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Good morning. Thank you. So,
I want to continue today on the

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theme of neurobiology. Last
time we spoke about the action

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potential mechanism. Today
I'd like to go from action

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potential to the synapse. But
let me briefly remind us what we

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say. So, I'm going to give
section zero a recap here.

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The relevant things that we said
last time was there's a membrane

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potential which at rest is about
minus 70 millivolts as the membrane

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potential, and that's what we work
with. That membrane potential is

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set up by concentration gradients.
More calcium, more potassium on the

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inside. More sodium on the outside.
More calcium on the outside. And

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I'm also going to mention chloride,
there's more chloride on the outside

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at 116 millimolar, four
millimolar on the outside.

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These concentration gradients are
set up by various different pumps.

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They're there all the time. Then
we have this resting channel.

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So, here we have transporters.

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We have a resting potassium channel.
It means that it's open all the

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time. It's not
activated by anything.

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That allows potassium to leave.
Potassium leaves until it builds up

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this membrane potential about
minus 70. At that point it is

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electrically unfavorable for more
positive charges to go out into the

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more positive environment.
Notwithstanding the greater

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internal concentration.
And we reach an equilibrium

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potential of minus 70. We
then have some voltage-gated

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channels.

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And the voltage-gated channels
come in two flavors here.

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We have the voltage-gated sodium
channel. The voltage-gated sodium

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channel opens itself up
around minus 70. Oh, sorry,

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around minus 50. So, if
you can get up to minus 50

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it opens up. Then your sodium
rushes in. It shifts the membrane

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potential from minus
50 to zero to plus 50.

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The channel shuts. Somewhere
around plus 30 or so

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opens the potassium channel, the
voltage graded potassium channel,

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and allows the potassium to rush out
and restore the resting potential.

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The effect of this is that,
if this is zero here, we have

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a resting potential. If we
climb up a little bit above it

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we shoot up and then we come back
down. And then a millisecond or so

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later another action potential
could go down that same neuron.

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And, last of all, if we look
along the length of an axon,

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an action potential here causes
charges to migrate over which

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launches an action potential here
which causes charges to migrate over

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which etc., etc. propagates
an action potential down

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the length. It's
a beautiful system.

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And then the very last thing was
that by insulating this we were able

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to make the conduction velocity
go faster by effectively making the

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effective length be shorter there
being a whole bunch of electrically

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insulated regions. So,
that's it. It's a beautiful

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piece of engineering. How do
we know any of this is true?

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As an interesting
side point,

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I might just mention that
when this was worked out,

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this was worked out by two
folks called Hodgkin and Huxley.

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Hodgkin and Huxley won a Nobel
prize for this beautiful work on

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this squid giant axon which is
the fastest axon that there is.

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And here we're not talking about
the giant squid somebody raised last

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time. It's an ordinary squid.
It has one big fat axon. It's

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sufficiently big that you can just
like stick a wire in the middle of

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it and all that.
It's a very big axon.

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It's a very, very
high diameter axon.

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And they were able to measure
these things electrically.

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And on the basis of the electrical
measurements they made in different

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kinds of solutions, they
were able to infer the

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existence of sodium channels
and potassium channels.

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But this all happened mid 20th
century. And they certainly

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couldn't see any. They
couldn't clone them.

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They couldn't see anything. And
so the notion that there were

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individual molecular channels that
swung open, did all this stuff was

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an indirect inference, maybe
kind of a little bit like

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Mendel's inference of a gene
or Sturtevant's inference

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of genetic maps. But more
recently people have come

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along with an extraordinary
technology, also these people won a

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Nobel prize for this because it was
way cool, which is called the Patch

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Clamp. The patch clamp is the
following ridiculously simple

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technology. Suppose I were
to make a glass pipette.

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So, this is a cross-section
of a glass pipette.

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So, it goes around like that.
And I could bring it up really

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tight up against the membrane.
And suppose I did it in such a way

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that I could get a really great
seal and I just have a teeny patch of

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membrane. Suppose that teeny
patch of membrane had just

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one channel in it. And
now, so this is a pipette,

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suppose I were to rip off that
patch of membrane from the cell,

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poor cell, and have a glass pipette
with a little patch of membrane on

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its end with a single
isolated ion channel. Now,

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if I measured the current through
this channel by putting it in an

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appropriate solution,
maybe I ripped off a resting

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potassium channel, OK? If
I put this in a potassium

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solution and I apply a current,
I apply a voltage difference, I

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should be able to see a current.
And you can actually measure a

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current. Even more cool, if I
do this and I've ripped off a

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voltage-gated sodium channel, then
it turns out that I ought to be

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able to study its properties by
changing the voltage on it and

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measuring the current as
a function of the voltage.

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And, well, it turns out that if I do
this I'm able to measure in resting

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or in these voltage-gated channels
current flows conductivities,

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actually, what I'm really measuring
is the conductivity of the channel

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like this, I can see the channel
opening and closing and opening and

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closing quantily. I
can measure quantily the

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conductivity. That's not quantum
mechanics. It's just quanta

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measurements of the conductivity.
What would happen if I had two

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channels that had been ripped
off? Now I'd see it go like this.

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Well, maybe another one opens.
Oops, now one closes. Now the

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other one closes. And
quite remarkably you can get

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this. So, you can study single
molecule, single molecular channels.

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You want to know how this channel
opens and at what voltage it opens?

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Just dial in the voltage and see if
it's open. Do you want to know how

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long it stays open? Just
turn it on and see how long it

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stays open. It's really cool.
You want to see if any other

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chemicals could affect it, any
ions, any other intracellular or

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extra cellular
chemicals? You can do it.

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So, the ability to study isolated
single channels came along with

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patch clamping. And what
it allows is a tremendous

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study of the biophysics
of individual channels.

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And, whereas, before people had to
look at the total conductivity of an

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entire axon. Now they're able,
and from that infer the behavior of

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single channels, now what
they can do is study the

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behavior of single channels and
synthetically build up a picture of

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the total conductivity of an axon
from its individual components and

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see if the components we've
identified are sufficient to explain

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the behavior that we see.
Anyway, that's patch clamping.

