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We're going to talk about the
nervous, and continue to talk about

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the nervous system.
And in the game board of life and

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our journey through life we are well
into the course.

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We've talked about the foundations,
where things come from.  And now

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we're talking about how different
organs work together in the system

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module.  We'll talk about the
nervous system.

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Professor Jacks will move on into
the immune system,

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probably not immediately after,
but later into the immune system.

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And you're going to get a broader
perspective on how things work in a

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biology sense.
So we talked last time about the

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notion of the nervous system and how
the nervous system is really a

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wiring diagram,
a circuit.  And it's actually,

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the circuitry in the nervous system,
if you were to take wires and

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connectors and connect it up is very
simple.  What's not simple is that

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the circuit is incredibly complex.
Enormous, of enormous complexity.

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And what's also not simple is that
unlike many electrical circuits,

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it's a very flexible circuit.
And, unlike most electrical circuits,

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it learns.  It's plastic.
It learns from its mistakes and it

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learns from its triumphs.
And that's where the difference

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comes in.  We talked last time about
neurons as the wires of the nervous

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system.  And today I want to talk
about synapses,

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or you might hear them pronounced
synapses, but this is an

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unusual pronunciation.
Synapses, which are the connectors

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between the different wires.
And then next time we'll talk about

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how these things are all put
together into circuits.

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And that will be in our lecture on
Friday.  Actually,

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Claudette, did you want me to make
an announcement about what you have

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on the board there?
Can you guys see this?

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I can read it.  It says RO6
Lesley's 10:00 AM,

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R16 Kyle's 11:00 AM.
Go to 8119 tomorrow and next

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Thursday.  OK?
So if you are in Kyle's or Lesley's

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section, please note what is on the
board.  OK.  So what about the

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number of connections?
So this is a staggering figure.

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So the figure of the number of
cells in our body ranges between ten

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to the twelfth and ten
to the thirteenth.

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The number of neurons that are
estimated to be in the brain is

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about ten to the tenth.

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Each neuron can make about ten to
the third, a thousand synapses.

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But in some neurons there can be

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even more than that.
There can be about, there can be up

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to about ten to the fifth
connections between neurons.

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And if you start doing some simple
math you can get to a realization

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that the complexity of the circuitry
that you can get between neurons,

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just within the brain, is really
staggering.  OK?

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And it's way beyond our
understanding right now to figure

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out how you get,
at least these ten to the third

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connections, ten to the thirteenth
connections.  But wait.

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It may be a couple of orders of
magnitude more than that,

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how you get those set up and how you
get them maintained.

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So let's try to simplify the
problem a bit and talk about the

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connections between neurons because
that is a much simpler question than

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how you get this enormous number of
circuits set up as you wire

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the nervous system.
This is a simple circuit that I took

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from your book.
A diagram of a simple circuit that

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I took from your book,
motor neurons that are in the spinal

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cord innervate the leg muscle.
Sensory neurons that are in the leg

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muscle innervate the spinal cord,
and there is connectivity between

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the muscle, this sensory neuron and
the motor neurons in the spinal cord

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that give you the classic reflex
when the doctor taps your knee.

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I don't even know.
I guess they do that when you're

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little, not when you're older,
unless you look like you're in bad

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shape.  But that is a simple reflex
arch that has a number of

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connections between neurons but
accountable number of connections,

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just a few kinds of synapses.
So let's talk about the synapse.

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And I'm going to do some board work
here and give you a sense of what

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the wiring in the nervous system
looks like and where these

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connections take place.
And one needs to consider some kind

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of input which can be from a neuron
or it can be from some kind of

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external stimulus like light or the
food you eat. And this input

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interfaces with sensory neurons,
hence the name sensing.

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Sensory neurons generally connect to
things called interneurons which are

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wires that connect one part of the
nervous system to another.

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These connect to motor neurons.
And motor neurons are the things

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that direct what the output is going
to be, muscle contraction,

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swallowing, etc.
Wherever there is a connection

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between neurons there is a synapse.

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And often, especially in the case of
muscle, there can be a synapse

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between motor neurons
and their output.

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There are two kinds of connections
between neurons,

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two kinds of synapses.
There are those that are electrical

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where the electrical input from the
axon of one neuron is transferred to

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the next neuron,
and you keep the signal an electric

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one.  Electrical synapses
are very rapid.

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They involve things called GAP
junctions, which we've talked about

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briefly, which are direct
connections between cells.

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And you get direct movement of ions
between cells.

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And electrical synapses are used at
some points in the Animal Kingdom.

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And they are, in fact, used in our
nervous system,

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particularly when it's developing.
This is new work.  But the type of

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synapse that is much more prevalent
is the chemical synapse.

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Chemical synapses are relatively

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slow.  So electrical synapses are
extremely rapid and they are almost

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instantaneous.
You get the action potential moving

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down an axon, moves across the
synapse, and there is really no

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break in the sequence or in the
timing of the movement of the signal.

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Chemical synapses are slower.
And there is a lag of milliseconds

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to minutes, in some cases,
from the receipt of the signal at

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the one side of the synapse to its
transference to the other

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side of the synapse.
So mini-seconds.

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That should say seconds,
S-E-C, to minutes.  And the thing

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about them, about chemical synapses
that makes them so attractive is

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that you can regulate them in
various ways.  So I'll

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say regulatable.
And I'm going to spend this lecture

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talking about chemical synapses and
not about electrical synapses.

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If you're interested in knowing
more about electrical synapses,

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email me and I'll direct you to some
literature that will be of interest

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to you.  So let me draw on the board
the essence of a synapse.

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And let's draw, and you should draw
it at the same time.

