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HAZEL SIVE: Some good questions.
Let's zip through quickly.
Why can't an initial depolarization travel along
the length of the axon?
Last time, we went through in detail
how a signal is transmitted from the outside
to the inside of the cell by ion flux across the membrane,
and then how that ion flux is transmitted down the neuron.
Remember that the ions entering the cell are just ions.
They'll diffuse away.
And so the depolarization kind of dissipates.
And it then needs to be regenerated.
The action potential, each small depolarization
or the whole signal, each small depolarization
with a specific magnitude, the reversal of membrane potential
going from about minus 60 millivolts, negative inside,
to plus 55 or 60 millivolts, positive inside.
Each of those is an action potential.
And here is an interesting one.
Why doesn't the membrane potential
stop at zero when sodium rushes into the cell
during an action potential, which
is what you'd expect if sodium was just moving along
its concentration radian?
Because the potential's not only governed by sodium influx.
There are chloride ions outside the cell and potassium ions
inside over the duration of the potential.
And as we'll discuss briefly in a moment,
it's during the rectification process
that you go back to zero, and then
you reverse membrane potential again.
Well, let's move on to Nervous System 2.
And I want to cover two things today, both of which
connect with last lecture, and then move on to our topic
today.
We've drawn the analogy of the nervous system
as a communication system through the body
where there are wires, there are connections between the wires,
and there are circuits that need to be laid down.
Today, we're mostly going to talk about the connections.
But I want to talk a little more about pumps and channels.
And then we're going to talk about the connections
between neurons, which is also called synapses.
Let's begin with a little more about pumps and channels.
And I want to briefly summarize where
we were with talking about an action potential,
and introduce one last kind of pump--
of channel, excuse me--
that we didn't quite get to at the end of last lecture.
And then we'll talk about the pumps and channels involved
in synapses.
So in an action potential--
and the sequence of an action potential--
we define three phases, along the length of the axon
with regard to the membrane potential
that was involved in transmitting the signal,
along the very long axon, intracellular signaling those
with arresting potential, the threshold or the action
potential of the threshold leading to the action
potential, and then the question of repolarization,
resetting the membrane potential, which is pivotal.
Otherwise, the cell can't fire again.
And we talked about one pump, which is really pivotal
for life-- we study it in my own laboratory--
but one pump which is on all the time
and which is involved primarily in the resting potential
and the repolarization.
This is the sodium potassium pump.
It pumps sodium out and potassium in, but less sodium
out and potassium in.
And it is on all the time.
There are other channels that are open all the time.
The key one are potassium channels,
but there are also open chloride and sodium channels.
And those are open all the time.
And depending on the concentration
of the ions, and also electrostatic repulsion,
which will counter sometimes movement along a concentration
gradient, those are involved in everything.
But primarily-- they're open all the time--
but they are primarily involved in setting up resting potential
and repolarization.
So we'll put some dots.
I'm going to dash the line in the action potential area,
which indicates that those pumps and channel, that pump
and channel are being used and active,
but they're not pivotal in those processes.
The one that's really pivotal in the action potential
is the voltage gated sodium channel.
We talked about this last time.
You can look a bit more on the slides
that I posted with regard to the ideas
behind how the channel is closed at certain membrane potential,
how if the membrane potential changes slightly,
there's a conformational change in the protein.
And a pore opens that allows sodium
to rush in down its concentration gradient,
over a very small area of membrane.
So the voltage gated sodium channel allows sodium in,
and it is closed, if we look at this.
It's open during an action potential.
It is closed at resting, but is ready to be open.
And then subsequently, it is closed during repolarization
when the membrane potential is reset.
And it's not openable--
it's not actually clear why-- there's some funny confirmation
and that pump is not ready to be opened for some period of time
until the protein structure resets itself.
And then it's openable.
So it's closed and it's not ready to be opened.
And this is really pivotal in making sure
that an action potential traverses
in one direction along the axon, and doesn't go backwards
as the ions diffuse backwards.
And then finally, I want to mention--
or I want to tell you--
that there is a voltage gated potassium channel that opens up
after the action potential.
And that is one of the things that
is pivotal in resetting the membrane potential
during repolarization.
The other thing that is really pivotal
is this sodium potassium pump.
So the voltage gated potassium channel
gets potassium out of the cell in the area
where there has been depolarization.