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Lots of fun. So, now, what I
want to turn now to is signaling

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at the synapse.

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So, we have our cell body here.
It's got its dendrites on it.

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Here's our axon. We've
managed to get an action

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potential started on it and
it moves all the way down.

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Now we get here to one
of the synaptic terminals.

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The electrical signal makes it all
the way to the synaptic terminal,

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but how does it affect
the post-synaptic cell?

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Well, let's get a
close-up of that.

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Here we go. Here's the synaptic
terminal. We've got our action

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potential coming.
Action potential coming.

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And then it gets here.
Action potential's arrived.

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I would like to release
chemicals into the synaptic cleft,

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the space between the pre
and the post-synaptic cell.

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I'd like to spill out chemicals
that are neurotransmitters.

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So, the pre-synaptic cell
conveniently has vesicles,

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little membrane-bound vesicles
with prepackaged neurotransmitters.

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OK? These prepackaged
neurotransmitters have been

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conveniently synthesized by the
cell and they're just sitting there

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waiting to be released in
response to an action potential.

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When the action potential comes,
it causes these synaptic vesicles to

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fuse --

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-- with the membrane. And
in fusing the insides become

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continuous with the outsides,
here's a little fusion picture here,

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and the neurotransmitters
leak out. OK?

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How does it do that,
though, mechanistically?

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How in the world does an action
potential cause these vesicles to

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fuse with the membrane? Well,
somehow it's got to read out

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electrical activity into some
kind of a chemical activity

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intracellularly.
Here's what it does.

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When the electrical signal comes
down, remember originally the

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membrane potential is negative,
but when an action potential comes

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by what does it do to the
membrane potential? It reverses it.

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It makes it positive inside briefly.
OK? So, this is the sign of an

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action potential,
an AP coming down.

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In this membrane we have us
another voltage-sensitive channel.

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This voltage sensitive channel is
a voltage sensitive calcium channel.

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OK? Who would like to design a
voltage-sensitive calcium channel?

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What should it do? What would you
like to have its opening and closing

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properties be?
When does it open?

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At a positive charge. So,
when you get to a positive

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membrane potential it swings
open. And then what does it do?

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Lets calcium move. Which
way does calcium want to go?

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In because it's more out. So,
what's going to happen is in

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response to the action
potential calcium will rush in.

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Now, calcium, you will recall,
was in vanishingly small traces

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inside, 0.1 micromolar we said.
And influx of calcium is a very

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serious matter and it is
sensed by variety of proteins.

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In particular, there is,
floating around in the

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cell, a protein here called a
calcium-dependent protein kinase.

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The calcium-dependent
protein kinase

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is a protein that is capable
of putting a phosphate group.

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Its kinase puts a phosphate
group on other proteins.

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So, the calcium-dependent protein
kinase over here will go along and

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catalyze the addition of a
phosphate group to other proteins.

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So, it will enzymaticly catalyze
this. But it only does so in the

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presence of calcium. So,
when there's calcium in the

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cell, the calcium-dependent kinase
is activated and it runs around and

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sticks phosphate groups on
specific target proteins.

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You know where one of those target
proteins lives? In the vesicles.

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The vesicles happen to
be a target for this. So,

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the vesicles have a protein on them.
And in one of these extraordinary

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coincidences in molecular biology,
the protein on the synaptic vesicle

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happens to be called,
coincidently, synapsin.

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OK? It's not actually entirely
a coincidence that it's called

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synapsin. It was named synapsin
because it was found on the synaptic

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vesicles, obviously. And
so what happens is when the

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action potential comes down it
causes the calcium channel to open

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in response to positive
voltage. Calcium comes in,

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actives at the kinase. The
kinase phosphorilates synapsin.

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And now the phosphorilated form of
synapsin likes to bind to something

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in the membrane. That's
it. How many of you still

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know what a Rube Goldberg machine
is? Good. OK. This is one of these

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just great, well, others
of you should look it up on

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the Web because they're just great
cartoons, the Rube Goldberg cartoons

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about the machine where the rooster
crows startling the cat which tugs

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the thing with causes this to flop
which causes the eggs to go in the

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pan which causes the thing
to cook which causes whatever.

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And I always think about these
in terms of great molecular Rube

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Goldberg machines. So,
this is the Rube Goldberg

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machine that gets this
synaptic vesicle to fuse there.

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OK? Good. Every bit of
neurobiology has a molecular

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mechanism to be explained like
this. So, now let's go onto the next

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bit. How does this
signal gets sensed at

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the next cell?
What are we up to?

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Number three. So, let's
look at a specific junction.

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Instead of looking at the
junction between two nerve cells,

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let me start with the junction
between a nerve cell and a muscle

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cell, the neuromuscular junction.
OK? So, I've now replaced my

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post-synaptic neuron by a
muscle fiber here. This is

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a muscle fiber. So, when
it spritzes out the stuff

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the neurons that innervate
muscle fibers, actually,

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I'm going to expand that a bit,
the neurons that innervate muscle

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fibers, here's the muscle, and
I'll put it at some distance

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here, muscle, spray out a
particular transmitter in response

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to the calcium influx. And
that transmitter is called

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acetylcholine,
henceforth ACH.

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Acetylcholine is spritzed out into
the synaptic cleft and comes out.

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And what do you think
acetylcholine is going to do?

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I've got to send the chemical
signal to the next cell.

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I've got to somehow send
that signal to the surface.

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It's going to bind to
something on the next cell.

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You know the deal, right?
So, it's going to have to

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bind to a protein on this cell.
And, remarkably, what it binds to

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is called an acetylcholine receptor.
OK? Very reasonable stuff. An

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acetylcholine receptor. The
acetylcholine receptor happens

224
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to be an ion channel, but
it's not a voltage-gated ion

225
00:19:06,000 --> 00:19:12,000
channel. It's not an ion channel
that opens in response to the

226
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voltage. It's an ion channel that
opens in response to acetylcholine.