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And so let's draw the axon of one
neuron.

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So this is neuron one and this is
its axon.  And here's another neuron.

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And this is going to be a part of
the neuron termed [the 41?

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.  I have a new item.  I have a new
item as an incentive.

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I have, since it's getting to be
summer, I have a clownfish,

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a clownfish squirt.
You will need a bottle of water to

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use this item.
OK.  What part of the next neuron

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is the axon going to connect to?
Isn't it the dendrites?  It is

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indeed the dendrite.
Yes.  Thank you.  OK.

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OK.  So here is neuron two and the
dendrite.

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And what is going to happen is stuff
that is really not specific to the

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nervous system,
except in the details.

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It is stuff that you've heard about
in cell biology,

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that we've talked about in the
formation module,

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and it involves receptor ligand
interactions and signal transduction

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but in a specialized way.
Here comes the action potential,

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hereafter abbreviated AP, coming
down neuron one.

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And that action potential,
as you remember, is driven by

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transient depolarization and inward
sodium current.

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At the very terminal of this axon,
which is called the presynaptic

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terminal or the presynaptic cell,
there is a system of vesicles.  And

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these vesicles contain stuff called
neurotransmitter,

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which we'll talk more about in a
moment.

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And on the opposite cell,

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which has the name of the
postsynaptic cell,

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on its membrane are things that
we've talked about many

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times, receptors.

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And this is the deal.
The action potential moves along

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the axon of the presynaptic cell.
As it gets towards the terminus of

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the presynaptic cell,
you can call that the presynaptic

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terminus also,
it activates another set of channels.

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These are calcium channels that
give an inward calcium flow,

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an inward calcium ion flux that
causes these vesicles to fuse with

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the presynaptic membrane in the
process that you learned about in

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cell biology called exocytosis.

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And these presynaptic vesicles
disgorge their contents,

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their neurotransmitter into the
space between the presynaptic cell

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and the postsynaptic cell.
This space is called the synaptic

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cleft or the presynaptic cleft.
It doesn't matter.  Well, it does

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matter.  You should know that,
but it's just a space.  And it's a

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space that is usually about ten to
twenty nanometers.

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So it's a fairly substantial space.
And that neurotransmitter diffuses

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across the space,
binds to receptors and signal

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transduction happens.
And we'll talk about what the

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signal transduction is and what the
outcome may be.

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And the outcome may be an action
potential, but it is not guaranteed

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to be an action potential.
And the thing about chemical

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synapses that makes them slow is
that there is a diffusion driven

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process.  The stuff has to,
these neurotransmitter molecules

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have to diffuse across the synaptic
cleft, and that takes time.

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And that is why chemical synapses
is slow.  You also have to get

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exocytosis of those vesicles,
and that is slow as well.  All right.

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So synaptic density.
Here's a slide to show you synaptic

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density.  Increase in synaptic
density during development is really

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extraordinary.
And the number of synapses and the

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type of synapses changes in
childhood but also throughout life.

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This is a movie to illustrate what
I've told you.

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You can look at it again.
And graphically here's your

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electrical message being transferred
into a chemical message,

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and then recreating an electrical
message.

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So there's change in the
transduction mechanism of this

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particular, oh,
it's supposed to be a loop but I

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guess it's not,
in this particular mechanism of

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transmission.  Here are the
presynaptic vesicles disgorging

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their neurotransmitter.
Look in this case, the

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neurotransmitter is going back into
the vesicles.  And we'll talk about

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this more in a moment.  OK.

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Item one on your handout today is a
diagram from your book,

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which shows you the synapse,
the presynaptic cell, the

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postsynaptic cell.
You'll get all the information that

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I have put on the board in a more
complicated way.

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And this is done for a cell that
has got something called acetyl-CoA

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in it.  OK.  So you can bear that in
mind.  I want to address a number of

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issues now, a number of issues now.
And I want to point out a diagram,

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actually, let me go back to this one,
number one on your handout.

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One thing I would like you to look
at and to think about and to compare

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with your cell biology module is the
exocytosis of these vesicles.

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So you talked about transport of
molecules around the cell,

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particularly proteins, and you
talked some about exocytosis

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and endocytosis.
The exocytosis of these

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neurotransmitter vesicles is a
classic example of exocytosis.

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The proteins involved in this are
the same proteins involved in

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exocytosis in many different cell
types.  In addition,

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there's a process I'll mention later
on of endocytosis where the

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neurotransmitter may be taken back
up into the cell and used again.

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On your handout that's on the Web
is this diagram.

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You can look at it in more detail.
I'm not going to dwell on it here.

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You can look at it in more detail.
It will indicate where calcium comes

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into the triggered exocytosis of the
neuro transmitter.

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But moving right on,
I want to talk to you now about

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neurotransmitters.

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Neurotransmitters,
the ligands that transfer a signal

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from one neuron to another.

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Here are some facts.
Any kind of neuron can make more

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than one neurotransmitter.
And different neurotransmitters are

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usually in different vesicles.
And they can be used at different

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times and different places in the
neuron where it synapses onto

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another neuron.
Neurotransmitters are typically

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three things, and you'll be
surprised at what some of them are.

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It's very interesting.  They can be
nucleosides, they can be amino acids,

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and they can be peptides.

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Let that on the table here.
All right.  So here are some

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neurotransmitters.
Most of these, you can go and look

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at these later.
Most of these come from amino acids.

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Acetylcholine which is one of the
largest most important

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neurotransmitters does not,
but the other ones do.