Your very positive inside ions go out
along their concentration gradient,
or along an electrostatic gradient.
And so potassium goes out, both in this case.
And so it is open during repolarization,
and it is closed for the rest of the time.
OK.
The thing you're going to have to do with these channels,
that you will do in section and with your problem set,
is to really work through the kind of logic
behind what pump and channel is doing what at what
stage of the action potential.
And then it will start to make sense.
OK.
So we're going to move on in a moment
and talk about the synapse.
But I'm going to talk about the pumps and channels
during a synapse, and point out to you that these pumps
and channels are being used, but there are others,
which are really crucial.
One of them is the voltage gated--
VG for voltage gated--
calcium channel.
And the other are a series of ligand gated,
or second messenger gated.
Second messenger regulated, let's say, not gated, ion
channels.
And these ligand gated, or voltage gated second messenger
regulated channels, these things are specific to the synapse,
and are specific to the connections between cells.
So let's move on to the major topic
today, which is this question of the synapse, the connection
between cells.
And let me throw out some facts.
And then I'll show you kind of a cool picture.
Neurons connect with one another to make circuits.
That's the deal.
That's the wiring.
So how complex is this wiring?
I showed you a very cool 3D reconstruction
of the brain that showed you the packing
of the neurons in the brain.
But quantitatively, what does that mean?
One neuron can connect with, can synapse with up to 100,000
other neurons.
In the brain alone, there are at least 10 to the 10th neurons.
It's not clear really, to anyone,
how you put those two numbers together,
whether you can multiply them, and whether that's fair.
But whatever you come out with, that's
a lot of connections, just in the brain.
OK?
The number of synapses, therefore, is huge.
So what kinds of connections are there?
Let's just write this.
I'm not going to try to--
huge number of synapses.
There you go.
That's quantitative.
What are these connections?
We've talked a lot about an electrical signal moving down
the axon.
But now I'm going to tell you that most
connections between cells are not electrical,
they're chemical.
And I told you last time when we explored the reason
that you have these long axons and intracellular
signaling rather than cells all piled up next to one
another doing intracellular signaling, that's slow.
I told you that last time.
And that's still true in a synapse.
The connections between the cells
is the slow point of neural transmission.
There are electrical synapses.
And they are used sometimes, but rarely.
They are fact because they are connected by gap junctions, one
neuron to another.
And that allows ion flow.
But the thing about electrical synapses
is that they're always open.
The cells are always connected.
They're unregulated.
And the thing about the nervous system
is that it is exquisitely regulated.
It is fine-tuned to respond to the smallest stimuli,
both from within your body and from without.
And unregulated synapses will not do that for you.
So the flip of those are chemicals synapses.
They are slow, their diffusion limited,
and they're diffusion limited of chemicals
that we'll discuss in detail, that
are called neurotransmitters.
But they have the wonderful property
of being highly regulatable.
And so the majority of synapses in higher animals
are these chemical synapses.
And that's what we'll talk about today.
This is a picture which I really like.
It's a neuron where--
and these are the dendrites.
And here's the cell body and the axon coming out.
And each of these dots represents a synapse.
Well, it doesn't represent a synapse.
It is, it's stained for a protein that's
only found in synapses.
And you can see this tremendous studding of the dendrites
with synapses, which gives you a sense of the complexity.
OK.
It's really pivotal, when we talk about the connections,
that we get some of the principles correct.
So I want to spend a board going through some of the principles
that we have to bear in mind in thinking about the connections.
So let's think about this.
Here are neurons-- well, let's have Neuron 1.
But we could actually have Neuron 1 to n.
It doesn't matter.
It could be a whole bunch of Neuron 1.
And along that one neuron, or those bunches of neurons,
is coming an action potential.
And over here is Neuron 2.
And between them is a connection, is a synapse.
And the thing that Neuron 2 has to decide when it connects
with Neuron 1 is whether it's going
to make an action potential, whether it's
going to send a signal.
That is the big decision that this neuron has to make.
So Neuron 2 must decide to make an action potential,
and it is a yes/no decision.
It's not a sort of an action potential
or a half an action potential.
And so we need to remember action potential facts, all
or none.
You either get an action potential or you don't.
That means you get complete depolarization or nothing.
And if you have a lot of action potentials coming along Neuron
1, the way Neuron 2 can respond is not
to make a big action potential, obviously.