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It's what we'd call a ligand-gated
ion channel because it's gated by a

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00:19:24,000 --> 00:19:31,000
ligand, acetylcholine. So,
this guy here is a ligand-gated

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00:19:31,000 --> 00:19:39,000
ion channel which, when
acetylcholine binds to it,

230
00:19:39,000 --> 00:19:47,000
swings open. And what it
does is it allows in sodium.

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00:19:47,000 --> 00:19:55,000
Bingo. Now, when sodium comes in
what happens? Action potential.

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But what a second.
This is a muscle.

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All membranes have
the machinery to

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have an action potential? Nah,
liver cells are pretty passive.

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You do this to a liver
cell it kind of sits there.

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But muscle cells do have an
action potential mechanism.

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They do respond here like a neuron,
an action potential. And so what

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00:20:30,000 --> 00:20:34,000
happens when I open up some sodium
channels to the resting potential

239
00:20:34,000 --> 00:20:38,000
of my muscle? What was
the resting potential of my

240
00:20:38,000 --> 00:20:42,000
muscle? About minus 70. What
happens when I open up these

241
00:20:42,000 --> 00:20:45,000
ligand-gated sodium channels?
Sodium rushes in. What does it do

242
00:20:45,000 --> 00:20:49,000
to my membrane potential?
It makes it more positive.

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00:20:49,000 --> 00:20:52,000
What does that do? It triggers
an action potential spreading

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00:20:52,000 --> 00:20:56,000
throughout the muscle. And
because the muscle has an

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00:20:56,000 --> 00:21:04,000
action
potential --

246
00:21:04,000 --> 00:21:09,000
-- all you have to do is manage to
get this going in a little patch of

247
00:21:09,000 --> 00:21:14,000
the muscle and it spreads
throughout the muscle fiber.

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00:21:14,000 --> 00:21:19,000
One neuromuscular synapse will be
sufficient to activate the muscle,

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00:21:19,000 --> 00:21:24,000
in principle, because you have
this action potential mechanism.

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00:21:24,000 --> 00:21:29,000
And then when the action potential
fires in the muscle it actually

251
00:21:29,000 --> 00:21:34,000
causes other channels to open,
including some calcium channels.

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00:21:34,000 --> 00:21:38,000
The calcium channels cause calcium
to come in. The calcium causes your

253
00:21:38,000 --> 00:21:42,000
muscle to contract because of
sliding of actins and myosins and

254
00:21:42,000 --> 00:21:47,000
things like that.
That's how it works.

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00:21:47,000 --> 00:21:51,000
That's this Rube Goldberg machine.
All right. So, let's get ready.

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00:21:51,000 --> 00:21:55,000
Let's fire. Let's send a
neuromuscular signal down.

257
00:21:55,000 --> 00:22:00,000
Contract. Now here's the problem.
I've got all this acetylcholine

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00:22:00,000 --> 00:22:05,000
sitting around in my synapse
activating the ligand-gated sodium

259
00:22:05,000 --> 00:22:10,000
channel causing sodium to come in,
but I would like to relax my muscle,

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00:22:10,000 --> 00:22:16,000
please. What are we
going to do about this?

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00:22:16,000 --> 00:22:24,000
I could trigger
another channel,

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00:22:24,000 --> 00:22:28,000
and maybe it could be a delayed
acetylcholine activated yeah,

263
00:22:28,000 --> 00:22:32,000
dah, dah, dah, dah, dah, dah, that's
possible. I could have it close

264
00:22:32,000 --> 00:22:36,000
itself. These are all perfectly
reasonable possibilities,

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00:22:36,000 --> 00:22:41,000
and we're going to refer them
to the engineering committee.

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00:22:41,000 --> 00:22:45,000
What else? You could get rid of
the acetylcholine some other way.

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00:22:45,000 --> 00:22:49,000
It turns out the latter
is the solution here.

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00:22:49,000 --> 00:22:53,000
We would like to have some enzyme
that chews up the acetylcholine.

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How about acetylcholinesterase?
So, let's put acetylcholinesterase,

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00:22:59,000 --> 00:23:06,000
ACHE, acetylcholinesterase
in the synaptic cleft.

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00:23:06,000 --> 00:23:13,000
Then when I spritz acetylcholine
it gets to the other side,

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00:23:13,000 --> 00:23:19,000
but very rapidly the
acetylcholinesterase is degrading it.

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00:23:19,000 --> 00:23:26,000
And so it has a very short time
of persistence in the synaptic

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00:23:26,000 --> 00:23:32,000
cleft. OK?
That works. So,

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00:23:32,000 --> 00:23:37,000
that's how I run a
neuromuscular junction. OK?

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00:23:37,000 --> 00:23:42,000
So, acetylcholinesterase
is very important. Now,

277
00:23:42,000 --> 00:23:47,000
again, as with many of the
things I've talked about,

278
00:23:47,000 --> 00:23:52,000
we really know these things are true
when we're able to inhibit them in

279
00:23:52,000 --> 00:23:57,000
different ways. So, I
want to take a moment and

280
00:23:57,000 --> 00:24:03,000
talk about drugs and toxins.
Because they help us to probe these

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00:24:03,000 --> 00:24:11,000
different processes.
Anybody ever have fugu?

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Does anybody know what fugu is?
What's fugu? It's a blowfish.