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They come from glycine from
glutamate, tyrosine,

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tryptophan, and so on.
And that monosodium glutamate that

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you have often on food,
on Asian food that makes the food

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taste better, the reason it makes
the food taste better is that it's a

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neurotransmitter and it increases
synaptic transmission across some of

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the neurons that are involved and
taste perception.

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So, yeah.  All right,
so neurotransmitters.

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Peptides, amino acids and
nucleosides.  It's very interesting

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that these ligands are very small.
Amino acids are very small.

224
00:20:09,000 --> 00:20:14,000
Nucleosides are very small.
And it's interesting that these are

225
00:20:14,000 --> 00:20:18,000
used as neurotransmitters.
And I think there are two reasons.

226
00:20:18,000 --> 00:20:23,000
One of the reasons is that because
they're small they diffuse

227
00:20:23,000 --> 00:20:28,000
relatively rapidly,
and so they minimize the time of

228
00:20:28,000 --> 00:20:33,000
getting the synapse in the
postsynaptic cell activated.

229
00:20:33,000 --> 00:20:36,000
And also because nerve cells are
evolutionarily very ancient.

230
00:20:36,000 --> 00:20:40,000
These were the molecules that were
around at the time,

231
00:20:40,000 --> 00:20:44,000
and perhaps they were around at a
time where it was easiest to use

232
00:20:44,000 --> 00:20:48,000
things that were preexisting.
So in some ancestral cell, which we

233
00:20:48,000 --> 00:20:52,000
don't really understand,
perhaps before there was a very

234
00:20:52,000 --> 00:20:56,000
large protein cohort and cells
wanted to communicate with one

235
00:20:56,000 --> 00:21:00,000
another, a very ancestral
type cell.

236
00:21:00,000 --> 00:21:04,000
These were the types of things that
would have been around.

237
00:21:04,000 --> 00:21:08,000
And these, perhaps there's an
evolutionary reason that these

238
00:21:08,000 --> 00:21:12,000
things are used as neurotransmitters.
There are a vast number of

239
00:21:12,000 --> 00:21:16,000
neurotransmitters.
There are about 25 known

240
00:21:16,000 --> 00:21:20,000
neurotransmitters,
and they have different functions.

241
00:21:20,000 --> 00:21:24,000
So the two big classes you should
know about are the ones that are

242
00:21:24,000 --> 00:21:29,000
excitatory and the ones
that are inhibitory.

243
00:21:29,000 --> 00:21:35,000
And we'll talk about this in detail
in a moment, but excitatory

244
00:21:35,000 --> 00:21:42,000
neurotransmitters are ones which
will promote an action potential in

245
00:21:42,000 --> 00:21:49,000
the postsynaptic cell.
And, in fact, the major one in the

246
00:21:49,000 --> 00:21:55,000
central nervous system is glutamate.
And the major one that works

247
00:21:55,000 --> 00:22:02,000
between your nerve cells and your
muscles, at the neuromuscular

248
00:22:02,000 --> 00:22:11,000
junction, is acetylcholine.

249
00:22:11,000 --> 00:22:15,000
And then there are inhibitory
neurotransmitters,

250
00:22:15,000 --> 00:22:19,000
and these are the ones which will
tend to inhibit an action potential

251
00:22:19,000 --> 00:22:23,000
from taking place in the
postsynaptic cell.

252
00:22:23,000 --> 00:22:27,000
And one of the major ones there is
gamma-aminobutyric acid,

253
00:22:27,000 --> 00:22:32,000
abbreviated GABA.
And another one is glycine.

254
00:22:32,000 --> 00:22:36,000
And those are both found in the
central nervous system.

255
00:22:36,000 --> 00:22:41,000
However, I'm going to also add to
this inhibitory list acetylcholine,

256
00:22:41,000 --> 00:22:46,000
which will indicate an important
principle you should understand.

257
00:22:46,000 --> 00:22:50,000
And you'll see it gets more and
more complicated,

258
00:22:50,000 --> 00:22:55,000
that neurotransmitters can either be
excitatory or they can be inhibitory

259
00:22:55,000 --> 00:23:00,000
depending on the receptors
to which they bind.

260
00:23:00,000 --> 00:23:04,000
This is a table from your book.
You should look at it.  You do not

261
00:23:04,000 --> 00:23:08,000
need to memorize what each of these
neurotransmitters does,

262
00:23:08,000 --> 00:23:12,000
but you should become familiar with
their names.  And you will be

263
00:23:12,000 --> 00:23:17,000
interested to read what some of them
do.  And I'll come back to a couple

264
00:23:17,000 --> 00:23:21,000
of them later.
I'll come back to acetylcholine,

265
00:23:21,000 --> 00:23:25,000
already mentioned.  Serotonin which
is involved in promoting

266
00:23:25,000 --> 00:23:30,000
good mood.
And I'll also talk about adenosine

267
00:23:30,000 --> 00:23:35,000
as something that you affect every
morning when you drink a cup of

268
00:23:35,000 --> 00:23:40,000
coffee.  But before we get there,
let's talk about receptors.

269
00:23:40,000 --> 00:23:54,000
And let me introduce you to two

270
00:23:54,000 --> 00:24:00,000
classes of receptors that you should
be familiar with.

271
00:24:00,000 --> 00:24:05,000
So you could imagine,
as we've been talking about,

272
00:24:05,000 --> 00:24:10,000
that the receptors for these
neurotransmitters could directly

273
00:24:10,000 --> 00:24:15,000
influence an action potential in the
next cell by allowing ions in or out

274
00:24:15,000 --> 00:24:20,000
of the cell.  And,
in fact, I'm going to add it to your

275
00:24:20,000 --> 00:24:25,000
first diagram.
A lot of the receptors have

276
00:24:25,000 --> 00:24:31,000
eventually the effect of allowing
sodium to flow in.