But it can make a lot of action potentials.
So a change in input where we can call this action potential
from Neuron 1, the input, a change
in input results in an increase or change,
let's just say, a change in the number
of action potentials per time, or the frequency of action
potentials in Neuron 2.
Other facts, other really key facts.
Resting potential can change.
Threshold potential and the action potential,
as I've been belaboring, do not change.
And you can see that nicely in the slide, where here's
a neuron firing, and this is a different way
of showing the neuron firing.
Here is the action potential showing
as a spike of depolarization.
And then there's a time, another spike,
another action potential, wait, another spike, and so on.
Here is a neuron that's gotten a lot of input.
And look at it.
It's spike, spike, spike, spike, spike.
But if you look at the height of that spike,
that is the depolarization height.
It's the same within the sensitivity
of the recording device for each of these action potentials.
So I really like that slide to exemplify these principles
that I've just put on this board.
OK.
There are the principles.
How does it work?
Very cool.
This is really amazing.
Let's again have Axon 1.
We're going to have Axon 1 here.
OK?
Axon, oh, let's have axon derived from Neuron 1.
And now we've got to distinguish two different parts
of the axon.
And I'm going to draw this on the board
and then I'm going to go through it with you on a hand out,
because it's important.
There's an electrical signal coming along Axon 1.
And you know that it involves an action
potential via the voltage gated sodium channels.
As that signal nears the end of the axon,
the axon kind of bulges out into a terminal,
and the voltage gated channels change from sodium to calcium.
So here's the end of the axon.
And here you change to voltage gated calcium
channels that are activated.
OK.
These voltage gated calcium channels,
this is called-- actually, let's put some terminology.
This is called the pre-synaptic neuron.
And the voltage gated calcium channels are
at the pre-synaptic terminus.
Now the thing about calcium that we've mentioned
before is that it is a mediator of exocytosis,
of having little vesicles containing
proteins or other molecules released from the cell.
These voltage gated calcium channels increase intracellular
calcium and lead to the exocytosis,
the release of chemicals that are
contained in vesicles at the end,
at the pre-synaptic terminus.
So the pre-synaptic terminus contains vesicles
with neurotransmitter.
We'll talk about this in detail.
The voltage gated calcium channels,
which increase intracellular calcium,
lead to exocytosis release of the neurotransmitter, which
is released outside the cell.
And that neurotransmitter diffuses across the space
between Neuron 1 and Neuron 2.
It's about 30 nanometers.
And it diffuses across the space.
And when it gets to the other side to--
here's Neuron 2, called the post-synaptic neuron--
when it gets to the other side, and it'll
get to either the dendrites or the cell body,
this neurotransmitter binds to things
that we've talked about a lot, it binds to receptors.
Those receptors plus ligand do all the things
we've talked about in many lectures.
They do something.
In this case, they can do one of two things,
as we'll talk about.
But it all culminates in changing ion flux
across the post-synaptic membrane.
So the neurotransmitter diffuses.
It hits the dendrites, or cell body.
It binds receptors to change ion flux, or ion movement.
And this eventually gets turned into the action
potential decision.
OK.
So let's put some more on here.
Here's an electrical signal from Neuron 1.
Here, this neurotransmitter diffusion
is a chemical signal across what is
called the synaptic cleft, which is the space between neurons.
And the signal in Neuron 2 becomes electrical again.
So there's a conversion device, which
converts electrical to chemical to electrical signals.
All right.
Let's look at your first handout and we'll
hammer this in in more detail.
Here's the action potential.
So let me stand here in case you're--
they don't like me doing it.
OK.
Let me stand here.
Here's the action potential coming along Neuron 1.
Voltage gated sodium channels until you
get near the end, when you switch
to these voltage gated calcium channels.
Calcium flows in, leads to exocytosis of vesicles
containing neurotransmitter.
The neurotransmitter diffuses across the synaptic cleft,
binds to receptors on either side, which changes the ion
flux into Neuron 2.
And there is an action potential decision--
it's on your sheet--
an action potential decision that eventually,
as we'll discuss, involves voltage gated sodium channels
so that the cell decides whether or not
it's going to fire an action potential.
OK.
We'll talk about the neurotransmitters
and the receptors in more detail in a moment.
But I want to introduce you to three concepts
of the synapse, which are really very important.
The first is the concept of summation.