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00:24:18,000 --> 00:24:26,000
Right. It's a puffer fish eaten
in sushi, and it's an extraordinary

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00:24:26,000 --> 00:24:32,000
delicacy. And why is that? Right.
Because it's one of the only

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00:24:32,000 --> 00:24:36,000
sushis where you really have to
worry about improper preparation,

286
00:24:36,000 --> 00:24:40,000
not just giving you food poisoning
or a stomachache or something like

287
00:24:40,000 --> 00:24:44,000
that, but it's lethal prepared
incorrectly. The reason it's lethal

288
00:24:44,000 --> 00:24:48,000
incorrectly prepared is because
the blowfish has a specific poison

289
00:24:48,000 --> 00:24:52,000
called tetrodotoxin.
So, if you eat sushi,

290
00:24:52,000 --> 00:24:56,000
so, in fact, chefs in Japan
require a license to prepare fugu

291
00:24:56,000 --> 00:25:01,000
for customers. Every
once, every couple of years

292
00:25:01,000 --> 00:25:08,000
some famous actor or personality
prepares his or her own fugu and

293
00:25:08,000 --> 00:25:15,000
dies from it and it's in the papers.
Seriously. This has happened to

294
00:25:15,000 --> 00:25:22,000
people. They're able to do this.
Anyway, tetrodotoxin, tetrodotoxin

295
00:25:22,000 --> 00:25:29,000
is from puffer fish, fugu.
Why does this stuff kill you?

296
00:25:29,000 --> 00:25:36,000
It turns out that what tetrodotoxin
does, this wonderful poison from

297
00:25:36,000 --> 00:25:43,000
this sushi, is that it irreversibly
binds, irreversible binding and

298
00:25:43,000 --> 00:25:50,000
inhibition of voltage-gated
sodium channels.

299
00:25:50,000 --> 00:25:54,000
Why would this be an
inadvisable thing to have?

300
00:25:54,000 --> 00:25:59,000
Suppose you irreversibly bound to
and inhibited your sodium channels,

301
00:25:59,000 --> 00:26:04,000
your voltage-gated sodium
channels, what would you be unable

302
00:26:04,000 --> 00:26:09,000
to accomplish? An
action potential.

303
00:26:09,000 --> 00:26:14,000
This is ill-advised to be unable
to accomplish an action potential.

304
00:26:14,000 --> 00:26:19,000
You can imagine that what it leads
to then is a paralysis and a very

305
00:26:19,000 --> 00:26:24,000
serious one, and if it's
irreversible this is not a good

306
00:26:24,000 --> 00:26:29,000
thing. There are other things.
Has anyone ever fired poison darts

307
00:26:29,000 --> 00:26:34,000
in South American
jungles? [LAUGHTER]

308
00:26:34,000 --> 00:26:41,000
Well, if you have, you
would have tipped them with

309
00:26:41,000 --> 00:26:48,000
qurare. Qurare is used to make
poison darts. What qurare does is

310
00:26:48,000 --> 00:26:55,000
it reversibly binds,
still not good, but it's a

311
00:26:55,000 --> 00:27:02,000
reversible binder to the
acetylcholine receptor and it

312
00:27:02,000 --> 00:27:10,000
prevents it, it blocks the
binding of acetylcholine.

313
00:27:10,000 --> 00:27:14,000
Your acetylcholine receptors,
therefore, cannot respond to your

314
00:27:14,000 --> 00:27:18,000
acetylcholine.
What will that do?

315
00:27:18,000 --> 00:27:22,000
A flaccid paralysis because
you're unable to move your muscles.

316
00:27:22,000 --> 00:27:26,000
So, if you were trying to shoot
prey in the forest and you send the

317
00:27:26,000 --> 00:27:30,000
poison dart that has qurare,
it will cause the animal to then

318
00:27:30,000 --> 00:27:36,000
flop over. Yes?
Snakes. Ooh,

319
00:27:36,000 --> 00:27:43,000
what kind of snakes?
Venomous steak snakes,

320
00:27:43,000 --> 00:27:50,000
yeah. [LAUGHTER] Like bungarus
snakes, the really poisonous ones.

321
00:27:50,000 --> 00:27:57,000
So, it turns out, great question,
that they make something called

322
00:27:57,000 --> 00:28:03,000
alpha-bungerotoxin.
Venomous snakes,

323
00:28:03,000 --> 00:28:09,000
next thing on my list, exactly.
The only improvement they

324
00:28:09,000 --> 00:28:15,000
make here is that this is
an irreversible binder to the

325
00:28:15,000 --> 00:28:21,000
acetylcholine receptors. Very
impressive stuff. Different

326
00:28:21,000 --> 00:28:27,000
stuff. We'll come back to
jellyfish. But, basically,

327
00:28:27,000 --> 00:28:33,000
everything you know out there that's
noxious is being noxious in some way

328
00:28:33,000 --> 00:28:37,000
that affects molecular biology.
Not all of it affects the nervous

329
00:28:37,000 --> 00:28:41,000
system. Those of you who like to
collect mushrooms may wish to avoid

330
00:28:41,000 --> 00:28:45,000
amanitas mushrooms.
They make amanitas.

331
00:28:45,000 --> 00:28:48,000
Amanitan is an irreversible
binder that affects polymerase,

332
00:28:48,000 --> 00:28:52,000
RNA polymerase. Not a good
thing to lose either. So,

333
00:28:52,000 --> 00:28:56,000
all parts of this course have
interesting poisons that will affect

334
00:28:56,000 --> 00:29:00,000
it but we'll focus on the poisons
effecting neurobiology today.

335
00:29:00,000 --> 00:29:06,000
And then there's a human made thing.
Do you remember the, well, those of

336
00:29:06,000 --> 00:29:12,000
who have heard of World War I,
nerve gas or, in particular, who

337
00:29:12,000 --> 00:29:19,000
remember the attack in the
Tokyo subways with sarin,

338
00:29:19,000 --> 00:29:25,000
a particular kind of nerve gas.
Do you know what that stuff does?

339
00:29:25,000 --> 00:29:32,000
It is a potent inhibitor of
the enzyme acetylcholinesterase.

340
00:29:32,000 --> 00:29:36,000
What would happen if I inhibited
your acetylcholinesterase?