277
00:24:31,000 --> 00:24:37,000
But these receptors also may allow
the influx of calcium or they may

278
00:24:37,000 --> 00:24:43,000
allow the efflux,
the removal of chloride.

279
00:24:43,000 --> 00:24:49,000
And we'll talk more about this and
I've got diagrams for you in a

280
00:24:49,000 --> 00:24:55,000
moment.  So the receptors in general
have got something to do with ion

281
00:24:55,000 --> 00:25:02,000
channels.  And they can either be
ion channels themselves directly.

282
00:25:02,000 --> 00:25:09,000
And in this case they get the name
ionotropic receptors or they can be

283
00:25:09,000 --> 00:25:16,000
indirect and they can influence the
activity of ion channels in an

284
00:25:16,000 --> 00:25:23,000
indirect way.  And in this case they
are called metabotropic.

285
00:25:23,000 --> 00:25:38,000
Metabotropic.

286
00:25:38,000 --> 00:25:43,000
OK.  So the end result is that ion
channel activity is changed.

287
00:25:43,000 --> 00:25:49,000
Ionotropic receptors, because they
are the ion channels respond to

288
00:25:49,000 --> 00:25:54,000
neurotransmitters very rapidly.
Within the millisecond timeframe,

289
00:25:54,000 --> 00:26:00,000
metabotropic receptors are much
slower and they respond much more

290
00:26:00,000 --> 00:26:06,000
slowly within the second
to minute range.

291
00:26:06,000 --> 00:26:11,000
And the deal with metabotropic
receptors, I'll talk about both of

292
00:26:11,000 --> 00:26:16,000
them with pictures in a moment.
The deal with metabotropic

293
00:26:16,000 --> 00:26:21,000
receptors is that between the
receptor ligand interaction and

294
00:26:21,000 --> 00:26:27,000
activation of the ion channel,
so the ligand will bind a

295
00:26:27,000 --> 00:26:32,000
metabotropic receptor.
And the metabotropic receptor will

296
00:26:32,000 --> 00:26:36,000
then very often activate the system
of G-proteins that you've talked

297
00:26:36,000 --> 00:26:40,000
about previously.
And those G-proteins will then

298
00:26:40,000 --> 00:26:44,000
activate downstream ion channels.
Here's an example of the

299
00:26:44,000 --> 00:26:49,000
acetylcholine receptor,
which was the first receptor,

300
00:26:49,000 --> 00:26:53,000
neurotransmitter receptor to be
purified.  This is an ionotropic

301
00:26:53,000 --> 00:26:57,000
receptor.  It's a complex of
multiple subunits.

302
00:26:57,000 --> 00:27:01,000
And it works in a way that we
talked about long ago when we talked

303
00:27:01,000 --> 00:27:06,000
about enzymes.
And we talked about allosteric

304
00:27:06,000 --> 00:27:10,000
activation of enzymes.
Remember that way back when?

305
00:27:10,000 --> 00:27:15,000
Something binds to a protein and
changes its confirmation and changes

306
00:27:15,000 --> 00:27:19,000
the activity of the protein.
That's exactly what happens here.

307
00:27:19,000 --> 00:27:24,000
Acetylcholine binds to the receptor
in defined places,

308
00:27:24,000 --> 00:27:28,000
it changes the confirmation of
various subunits,

309
00:27:28,000 --> 00:27:33,000
and going from a closed channel it
now opens this channel.

310
00:27:33,000 --> 00:27:36,000
So this is a gated channel.
OK?  It's a gated channel in the

311
00:27:36,000 --> 00:27:40,000
same way that the sodium channel we
talked about was gated,

312
00:27:40,000 --> 00:27:43,000
but it's gated not by voltage but by
neurotransmitter binding.

313
00:27:43,000 --> 00:27:47,000
All right?  That is the definition
of gated.  It can be gated by

314
00:27:47,000 --> 00:27:50,000
anything.  So this is the
acetylcholine receptor.

315
00:27:50,000 --> 00:27:54,000
It's also called the nicotinic
receptor because it is the thing

316
00:27:54,000 --> 00:27:58,000
that binds nicotine,
and can be activated by binding of

317
00:27:58,000 --> 00:28:02,000
nicotine.
Metabotropic receptors activate ion

318
00:28:02,000 --> 00:28:06,000
channels.  Here is something from
your book.  And I have these on your

319
00:28:06,000 --> 00:28:11,000
handout.  So these are number two
and three on your handout.

320
00:28:11,000 --> 00:28:15,000
Here is the neurotransmitter
binding a receptor,

321
00:28:15,000 --> 00:28:20,000
interacting with various G-proteins,
hydrolysis of GTP.  One of the

322
00:28:20,000 --> 00:28:25,000
subunits goes off,
and through a series of events opens

323
00:28:25,000 --> 00:28:29,000
up another ion channel that is not
linked physically to

324
00:28:29,000 --> 00:28:34,000
the receptor.
Metabotropic receptors.

325
00:28:34,000 --> 00:28:38,000
Now, interestingly, and here is
another note you can make,

326
00:28:38,000 --> 00:28:42,000
a neurotransmitter can either
activate an ionotropic or a

327
00:28:42,000 --> 00:28:46,000
metabotropic or both types of
receptors.  Acetylcholine is

328
00:28:46,000 --> 00:28:51,000
ionotropic.  It can also be
metabotropic.  In hot muscle there

329
00:28:51,000 --> 00:28:55,000
are these things called muscarinic
acetylcholine receptors,

330
00:28:55,000 --> 00:28:59,000
and they are responsible for slowing
down or speeding up the contraction

331
00:28:59,000 --> 00:29:04,000
of the heart muscle.
So there is a lesson there.