And now we go back to the notion that many neurons
can give signals to another neuron, such
that that other neuron is deciding yes, no, I'm
going to fire an action potential
and transmit the signal.
The neuron that's receiving all of that signaling
has to add up its inputs and say what's the sum of the inputs.
Literally, it has to add up the inputs.
So summation is the addition of all synaptic input, which
is change in membrane potential governed by change in ion
movement on a recipient neuron.
OK.
So the addition of all synaptic input
on a recipient neuron, or bio-recipient neuron,
if you like.
There's two kinds.
There's spatial summation, which has to do
where the signal is received.
And so those synapses that I showed you
in that picture of the cell with all its dendrites
and all of those little dots were all over the place?
Each of those little dots is getting
a signal on the dendrites, on the ends
of the dendrites, near the cell body, in the cell body.
All of those inputs have to be added up.
So where the signal received, is received,
cell body plus dendrites, that would be spatial summation.
And then temporal summation means over time,
when the signal is received.
Over a period of a millisecond or so,
all of those inputs to the neuron are added up.
And the addition is actually a simple one.
The addition is how much has the membrane potential changed,
and overall, have you brought the membrane potential
of the recipient neuron up to threshold.
If you have, that recipient neuron fires.
And if you haven't, it doesn't.
So the total membrane potential--
so the answer of whether to fire or not,
is the total membrane potential, which is the decision.
And if it's threshold potential, out of that,
an action potential results.
The addition, the summation is done in the dendrites
and the cell body.
And the answer is read at the place where the axon comes off
the cell body, which is called the axon hillock.
So the sum is calculated over all of the dendrites
plus the cell body.
But it is read at this thing called the axon hillock.
And they only read the axon hillock
is where the axon leaves the cell body,
or originates from the cell body.
And the reason that that is an important place
is that that is where the voltage gated
sodium channels are found.
It's only there.
They start at the axon hillock, and they are present
all the way down the axon.
There are no-- and you can look at your diagram
for this-- there are no voltage gated sodium
channels in the cell body or the dendrites.
So they can't fire an action potential.
They can add up how membrane potentials changed,
but they can't do anything about it.
So the hillock is where the axon leaves the cell body,
and where the voltage gated sodium channels begin, begin,
and where an action potential can therefore come out.
That's a bunch of sentences.
OK.
Couple more terms.
Excitatory and inhibitory synapses,
excitatory and inhibitory.
It's kind of like a simple math problem
where you're adding positive numbers or negative numbers.
You know, you come out with something that's either 0,
negative, or positive.
Same idea here.
When you add all these inputs that a neuron gets,
it figures out what it's going to do.
And the inputs can be either pushing a neuron closer
towards an action potential, closer towards threshold,
or pushing a neuron away from being
able to make an action potential, further
away from threshold.
Excitatory synapses bring the resting potential
closer to threshold, whereas inhibitory
bring the resting potential further from threshold.
All right.
Here's where it gets even more complicated.
One neuron can be making both excitatory and inhibitory
synapses.
And depending on which predominate,
the recipient neuron will either be
told to fire or not to fire, to make
an action potential or not.
So one neuron can make both excitatory and inhibitory
synapses.
How does this work, you ask?
Well, you have all the tools to know.
It's all got to do with ion flux and which ions are flowing in
and which ions are flowing out.
And we can answer that by looking at your next handouts.
In Number 2 of your handouts, I've
shown you the synaptic cleft.
Here's a synaptic cleft.
And here are the voltage gated calcium channels
opening to allow calcium in and neurotransmitter
vesicle exocytosis.
Here is an excitatory synapse bringing the resting potential
closer to threshold.
Let's think about that.
You want positive ions to come in from the outside.
That would help bring your resting potential
closer to threshold.
So there is some sodium channels that can open,
maybe calcium channels that can open-- not the voltage gated
ones.
And that would increase the resting potential.
That would increase the potential inside the cell,
bring it more positive, closer to threshold.
Conversely, in an inhibitory synapse,
you'd get a net inflow of negative charges.
The chloride ions might move from the outside in.
That would take, make your inside of your cell
more negative and further away from threshold.
You could also get potassium out.
And that would, again, make the inside of the cell
more negative and further from threshold.
So you can see already I've got four different channels--
they're not the ones we've talked about before,
they're different ones--
four different channels which can
modulate the membrane potential on the recipient cell.