341
00:29:36,000 --> 00:29:40,000
The muscles tense up and I'm
unable to relieve them because,

342
00:29:40,000 --> 00:29:44,000
just like I was doing there,
because my acetylcholine is not

343
00:29:44,000 --> 00:29:49,000
broken down in the synapse.
So, this is a nice menu of

344
00:29:49,000 --> 00:29:53,000
interesting poisons and fun facts
to know and tell and good things to

345
00:29:53,000 --> 00:29:57,000
avoid. There are more drugs and
things that we can come back to.

346
00:29:57,000 --> 00:30:01,000
So, now let's talk about,
let's move onto other synapses.

347
00:30:01,000 --> 00:30:06,000
Let's take a look at
nerve-nerve synapses.

348
00:30:06,000 --> 00:30:16,000
So, we looked
at a nerve muscle

349
00:30:16,000 --> 00:30:22,000
synapse. What were the properties
of this nerve muscle synapse?

350
00:30:22,000 --> 00:30:29,000
Well, it had the property that a
single neuron innervates a single

351
00:30:29,000 --> 00:30:35,000
muscle fiber. All right? This
was a one-to-one single fiber,

352
00:30:35,000 --> 00:30:42,000
sorry, single
neuron, single fiber.

353
00:30:42,000 --> 00:30:52,000
When we get to nerve-nerve synapses,
they're more complex. Multiple

354
00:30:52,000 --> 00:31:02,000
different nerve terminals may
synapse upon the same neuron,

355
00:31:02,000 --> 00:31:11,000
as I indicated last time. There
might be a thousand different

356
00:31:11,000 --> 00:31:17,000
nerve terminals synapsing on the
dendrites of a postsynaptic cell,

357
00:31:17,000 --> 00:31:23,000
but let's look at one of them for a
moment. Then we'll come back to how

358
00:31:23,000 --> 00:31:29,000
a thousand can work
together. So, here's one.

359
00:31:29,000 --> 00:31:35,000
And here's my dendrite
that I'm synapsing on here.

360
00:31:35,000 --> 00:31:41,000
The nerve terminal releases into,
sorry, into the synaptic cleft some

361
00:31:41,000 --> 00:31:47,000
neurotransmitter. It turns
out there's a wide variety

362
00:31:47,000 --> 00:31:53,000
of neurotransmitters that get
released while the neuromuscular

363
00:31:53,000 --> 00:31:59,000
junction involves acetylcholine.
One example that might be involved

364
00:31:59,000 --> 00:32:04,000
here is something called
glutamate. What's glutamate?

365
00:32:04,000 --> 00:32:08,000
It's an amino acid. Glutamic
acid. It's the ion of

366
00:32:08,000 --> 00:32:12,000
glutamic acid. That actually
is a neurotransmitter.

367
00:32:12,000 --> 00:32:16,000
Ever have monosodium glutamate.
Does anybody get a headache from

368
00:32:16,000 --> 00:32:20,000
monosodium glutamate? I
do. That's because it's a

369
00:32:20,000 --> 00:32:24,000
neurotransmitter. It
messes with brain chemistry.

370
00:32:24,000 --> 00:32:28,000
So, glutamate.
Glutamate is released.

371
00:32:28,000 --> 00:32:35,000
And what is does is there is a
channel on the post-synaptic cell

372
00:32:35,000 --> 00:32:42,000
that binds glutamate. And
it, too, is a ligand-gated ion

373
00:32:42,000 --> 00:32:49,000
channel. And it could be,
for example, a sodium channel.

374
00:32:49,000 --> 00:32:56,000
Other neurotransmitters
might use other channels.

375
00:32:56,000 --> 00:33:03,000
What happens if I spritz some
glutamate on a dendrite of a cell

376
00:33:03,000 --> 00:33:11,000
that has a glutamate-activated
sodium channel?

377
00:33:11,000 --> 00:33:16,000
What will happen in that dendrite?
Sodium will rush in causing the

378
00:33:16,000 --> 00:33:22,000
membrane potential to become
depolarized and then positive and

379
00:33:22,000 --> 00:33:28,000
then causing an action potential?
No. It turns out that that last

380
00:33:28,000 --> 00:33:34,000
bit doesn't happen because the
dendrites don't have the action

381
00:33:34,000 --> 00:33:41,000
potential machine. The
action potential machinery is

382
00:33:41,000 --> 00:33:49,000
interestingly confined to the axon.
It's not found on the dendrites.

383
00:33:49,000 --> 00:33:58,000
So, when we spritz with glutamate,
what will happen is if this is a

384
00:33:58,000 --> 00:34:06,000
glutamate-bearing synaptic terminal
the membrane potential here will

385
00:34:06,000 --> 00:34:13,000
become locally positive.
But it is not an explosive

386
00:34:13,000 --> 00:34:19,000
regenerative action potential
because there are no voltage-gated

387
00:34:19,000 --> 00:34:24,000
sodium channels that are going
to open in response to that local

388
00:34:24,000 --> 00:34:30,000
depolarization. So, it
became a little positive

389
00:34:30,000 --> 00:34:35,000
over in this corner of the neuron.
Now, if it gets a little positive

390
00:34:35,000 --> 00:34:39,000
over in this corner of the neuron,
you know, it's going to draw some

391
00:34:39,000 --> 00:34:43,000
negative charges from over
here, right, to offset that local

392
00:34:43,000 --> 00:34:48,000
positivity. But if it's just a
local little patch of positive then

393
00:34:48,000 --> 00:34:52,000
it draws a little bit of negative
charge. But is that going to be

394
00:34:52,000 --> 00:34:56,000
enough to depolarize over here?
No. So what do you want to do?

395
00:34:56,000 --> 00:35:01,000
Have more. Suppose I
have two glutaminergic

396
00:35:01,000 --> 00:35:06,000
synapses and they fire,
it might be. Probably not.

397
00:35:06,000 --> 00:35:12,000
Maybe they have to fire at the same
time. Maybe if I have a hundred out

398
00:35:12,000 --> 00:35:17,000
of a thousand. Imagine
that I have a hundred

399
00:35:17,000 --> 00:35:22,000
different glutaminergic synapses
that fired simultaneously then what

400
00:35:22,000 --> 00:35:28,000
will happen? I'll get positive
charges at all of them.