332
00:29:04,000 --> 00:29:10,000
Receptors can be either or both
ionotropic or metabotropic.

333
00:29:10,000 --> 00:29:20,000
So up on the top board I've

334
00:29:20,000 --> 00:29:26,000
mentioned the terms excitatory and
inhibitory.  Let's go back to them

335
00:29:26,000 --> 00:29:32,000
and let's talk about excitatory
versus inhibitory synapses.

336
00:29:32,000 --> 00:29:38,000
So the deal is this.

337
00:29:38,000 --> 00:29:42,000
You've got your signal coming along,
you've got your next cell,

338
00:29:42,000 --> 00:29:46,000
or you've got your signal coming
along, you've got your next cell

339
00:29:46,000 --> 00:29:50,000
here, you're passing the information
to the next cell.

340
00:29:50,000 --> 00:29:54,000
And the question that that next
cell is trying to answer is should I

341
00:29:54,000 --> 00:29:58,000
fire an action potential?
That is the only question it is

342
00:29:58,000 --> 00:30:02,000
capable of answering.
That is the only output that has

343
00:30:02,000 --> 00:30:07,000
real relevance for a cell,
OK, is whether or not it's going to

344
00:30:07,000 --> 00:30:12,000
fire an action potential and
transmit the nervous information

345
00:30:12,000 --> 00:30:17,000
along the pathway of the nervous
system.  And in order to decide that

346
00:30:17,000 --> 00:30:22,000
there are two things that can happen.
Neurotransmitter receptor

347
00:30:22,000 --> 00:30:27,000
interaction can promote,
can facilitate, can make easier an

348
00:30:27,000 --> 00:30:33,000
action potential to happen in the
postsynaptic cell --

349
00:30:33,000 --> 00:30:38,000
-- or can inhibit an action
potential from occurring in the

350
00:30:38,000 --> 00:30:43,000
postsynaptic cell.
So let's go back to our discussion

351
00:30:43,000 --> 00:30:48,000
from last week where we talked about
resting potential,

352
00:30:48,000 --> 00:30:53,000
threshold potential and so on.
And let me give you some

353
00:30:53,000 --> 00:30:58,000
information.  The threshold
potential is constant.

354
00:30:58,000 --> 00:31:02,000
For one fish, could somebody please
define for me the threshold

355
00:31:02,000 --> 00:31:07,000
potential somewhere up here?
Threshold potential.  Yeah.  Yes,

356
00:31:07,000 --> 00:31:11,000
you're correct.  The threshold
potential is around negative 50

357
00:31:11,000 --> 00:31:16,000
millivolts where outside is more
positive than inside.

358
00:31:16,000 --> 00:31:20,000
What is this threshold potential?
What happens when you cross it?

359
00:31:20,000 --> 00:31:25,000
Yeah?  And action potential is
created.  Right.

360
00:31:25,000 --> 00:31:29,000
Good.  OK.  So one first for you.
And see me for another fish later

361
00:31:29,000 --> 00:31:34,000
on.  You came up here with one.
OK.  The threshold potential,

362
00:31:34,000 --> 00:31:38,000
the point of no return at which the
action potential is going to take

363
00:31:38,000 --> 00:31:43,000
place is constant from cell to cell.
It doesn't change.  What can change

364
00:31:43,000 --> 00:31:53,000
is the resting potential.

365
00:31:53,000 --> 00:31:58,000
And excitatory and inhibitory
synapses act upon the resting

366
00:31:58,000 --> 00:32:04,000
potential and bring the resting
potential closer or further away

367
00:32:04,000 --> 00:32:09,000
from the threshold potential.
So excitatory synapses and the

368
00:32:09,000 --> 00:32:15,000
interaction of neurotransmitters
with the receptors inhibit,

369
00:32:15,000 --> 00:32:21,000
OK, excitatory synapses will bring
the resting potential closer to the

370
00:32:21,000 --> 00:32:27,000
threshold potential.
They'll make it easier for an

371
00:32:27,000 --> 00:32:34,000
action potential to take place.
So they increase the resting

372
00:32:34,000 --> 00:32:42,000
potential.  RP for resting potential.
Inhibitory synapses decrease the

373
00:32:42,000 --> 00:32:50,000
resting potential and make it harder
to get to the threshold potential.

374
00:32:50,000 --> 00:32:58,000
OK?  So you increase the resting
potential and you still get closer

375
00:32:58,000 --> 00:33:05,000
to TP or the threshold potential.
And you here you get further from

376
00:33:05,000 --> 00:33:17,000
the threshold potential.

377
00:33:17,000 --> 00:33:23,000
And the way you do this is by acting
on specific channels directly or

378
00:33:23,000 --> 00:33:29,000
indirectly.  If you're going to
increase the resting potential so

379
00:33:29,000 --> 00:33:35,000
that you get closer to the threshold
potential the channels involved are

380
00:33:35,000 --> 00:33:40,000
sodium and calcium.
And those two ions will flow into

381
00:33:40,000 --> 00:33:44,000
the neuron.  If you are going to
decrease the resting potential,

382
00:33:44,000 --> 00:33:48,000
make it harder to get to that
threshold potential,

383
00:33:48,000 --> 00:33:52,000
you want to do the opposite.
So you could take sodium or calcium

384
00:33:52,000 --> 00:33:56,000
out, but that's not how the cell
usually does it.

385
00:33:56,000 --> 00:34:00,000
The way the cell does it is to open
up chloride channels.