All right.
Let us move on now to those neurotransmitters
and their receptors.
Neurotransmitters and neurotransmitter receptors
are very cool because they are probably
what makes us who we are in terms of personality,
in terms of ability, in terms of our interface with the world,
in terms of whether we're an intrinsically happy or not so
happy person, er cetera.
Neurotransmitters, however, are a class of molecule
we have previously encountered.
They are ligands, but they're different ligands.
When we talked about ligands previously,
we have largely been talking--
not entirely-- we've largely been
talking about peptides or molecules that
are sort of a reasonable size.
Not always.
The steroid, the steroid hormones are very tiny.
Neurotransmitters are pretty much all very tiny.
And the thing that you should know
is that you can have one or many types of neurotransmitter
per synapse.
Here's another complication.
Neurotransmitters can be peptides sometimes,
but they are very largely amino acids, the same amino acids
that you build proteins with, nucleotides,
or other small molecules, like the kinds of synapses.
Synapses are excitatory or inhibitory
because of the kinds of neurotransmitters
that they're making.
So there are excitatory neurotransmitters.
Glutamate, glutamate, glutamate, glutamic acid--
OK, the same one we've talked about before--
and adenine are both examples of excitatory,
are examples of excitatory neurotransmitters.
Glutamate is involved in being alert.
Adenine is involved in being sleepy.
And one of the things that caffeine does
is to counteract the effects of adenine
so that it's thought to competitively
interact or competitively inhibit adenine function.
Inhibitory neurotransmitters, something
called GABA, gamma-Aminobutyric acid, and glycine
are the two major CNS, Central Nervous System
neurotransmitters.
GABA particularly is an anti-anxiety neurotransmitter.
And things like Xanax, which I will get to today or Friday,
are things which will be agonists of GABA function.
And sometimes, neurotransmitters can be
both excitatory and inhibitory.
Acetylcholine, for example, which
is involved in connections between nerves and muscles.
Neuromuscular connections, and also found in the CNS,
can be both excitatory and inhibitory.
And serotonin-- and I'll put dopamine
on the same line for space-- serotonin
and dopamine, both of which are kind
of feel good neurotransmitters, also
involved in alertness and other things.
For dopamine-- locomotor activity movement--
they can be either excitatory or inhibitory.
What do they look like?
Let me go on and then I'll show you some pictures in a moment.
All right.
So how can something be excitatory and inhibitory?
What's downstream of these neurotransmitters?
The receptors.
Good job.
All right.
Neurotransmitters, ligands bind receptors.
And the way the neurotransmitters
affect what they're going to do is
by binding the appropriate receptor.
So here are the receptors for the neurotransmitters.
And like the neurotransmitters, there
can be many different kinds per synapse.
There are two classes of receptors that you should know.
One are ion channels.
They're receptors which bind the neurotransmitter,
and they open up.
They're ligand gated ion channels.
But the other kind are not ion channels.
They bind the receptor and then they
activate a second messenger system,
as we talked about before.
And it's the second messenger system that
later on opens an iron channel.
They have names.
So two classes, one are the iron channels.
They're called ionotropic receptors.
So they're ligand gated ion channels.
And the thing about these is that their response
is very rapid, in the millisecond range.
There's another class of those receptors
which activate ion channels.
They are called metabotropic.
It's the concept that is more important than the term,
but I'm giving you the term for completeness.
And they act via a second messenger
system that almost always involves G proteins.
And these are slow.
Their response is at least a second, often much greater
than a second.
OK.
And let me, as the last thing I'll tell you today,
I'll show you-- if we have a moment I'll
show you some pictures-- but I want
to tell you that one neurotransmitter can activate
different kinds of the receptor.
So one neurotransmitter can activate greater than one type
of receptor.
And this was implicit in the notion
that neurotransmitters could be both excitatory and inhibitory.
For example, serotonin binds to no fewer than 14
different receptors.
And one neuron can express probably not all 14,
but it could probably express five different serotonin
receptors.
And they do different things.
One of them is a ligand gated sodium channel.
Another type is G protein coupled, so
including both metabotropic and ionotropic receptors.
And to throw out at you the last couple of slides,
here are some of these amino acids and small molecules
that are neurotransmitters.
And this really exemplifies what I've said on the board.
So I'm going to stop here now.