401
00:35:28,000 --> 00:35:32,000
And maybe that's enough to draw some
negative charge away from the axon

402
00:35:32,000 --> 00:35:37,000
and start an action potential going,
or maybe not. Maybe you need two

403
00:35:37,000 --> 00:35:41,000
hundred. What if they don't
fire at exactly the same moment?

404
00:35:41,000 --> 00:35:46,000
Well, the minute one fires
it makes it locally positive,

405
00:35:46,000 --> 00:35:50,000
but then it starts restoring itself
so that if they're separated in time

406
00:35:50,000 --> 00:35:55,000
they're not as effective as
if they happen simultaneously.

407
00:35:55,000 --> 00:35:59,000
So, we have an extraordinary
complex analog integration

408
00:35:59,000 --> 00:36:04,000
circuit here. The analogy
integration circuit

409
00:36:04,000 --> 00:36:08,000
depends on the temporal
arrival of these signals.

410
00:36:08,000 --> 00:36:12,000
And what else does it depend on?
The number of the signals. So,

411
00:36:12,000 --> 00:36:16,000
let's get this down. We're
going to integrate the

412
00:36:16,000 --> 00:36:36,000
signals here.

413
00:36:36,000 --> 00:36:40,000
It'll depend on their timing,
the number, and the geometry,

414
00:36:40,000 --> 00:36:44,000
because it turns out that doing
it at different places in the,

415
00:36:44,000 --> 00:36:48,000
now, I drew my dendritic tree,
the dendrites as all these little

416
00:36:48,000 --> 00:36:52,000
hairy spikes coming off the cell
body, but the dendrites are vastly

417
00:36:52,000 --> 00:36:56,000
more complex than that. Some
cells have elaborate dendritic

418
00:36:56,000 --> 00:37:00,000
trees. The
dendritic tree,

419
00:37:00,000 --> 00:37:05,000
the dendrites of some neurons,
here's the cell body, can go off in

420
00:37:05,000 --> 00:37:10,000
all sorts of wonderfully complex
patterns. And it may be more

421
00:37:10,000 --> 00:37:14,000
effective to hit synapses close
to the cell body or synapses on

422
00:37:14,000 --> 00:37:19,000
different parts of the tree.
And so that the entire shape of

423
00:37:19,000 --> 00:37:24,000
that dendritic tree can have an
effect, and where you're hitting it

424
00:37:24,000 --> 00:37:29,000
has an effect. So, whereas
the action potential is

425
00:37:29,000 --> 00:37:33,000
a very simple thing, which
you might say just replace it

426
00:37:33,000 --> 00:37:38,000
by a wire for our computer
modeling studies, goodness,

427
00:37:38,000 --> 00:37:42,000
nobody has actually succeeded in
building a perfect model of the

428
00:37:42,000 --> 00:37:47,000
integration properties of an
dendritic arbor for a single neuron.

429
00:37:47,000 --> 00:37:51,000
They can get guess
and approximations.

430
00:37:51,000 --> 00:37:56,000
So, there's an amazing
integration that's going on here.

431
00:37:56,000 --> 00:38:00,000
But it turns out that it's
more complex than that because,

432
00:38:00,000 --> 00:38:05,000
you see, I said that we had these,
say, glutamate neurotransmitters

433
00:38:05,000 --> 00:38:10,000
here that were causing
positive charges to rush in.

434
00:38:10,000 --> 00:38:18,000
It turns out there are other
neurotransmitters that activate

435
00:38:18,000 --> 00:38:26,000
other channels in the membrane.
And, for example, there are some

436
00:38:26,000 --> 00:38:34,000
neurotransmitters that activate,
like glycine, another amino acid

437
00:38:34,000 --> 00:38:43,000
activates ligand-gated
chloride channels.

438
00:38:43,000 --> 00:38:48,000
So, glutamate, one amino
acid activates sodium

439
00:38:48,000 --> 00:38:54,000
channels. Sodium rushes in.
Glycine activates chloride channels.

440
00:38:54,000 --> 00:39:00,000
What will chloride
do? It can come in.

441
00:39:00,000 --> 00:39:06,000
What will it do when it comes
in? Negative. Oh, my goodness. So,

442
00:39:06,000 --> 00:39:12,000
when glycine is spritz on the
post-synaptic cell chloride comes in

443
00:39:12,000 --> 00:39:18,000
and the cell becomes locally
more negative. These are called

444
00:39:18,000 --> 00:39:28,000
inhibitory synapses.

445
00:39:28,000 --> 00:39:34,000
By contrast those that admit
positive ions excitatory synapses.

446
00:39:34,000 --> 00:39:42,000
Neurons can have
both inhibitory and

447
00:39:42,000 --> 00:39:47,000
excitatory synapses
on their dendrites. So,

448
00:39:47,000 --> 00:39:53,000
the postsynaptic cell will
be receiving positive signals,

449
00:39:53,000 --> 00:39:58,000
positive ions coming in from
excitatory synapse and negative

450
00:39:58,000 --> 00:40:04,000
signals, inhibitory signals
with negative ions coming in.

451
00:40:04,000 --> 00:40:08,000
The integration of charge in the
dendritic arbor is an integration

452
00:40:08,000 --> 00:40:12,000
problem of the timing,
number, geometry and sign,

453
00:40:12,000 --> 00:40:16,000
positive or negative, of
these activation signals.

454
00:40:16,000 --> 00:40:20,000
That's what's going on. And
what happens is the neuron

455
00:40:20,000 --> 00:40:24,000
integrates these signals,
positive and negative. So,

456
00:40:24,000 --> 00:40:29,000
we'll make this one a glycine
neuron, negative, negative, negative.

