we’re going to record the action potentials from this axon. In the first example, what we can see is that the graded potential, in this case, is minus 40 millivolts, so we’ll all agree that’s above the minus is 55 millivolts threshold that we’ve been using here. That allows the triggering of an action potential here at the axon initial segment, and we can record these action potentials along the axon. These will invade the terminal field and result in the release of neurotransmitter from the presynaptic neuron based on the mechanisms we’ve just discussed.

Question 41

What happens when there is a really big graded potential?

Answer 41

Now in the second scenario, a larger graded potential, which reaches the triggering zone in the axon initial segment with a higher threshold will induce more in action potentials as seen here by multiple action potentials in the top graph. This will invade the presynaptic terminal. Because it’s voltage dependent, or stimulus-dependent calcium channels, more of these calcium channels will be opened. Therefore, more calcium will flow into the cell. We will get more exocytosis of neurotransmitter, and therefore more neurotransmitter into the synaptic cleft to signal to the postsynaptic neuron. So we have the stimulus-dependence component where the postsynaptic neuron can sense both the activation, but also the level of activation, of its presynaptic partner. Now of course, once these neurotransmitters are released, we have to have a mechanism by which we can control this. We can’t just have them acting continuously. There are a number of mechanisms by which the neurotransmitters can be removed.

Question 42

How do we remove neurotransmitters when a crap ton are released from a presynaptic neuron into the cleft because of a really big graded potential setting off a really big action potential? What are the four mechanisms that might be involved?

Answer 42

1. The primary mechanism is actually reuptake into the presynaptic cell. So the presynaptic terminal will reuptake the neurotransmitters and recycle them back into vesicles to use again. 2. But they can also be taken up by support glial cells, for example, astrocytes here on the grey on the left hand side. This is a very energy efficient mechanism by which they can recycle these neurotransmitters. 3. Alternatively, on the postsynaptic membrane, there are mechanisms by which these neurotransmitters can be degraded. They can be broken down, and then, of course, the products are taken away into the bloodstream and then expelled. 4. The final mechanism is just the act of simple diffusion. These neurotransmitters will diffuse away from the synaptic cleft and can be taken off into the bloodstream, and taken away from the region. But as I mentioned, the presynaptic reuptake of these neurotransmitters is the primary mechanism and the most effective mechanism.

Question 43

How do SSRI's for mood disorders affect neurotransmitters?

Answer 43

In the context of mood disorders, this is actually a very important target. So for example, the antidepressant selective serotonin reuptake inhibitors, they actually act to prevent this reuptake of the serotonin. So if you imagine, now, the serotonin is released. It’s having its effect in the postsynaptic cell. These drugs now block its reuptake, so they potentiate (increase the power of) the effect of your normal release. They don’t have an artificial effect and increase the level of serotonin, but what they do is they potentiate your own endogenous, internal response, and that’s the mechanism by which they have their antidepressant effects. So this scenario here where we can potentiate or change the effect of the presynaptic talking to the postsynaptic neuron is very important in the context of mood disorders.

Question 44

What are the six stages of pre-synaptic release of neurotransmitters?

Answer 44

1. What we have here is we have, again, this incoming action potential, which is triggering a voltage change at the presynaptic terminal. 2. This is opening the voltage-gated calcium channels, and calcium - positively charged calcium - is flooding into the cell. 3. This triggers vesicle like cytosis, so these vesicles move towards the cell membrane. 4. They then fuse with the membrane and release the neurotransmitter across the synapse. 5. This activates, as you saw there, the local postsynaptic ion channels and allows, in this case, sodium flux into the postsynaptic dendrite. 6. What you see here, now, is this excitatory postsynaptic potential because sodium has a depolarising effect. But equally, this could have been hyperpolarising effect had the ion channel on the surface of the postsynaptic neuron been fluxing chloride ions, for example.

Question 45

Part 1

Answer 45

how the neurons are able to set up their resting membrane potential