386
00:34:00,000 --> 00:34:03,000
There's a lot of chloride.
I'll show you some diagrams in a

387
00:34:03,000 --> 00:34:06,000
moment.  There's a lot of chloride
on the outside of the axon.

388
00:34:06,000 --> 00:34:10,000
It opens chloride channels and the
chloride will flow into the cell.

389
00:34:10,000 --> 00:34:16,000
All right.  Let's look at some

390
00:34:16,000 --> 00:34:19,000
pictures and some of the things I've
drawn for you.

391
00:34:19,000 --> 00:34:22,000
So this is a diagram from last
lecture which I drew for you.

392
00:34:22,000 --> 00:34:25,000
It shows you the action potential
and it shows you the transient

393
00:34:25,000 --> 00:34:28,000
depolarization and reversal of
charge distribution across

394
00:34:28,000 --> 00:34:32,000
the membrane.
As a couple of you pointed out to me

395
00:34:32,000 --> 00:34:36,000
this is not accurate.
Of course it's not accurate.

396
00:34:36,000 --> 00:34:40,000
It's a cartoon.  And it's not
accurate specifically because things

397
00:34:40,000 --> 00:34:44,000
aren't all or none.
It's not entirely positive outside

398
00:34:44,000 --> 00:34:48,000
and entirely negative inside.
And there are a number of different

399
00:34:48,000 --> 00:34:52,000
ions involved.
So I have had a go at making it

400
00:34:52,000 --> 00:34:56,000
slightly more accurate.
And this is number four on your

401
00:34:56,000 --> 00:35:00,000
handout.  And now I've drawn it in
terms of synapses.

402
00:35:00,000 --> 00:35:04,000
It's a complicated diagram but we
can work through it.

403
00:35:04,000 --> 00:35:08,000
Outside the cell or in the synaptic
cleft.  And here's your postsynaptic

404
00:35:08,000 --> 00:35:12,000
cell.  Again, this line as
previously is the membrane.

405
00:35:12,000 --> 00:35:16,000
So here is your ion distribution.
Outside the cell there is high

406
00:35:16,000 --> 00:35:20,000
sodium.  Inside the cell low sodium
shown in red.  Inside the cell high

407
00:35:20,000 --> 00:35:24,000
potassium.  Outside relatively low
potassium.  And you remember that

408
00:35:24,000 --> 00:35:28,000
that potassium-sodium gradient is
constantly being generated by the

409
00:35:28,000 --> 00:35:32,000
sodium-potassium pump,
and then potassium is flowing

410
00:35:32,000 --> 00:35:37,000
outwards according to its gradient
through open potassium channels.

411
00:35:37,000 --> 00:35:41,000
That is going on all the time.
I haven't indicated that, but

412
00:35:41,000 --> 00:35:45,000
that's going on all the time.
In addition, outside the cell are

413
00:35:45,000 --> 00:35:49,000
high levels of calcium in brown and
high levels of chloride ion shown in

414
00:35:49,000 --> 00:35:53,000
gray.  Inside the cell there are
negative charges.

415
00:35:53,000 --> 00:35:57,000
A lot of them are on proteins
rather than free ions.

416
00:35:57,000 --> 00:36:01,000
OK.  And I've shown you your
resting potential is around minus 60

417
00:36:01,000 --> 00:36:05,000
millivolts and your threshold
potential around minus 50.

418
00:36:05,000 --> 00:36:09,000
So let's look what happens at an
excitatory synapse.

419
00:36:09,000 --> 00:36:13,000
And the thing that you want to look
for are channels that will

420
00:36:13,000 --> 00:36:17,000
hypopolarize, that will make the
potential difference lower so that

421
00:36:17,000 --> 00:36:21,000
you get closer to that threshold
potential.  And the way you do that

422
00:36:21,000 --> 00:36:25,000
is to open up a series of gated
sodium channels.

423
00:36:25,000 --> 00:36:29,000
Those same voltage gated sodium
channels which we previously

424
00:36:29,000 --> 00:36:34,000
talked about.
But I should tell you that there are

425
00:36:34,000 --> 00:36:38,000
dozens of different channels that
are gated.  And different cells have

426
00:36:38,000 --> 00:36:42,000
different types of gated channels
but the idea is the same.

427
00:36:42,000 --> 00:36:47,000
These are voltage-gated sodium
channels, and they are going to

428
00:36:47,000 --> 00:36:51,000
allow an inward flow of positive
ions.  In addition,

429
00:36:51,000 --> 00:36:55,000
there are gated calcium channels
which will allow an inward flow of

430
00:36:55,000 --> 00:37:00,000
calcium.  So this is an
excitatory synapse.

431
00:37:00,000 --> 00:37:04,000
And you will get here a
hypopolarization.

432
00:37:04,000 --> 00:37:09,000
Conversely, on your next handout
and number six,

433
00:37:09,000 --> 00:37:14,000
at an inhibitory synapse channels
that hypopolarize,

434
00:37:14,000 --> 00:37:18,000
that make you more negative will
open.  And these particularly are

435
00:37:18,000 --> 00:37:23,000
chloride channels that will give you
an inward flow of chloride ion and

436
00:37:23,000 --> 00:37:28,000
make the inside of the postsynaptic
cell even more negative and move it

437
00:37:28,000 --> 00:37:33,000
even further away from
threshold potential.

438
00:37:33,000 --> 00:37:37,000
This is a diagram from your book I'm
not going to dwell on.

439
00:37:37,000 --> 00:37:41,000
And I want to point out here again
that I mentioned up here

440
00:37:41,000 --> 00:37:45,000
acetylcholine can either be
excitatory or inhibitory.