457
00:40:29,000 --> 00:40:33,000
All that integration takes place
right over here in the region of the

458
00:40:33,000 --> 00:40:38,000
cell called the axon hillock,
which is the first place that the

459
00:40:38,000 --> 00:40:42,000
action potential mechanism is found.
And, of course, that integration is

460
00:40:42,000 --> 00:40:47,000
nothing more and nothing less than
figuring out whether the membrane

461
00:40:47,000 --> 00:40:51,000
potential gets above minus 50. If
it gets above minus 50 it fires.

462
00:40:51,000 --> 00:40:59,000
OK? Yes?

463
00:40:59,000 --> 00:41:02,000
Does the nucleus participate in
the, in what way would the nucleus

464
00:41:02,000 --> 00:41:11,000
participate?

465
00:41:11,000 --> 00:41:14,000
It's an interesting question. I
mean the nucleus does, in a sense.

466
00:41:14,000 --> 00:41:17,000
The geometry of that cell body
there has some effect on the

467
00:41:17,000 --> 00:41:21,000
electrical properties and all
that, but if you think about the

468
00:41:21,000 --> 00:41:24,000
timescales. How often do neurons
fire? At a frequency often of about

469
00:41:24,000 --> 00:41:27,000
a millisecond. So, that
means everything I've just

470
00:41:27,000 --> 00:41:31,000
old you, this complex integration
problem is occurring within

471
00:41:31,000 --> 00:41:34,000
a millisecond. The processes
in the nucleus that I

472
00:41:34,000 --> 00:41:38,000
think about typically of
transcription and translation and

473
00:41:38,000 --> 00:41:41,000
all that are operating several
orders of magnitude more slowly than

474
00:41:41,000 --> 00:41:44,000
that. You know, they'll
operate, even in the best of

475
00:41:44,000 --> 00:41:48,000
circumstances, at seconds,
and often at more than

476
00:41:48,000 --> 00:41:51,000
that, minutes before you could get
transcription and translation and

477
00:41:51,000 --> 00:41:54,000
stuff like that going.
So, the nucleus, I think,

478
00:41:54,000 --> 00:41:58,000
for the most part, better get its
act together by producing stuff and

479
00:41:58,000 --> 00:42:01,000
getting it out to the periphery,
but probably through the expression

480
00:42:01,000 --> 00:42:05,000
of the genome can't do much in
a relevant millisecond or so.

481
00:42:05,000 --> 00:42:08,000
But I wouldn't be shocked if some
neurobiologist knows better than I

482
00:42:08,000 --> 00:42:11,000
do that nucleoli do something.
I mean there are many cleaver

483
00:42:11,000 --> 00:42:14,000
things that are going on. I'm
sure a cell has wasted anything,

484
00:42:14,000 --> 00:42:17,000
but with respect to the operations
we've talked about probably not.

485
00:42:17,000 --> 00:42:21,000
OK? But I'm always reluctant to
say something never happens in any

486
00:42:21,000 --> 00:42:24,000
possible way. All right. So,
now how does all this get stuck

487
00:42:24,000 --> 00:42:28,000
together? Well, not
only do we have this

488
00:42:28,000 --> 00:42:33,000
complex integration within
the dendritic arbor but,

489
00:42:33,000 --> 00:42:39,000
of course, the neurons are stuck
together into circuits themselves.

490
00:42:39,000 --> 00:42:44,000
If we had more time I would
draw the circuit that you use to

491
00:42:44,000 --> 00:42:49,000
integrate complex functions in
calculus, but not having much time

492
00:42:49,000 --> 00:42:54,000
I'm going to just go for a
much simpler circuit here.

493
00:42:54,000 --> 00:43:00,000
I'm just going to go back to
nerves and muscles. And here we go.

494
00:43:00,000 --> 00:43:06,000
Suppose I tap right here
below your knee. What happens?

495
00:43:06,000 --> 00:43:12,000
There's a reflex. Let's
at least get that going,

496
00:43:12,000 --> 00:43:18,000
OK? What happens is when I
tap there above your patella,

497
00:43:18,000 --> 00:43:24,000
here's your kneecap here,
there's a sensory neuron.

498
00:43:24,000 --> 00:43:30,000
The sensory neuron brings out
a signal and it goes into the

499
00:43:30,000 --> 00:43:35,000
spinal column here.
This is a reflex.

500
00:43:35,000 --> 00:43:39,000
It doesn't need to go up to your
brain. You don't need to think a lot

501
00:43:39,000 --> 00:43:44,000
about it. And it goes into the
spinal column here into the dorsal

502
00:43:44,000 --> 00:43:48,000
root ganglia. This
is a cross-section.

503
00:43:48,000 --> 00:43:53,000
The, sorry, sensory neuron comes
in here. And what it does is that

504
00:43:53,000 --> 00:43:57,000
sensory neuron makes a synapse,
and actually another synapse, and it

505
00:43:57,000 --> 00:44:04,000
makes a synapse on a motor neuron.
The motor neuron comes back and

506
00:44:04,000 --> 00:44:13,000
synapses on that very muscle. It
is the simplest possible circuit.

507
00:44:13,000 --> 00:44:23,000
I sense, I send one sensory
signal up into the spinal cord,

508
00:44:23,000 --> 00:44:32,000
there's an excitatory positive
synapse onto a motor neuron,

509
00:44:32,000 --> 00:44:42,000
this motor neuron fires and
contracts my muscle so I go back.

510
00:44:42,000 --> 00:44:48,000
At the same time, this
guy makes another synapse,

511
00:44:48,000 --> 00:44:55,000
a positive excitatory synapse on a
little cell that is an interneuron,

512
00:44:55,000 --> 00:45:02,000
that's an intermediate neuron. That
intermediate neuron makes a synapse

513
00:45:02,000 --> 00:45:09,000
on a second motor neuron, but
this is an inhibitory synapse.

514
00:45:09,000 --> 00:45:17,000
That motor neuron
sends its process

515
00:45:17,000 --> 00:45:23,000
out and is affecting the opposite
muscle. So now what happens?

516
00:45:23,000 --> 00:45:30,000
Let's get this straight.
I hit over here.