441
00:37:45,000 --> 00:37:50,000
At the neuromuscular junction
acetylcholine is an excitatory

442
00:37:50,000 --> 00:37:54,000
neurotransmitter.
Here it is increasing or making

443
00:37:54,000 --> 00:37:59,000
less negative the membrane
potential.

444
00:37:59,000 --> 00:38:04,000
So it is pushing you closer towards
threshold.  And here in the heart

445
00:38:04,000 --> 00:38:09,000
muscle it is acting as an inhibitory
neurotransmitter making the membrane

446
00:38:09,000 --> 00:38:14,000
potential, the resting potential
much lower.  OK.

447
00:38:14,000 --> 00:38:24,000
So I want to move on now to

448
00:38:24,000 --> 00:38:32,000
something called summation.
So we're building up the sense of

449
00:38:32,000 --> 00:38:36,000
whether a neuron,
once it makes the synapse is going

450
00:38:36,000 --> 00:38:40,000
to fire an action potential.
And that depends on this excitatory

451
00:38:40,000 --> 00:38:44,000
versus inhibitory stuff.
But there's anther wrinkle,

452
00:38:44,000 --> 00:38:48,000
and the other wrinkle is the one
that I alluded to and I've told you

453
00:38:48,000 --> 00:38:52,000
on the first board neurons make lots
of synapses.  They're not just

454
00:38:52,000 --> 00:38:57,000
making one synapse.
They're making lots of synapses.

455
00:38:57,000 --> 00:39:02,000
And the input from many synapses
needs to be added up,

456
00:39:02,000 --> 00:39:08,000
needs to be summated in order that
the neuron decides whether it's

457
00:39:08,000 --> 00:39:13,000
going to fire or not.
And that summation can be two-fold.

458
00:39:13,000 --> 00:39:19,000
It can be spatial in that a number
of different neurons,

459
00:39:19,000 --> 00:39:24,000
a number of different synapses are
made with the same neuron.

460
00:39:24,000 --> 00:39:30,000
And the sum of all the changes in
the membrane potential

461
00:39:30,000 --> 00:39:35,000
are added up.
And if you get above the threshold

462
00:39:35,000 --> 00:39:41,000
potential then you fire an action
potential.  Or they can be temporal

463
00:39:41,000 --> 00:39:46,000
where over a period of millisecond
all the inputs into a neuron are

464
00:39:46,000 --> 00:39:51,000
added up.  And if at the end of that
time period you are above threshold

465
00:39:51,000 --> 00:39:57,000
potential then an action potential
fires.  This is number seven on your

466
00:39:57,000 --> 00:40:02,000
handout.  Here is an axon.
Actually, here is a neuron.

467
00:40:02,000 --> 00:40:06,000
Here are a bunch of synapses.
They've said that they're

468
00:40:06,000 --> 00:40:10,000
excitatory synapses coming into the
axon.  The synapses can actually

469
00:40:10,000 --> 00:40:14,000
occur at many different places.
In an axon they've shown them here

470
00:40:14,000 --> 00:40:18,000
coming into a part of the cell body.
And there's this thing called the

471
00:40:18,000 --> 00:40:22,000
axon hillock which has got a
particular configuration of channels.

472
00:40:22,000 --> 00:40:26,000
And that's the place where the cell
often makes the decision as to

473
00:40:26,000 --> 00:40:30,000
whether it is going to fire an
action potential or not.

474
00:40:30,000 --> 00:40:34,000
But it is misleading to see these
synapses coming in all together

475
00:40:34,000 --> 00:40:39,000
because they can come in at multiple
different places on the neuron.

476
00:40:39,000 --> 00:40:43,000
OK.  So here are synapses coming in.
And you sum up the input from these.

477
00:40:43,000 --> 00:40:48,000
This is the next diagram on your
handout.  So here in a graphic way

478
00:40:48,000 --> 00:40:53,000
are a number of small changes in
membrane potential from a number of

479
00:40:53,000 --> 00:40:57,000
different synapses indicated by the
numbers here.  And these are

480
00:40:57,000 --> 00:41:02,000
summated at the axon hillock.
And then the decision as to whether

481
00:41:02,000 --> 00:41:06,000
or not you're above threshold and
whether you make an action potential

482
00:41:06,000 --> 00:41:10,000
is made.  You can also do this over
a period of time,

483
00:41:10,000 --> 00:41:14,000
again, on the millisecond time scale,
and that will tell you whether an

484
00:41:14,000 --> 00:41:18,000
action potential fires or does not
fire.  OK.  So the thing you need to

485
00:41:18,000 --> 00:41:22,000
remember is that the action
potential is the output,

486
00:41:22,000 --> 00:41:26,000
and the decision is whether you make
an action potential or not.

487
00:41:26,000 --> 00:41:30,000
So the decision to make an action
potential.

488
00:41:30,000 --> 00:41:33,000
And the other thing that I should
note is your action potential is

489
00:41:33,000 --> 00:41:37,000
your action potential.
It has the same magnitude,

490
00:41:37,000 --> 00:41:41,000
and it's propagated once it starts.
What you can change is the

491
00:41:41,000 --> 00:41:45,000
frequency with which you make that
action potential.

492
00:41:45,000 --> 00:41:49,000
So you can have action potentials
arising at slow rate or you can have

493
00:41:49,000 --> 00:41:53,000
them arising very quickly.
So the decision is to make the

494
00:41:53,000 --> 00:41:57,000
action potential,
it's all or none.  I mentioned this

495
00:41:57,000 --> 00:42:01,000
last time.  But you can change the
frequency at which action

496
00:42:01,000 --> 00:42:07,000
potentials fire.

497
00:42:07,000 --> 00:42:16,000
All right.  Controlling
neurotransmitter activity.

498
00:42:16,000 --> 00:42:25,000
Neurotransmitters, here's
acetylcholine and here is atropine,

499
00:42:25,000 --> 00:42:35,000
which is an inhibitor of
acetylcholine receptor activity.

500
00:42:35,000 --> 00:42:39,000
Acetylcholine is an example of a
neurotransmitter that is made and

501
00:42:39,000 --> 00:42:43,000
then destroyed.
There it is being made,

502
00:42:43,000 --> 00:42:48,000
being used for receptor binding and
for doing whatever it's going to do

503
00:42:48,000 --> 00:42:52,000
in the postsynaptic cell.
And here is an enzyme called

504
00:42:52,000 --> 00:42:56,000
acetylcholinesterase that cleaves
the acetylcholine and prevents it

505
00:42:56,000 --> 00:43:01,000
from being used again.
Acetylcholinesterase is essential to

506
00:43:01,000 --> 00:43:07,000
acetylcholine function.
Nerve gases, very typically,

507
00:43:07,000 --> 00:43:12,000
inhibit acetylcholinesterase.  That
is a very popular way that nerve

508
00:43:12,000 --> 00:43:18,000
gases work.  And when they do so,
what happens is that you have an

509
00:43:18,000 --> 00:43:24,000
excess of acetylcholine around and
you get occupation of the

510
00:43:24,000 --> 00:43:29,000
acetylcholine receptors on the
postsynaptic membrane that makes

511
00:43:29,000 --> 00:43:35,000
that postsynaptic cell fire
repeatedly or fire

512
00:43:35,000 --> 00:43:40,000
without stopping.
And that will inhibit your ability

513
00:43:40,000 --> 00:43:44,000
to breathe and not breathe and
breathe and not breathe.

514
00:43:44,000 --> 00:43:48,000
And you will not be able to get
contraction and relaxation and

515
00:43:48,000 --> 00:43:52,000
contraction and relaxation of the
muscles that allow you to breathe.

516
00:43:52,000 --> 00:43:56,000
And nerve gases are generally toxic
for that reason.  They

517
00:43:56,000 --> 00:44:01,000
paralyze the muscles.
Our troops in Iraq and elsewhere

518
00:44:01,000 --> 00:44:05,000
have in their pockets atropine
syringes.  Syringes filled with a

519
00:44:05,000 --> 00:44:09,000
substance called atropine.
Atropine is a nerve gas antidote.

520
00:44:09,000 --> 00:44:13,000
And the way it works is in the
following way.

521
00:44:13,000 --> 00:44:17,000
It acts by blocking.
It's a competitive inhibitor of the

522
00:44:17,000 --> 00:44:21,000
acetylcholine receptor.
And so even in the presence of

523
00:44:21,000 --> 00:44:25,000
nerve gas, the acetylcholine that is
free and floating around in the

524
00:44:25,000 --> 00:44:29,000
synaptic cleft will not be able to
do its thing because atropine is

525
00:44:29,000 --> 00:44:32,000
preventing it from doing so.
Now, it's interesting.

526
00:44:32,000 --> 00:44:36,000
I've told you acetylcholine does
many things through both ionotropic

527
00:44:36,000 --> 00:44:40,000
and metabotropic receptors.
And atropine will affect all of

528
00:44:40,000 --> 00:44:44,000
these things.  OK?
It will affect the ionotropic

529
00:44:44,000 --> 00:44:48,000
receptors particularly,
but what is has the side effect of

530
00:44:48,000 --> 00:44:52,000
doing is making you very sleepy.
Nonetheless, it will save your life.

531
00:44:52,000 --> 00:44:56,000
OK.  Serotonin,
another neurotransmitter involved in

532
00:44:56,000 --> 00:45:00,000
mood.  It makes you feel
good about things.

533
00:45:00,000 --> 00:45:05,000
Here are two examples of ways that
serotonin activity is regulated.

534
00:45:05,000 --> 00:45:10,000
Prozac is a class of molecules
called a specific serotonin reuptake

535
00:45:10,000 --> 00:45:15,000
inhibitor.  Serotonin,
when it is made, is released and

536
00:45:15,000 --> 00:45:20,000
then is retaken up into the vesicles
and used again.

537
00:45:20,000 --> 00:45:25,000
Prozac slows down this reuptake and
allows the serotonin to act for a

538
00:45:25,000 --> 00:45:30,000
more prolonged period than it
normally would have.

539
00:45:30,000 --> 00:45:34,000
And here is another one that you're
very familiar with,

540
00:45:34,000 --> 00:45:38,000
caffeine.  Caffeine is a competitive
inhibitor of the neurotransmitter

541
00:45:38,000 --> 00:45:42,000
adenosine.  Here is adenosine and
here is caffeine,

542
00:45:42,000 --> 00:45:47,000
and you can see that they both have
this purine ring.

543
00:45:47,000 --> 00:45:51,000
Caffeine will bind to the adenosine
receptor.  Adenosine normally

544
00:45:51,000 --> 00:45:55,000
promotes signal transduction
pathways that make you sleepy.

545
00:45:55,000 --> 00:46:00,000
And adenosine can be counteracted
by caffeine.

546
00:46:00,000 --> 00:46:04,000
You can go and look later at the
pathway that caffeine and adenosine

547
00:46:04,000 --> 00:46:09,000
both act upon.
And I will talk more about this

548
00:46:09,000 --> 00:46:12,000
next time.