517
00:45:30,000 --> 00:45:34,000
And the signal goes back to my
spinal cord. The sensory neuron

518
00:45:34,000 --> 00:45:38,000
causes one motor neuron,
directly by firing on it,

519
00:45:38,000 --> 00:45:42,000
to contract. It causes an
interneuron to fire that inhibits

520
00:45:42,000 --> 00:45:46,000
the opposite motor neuron.
What happens if you inhibit the

521
00:45:46,000 --> 00:45:50,000
opposite motor neuron?
You relax the contraction,

522
00:45:50,000 --> 00:45:54,000
or you at least don't
contract the opposite muscle.

523
00:45:54,000 --> 00:45:58,000
So, what happens is you send a
positive signal to the muscle on one

524
00:45:58,000 --> 00:46:03,000
side and you inhibit the signal
to the muscle on the other side.

525
00:46:03,000 --> 00:46:07,000
It's a very simple circuit.
It's got one sensory neuron.

526
00:46:07,000 --> 00:46:11,000
Two motor neurons. One interneuron.
It's got two positive excitatory

527
00:46:11,000 --> 00:46:15,000
synapses. It's got one
negative inhibitory synapse.

528
00:46:15,000 --> 00:46:19,000
That's about it. Presumably,
everything else that goes on in

529
00:46:19,000 --> 00:46:23,000
daily life is basically the same
thing. This is probably what eating

530
00:46:23,000 --> 00:46:27,000
lunch is like, falling
in love is like and things

531
00:46:27,000 --> 00:46:31,000
like that, although the details
remain to be worked out for exactly

532
00:46:31,000 --> 00:46:34,000
how that stuff works. There
is a large collection of,

533
00:46:34,000 --> 00:46:38,000
I give you the simple examples
because obviously we don't know a

534
00:46:38,000 --> 00:46:42,000
lot of the complex examples.
There is a lot more to this.

535
00:46:42,000 --> 00:46:45,000
If had time in the course we could
go into what's known about more

536
00:46:45,000 --> 00:46:49,000
circuits. I joke. We know
about the circuits that

537
00:46:49,000 --> 00:46:53,000
help you see vision, that
allow you to pick up signals in

538
00:46:53,000 --> 00:46:56,000
your retina, transmit them back and
reconstruct things with positive and

539
00:46:56,000 --> 00:47:00,000
negative signals that allow
you to see a straight line,

540
00:47:00,000 --> 00:47:04,000
for example, and
recognize a straight line.

541
00:47:04,000 --> 00:47:07,000
And there are patterns of cells that
send positive signals and negative

542
00:47:07,000 --> 00:47:10,000
signals, and when you integrate them
you can get a signal if and only if

543
00:47:10,000 --> 00:47:14,000
there's a straight line at
this angle in your visual field.

544
00:47:14,000 --> 00:47:17,000
And people know about that kind of
stuff, but some of the more complex

545
00:47:17,000 --> 00:47:20,000
stuff we don't know about.
There are lots and lots of

546
00:47:20,000 --> 00:47:24,000
neurotransmitters,
glutamate, glycine,

547
00:47:24,000 --> 00:47:27,000
histamine, serotonin. ATP
can be a neurotransmitter.

548
00:47:27,000 --> 00:47:31,000
Adenosine can be a neurotransmitter.
There are peptide neurotransmitters.

549
00:47:31,000 --> 00:47:35,000
Endorphins, oxytocins and even gases.
Nitrous oxide is a neurotransmitter.

550
00:47:35,000 --> 00:47:39,000
And then some of the drugs you
may know work by affecting these

551
00:47:39,000 --> 00:47:44,000
neurotransmitters. Prozac
and the general class of

552
00:47:44,000 --> 00:47:48,000
selective serotonin reuptake
inhibitors. Prozac effects a

553
00:47:48,000 --> 00:47:52,000
specific process with
a neurotransmitter.

554
00:47:52,000 --> 00:47:57,000
There's a neurotransmitter
serotonin. After it's fired out,

555
00:47:57,000 --> 00:48:01,000
instead of acetylcholesterase being
in the synapse destroying it or some

556
00:48:01,000 --> 00:48:06,000
other enzyme destroying it,
it's taken back up by the cells.

557
00:48:06,000 --> 00:48:09,000
If you could inhibit the process
by which you take up your serotonin

558
00:48:09,000 --> 00:48:12,000
again, the serotonin would last
longer in your synapse and you would

559
00:48:12,000 --> 00:48:15,000
be happier, give or take, roughly
speaking to the extent that

560
00:48:15,000 --> 00:48:19,000
more serotonin is a good thing.
And that's what Prozac does.

561
00:48:19,000 --> 00:48:22,000
Actually, it's one of the things
Prozac does. There's good evidence

562
00:48:22,000 --> 00:48:25,000
now that Prozac does other things,
too, including causing neuronal cell

563
00:48:25,000 --> 00:48:29,000
growth, but that's
a whole other story.

564
00:48:29,000 --> 00:48:32,000
There are things like cocaine.
Cocaine is a bad thing because it

565
00:48:32,000 --> 00:48:36,000
inhibits certain sodium
transporters and other things.

566
00:48:36,000 --> 00:48:39,000
And if you go through all of the
different psychoactive drugs they're

567
00:48:39,000 --> 00:48:43,000
affecting different parts
of these processes. So,

568
00:48:43,000 --> 00:48:47,000
for Friday I've invited a colleague
who is a real neurobiologist,

569
00:48:47,000 --> 00:48:50,000
I'm not a card-carrying neurobiologist,

570
00:48:50,000 --> 00:48:54,000
to talk about some of the more far
out things of learning and memory.

571
00:48:54,000 --> 00:48:58,000
Andy Chess who's a good friend and
a colleague is going to talk about

572
00:48:58,000 --> 00:49:02,000
learning and memory. And then
have a good time with him,

573
00:49:02,000 --> 00:49:07,000
and I'll see
you subsequently.