1
00:00:01 --> 00:00:08
Good morning. Thank you. So,
I want to continue today on the

2
00:00:08 --> 00:00:16
theme of neurobiology. Last
time we spoke about the action

3
00:00:16 --> 00:00:24
potential mechanism. Today
I'd like to go from action

4
00:00:24 --> 00:00:31
potential to the synapse. But
let me briefly remind us what we

5
00:00:31 --> 00:00:37
say. So, I'm going to give
section zero a recap here.

6
00:00:37 --> 00:00:44
The relevant things that we said
last time was there's a membrane

7
00:00:44 --> 00:00:50
potential which at rest is about
minus 70 millivolts as the membrane

8
00:00:50 --> 00:00:56
potential, and that's what we work
with. That membrane potential is

9
00:00:56 --> 00:01:03
set up by concentration gradients.
More calcium, more potassium on the

10
00:01:03 --> 00:01:09
inside. More sodium on the outside.
More calcium on the outside. And

11
00:01:09 --> 00:01:16
I'm also going to mention chloride,
there's more chloride on the outside

12
00:01:16 --> 00:01:23
at 116 millimolar, four
millimolar on the outside.

13
00:01:23 --> 00:01:30
These concentration gradients are
set up by various different pumps.

14
00:01:30 --> 00:01:37
They're there all the time. Then
we have this resting channel.

15
00:01:37 --> 00:01:47
So, here we have transporters.

16
00:01:47 --> 00:01:53
We have a resting potassium channel.
It means that it's open all the

17
00:01:53 --> 00:02:00
time. It's not
activated by anything.

18
00:02:00 --> 00:02:04
That allows potassium to leave.
Potassium leaves until it builds up

19
00:02:04 --> 00:02:08
this membrane potential about
minus 70. At that point it is

20
00:02:08 --> 00:02:12
electrically unfavorable for more
positive charges to go out into the

21
00:02:12 --> 00:02:17
more positive environment.
Notwithstanding the greater

22
00:02:17 --> 00:02:21
internal concentration.
And we reach an equilibrium

23
00:02:21 --> 00:02:25
potential of minus 70. We
then have some voltage-gated

24
00:02:25 --> 00:02:32
channels.

25
00:02:32 --> 00:02:37
And the voltage-gated channels
come in two flavors here.

26
00:02:37 --> 00:02:42
We have the voltage-gated sodium
channel. The voltage-gated sodium

27
00:02:42 --> 00:02:47
channel opens itself up
around minus 70. Oh, sorry,

28
00:02:47 --> 00:02:53
around minus 50. So, if
you can get up to minus 50

29
00:02:53 --> 00:02:58
it opens up. Then your sodium
rushes in. It shifts the membrane

30
00:02:58 --> 00:03:04
potential from minus
50 to zero to plus 50.

31
00:03:04 --> 00:03:10
The channel shuts. Somewhere
around plus 30 or so

32
00:03:10 --> 00:03:17
opens the potassium channel, the
voltage graded potassium channel,

33
00:03:17 --> 00:03:23
and allows the potassium to rush out
and restore the resting potential.

34
00:03:23 --> 00:03:30
The effect of this is that,
if this is zero here, we have

35
00:03:30 --> 00:03:36
a resting potential. If we
climb up a little bit above it

36
00:03:36 --> 00:03:40
we shoot up and then we come back
down. And then a millisecond or so

37
00:03:40 --> 00:03:44
later another action potential
could go down that same neuron.

38
00:03:44 --> 00:03:48
And, last of all, if we look
along the length of an axon,

39
00:03:48 --> 00:03:53
an action potential here causes
charges to migrate over which

40
00:03:53 --> 00:03:57
launches an action potential here
which causes charges to migrate over

41
00:03:57 --> 00:04:01
which etc., etc. propagates
an action potential down

42
00:04:01 --> 00:04:06
the length. It's
a beautiful system.

43
00:04:06 --> 00:04:10
And then the very last thing was
that by insulating this we were able

44
00:04:10 --> 00:04:14
to make the conduction velocity
go faster by effectively making the

45
00:04:14 --> 00:04:18
effective length be shorter there
being a whole bunch of electrically

46
00:04:18 --> 00:04:22
insulated regions. So,
that's it. It's a beautiful

47
00:04:22 --> 00:04:26
piece of engineering. How do
we know any of this is true?

48
00:04:26 --> 00:04:29
As an interesting
side point,

49
00:04:29 --> 00:04:33
I might just mention that
when this was worked out,

50
00:04:33 --> 00:04:36
this was worked out by two
folks called Hodgkin and Huxley.

51
00:04:36 --> 00:04:40
Hodgkin and Huxley won a Nobel
prize for this beautiful work on

52
00:04:40 --> 00:04:43
this squid giant axon which is
the fastest axon that there is.

53
00:04:43 --> 00:04:47
And here we're not talking about
the giant squid somebody raised last

54
00:04:47 --> 00:04:50
time. It's an ordinary squid.
It has one big fat axon. It's

55
00:04:50 --> 00:04:54
sufficiently big that you can just
like stick a wire in the middle of

56
00:04:54 --> 00:04:57
it and all that.
It's a very big axon.

57
00:04:57 --> 00:05:01
It's a very, very
high diameter axon.

58
00:05:01 --> 00:05:04
And they were able to measure
these things electrically.

59
00:05:04 --> 00:05:07
And on the basis of the electrical
measurements they made in different

60
00:05:07 --> 00:05:10
kinds of solutions, they
were able to infer the

61
00:05:10 --> 00:05:13
existence of sodium channels
and potassium channels.

62
00:05:13 --> 00:05:17
But this all happened mid 20th
century. And they certainly

63
00:05:17 --> 00:05:20
couldn't see any. They
couldn't clone them.

64
00:05:20 --> 00:05:23
They couldn't see anything. And
so the notion that there were

65
00:05:23 --> 00:05:26
individual molecular channels that
swung open, did all this stuff was

66
00:05:26 --> 00:05:30
an indirect inference, maybe
kind of a little bit like

67
00:05:30 --> 00:05:33
Mendel's inference of a gene
or Sturtevant's inference

68
00:05:33 --> 00:05:37
of genetic maps. But more
recently people have come

69
00:05:37 --> 00:05:42
along with an extraordinary
technology, also these people won a

70
00:05:42 --> 00:05:47
Nobel prize for this because it was
way cool, which is called the Patch

71
00:05:47 --> 00:05:52
Clamp. The patch clamp is the
following ridiculously simple

72
00:05:52 --> 00:05:58
technology. Suppose I were
to make a glass pipette.

73
00:05:58 --> 00:06:04
So, this is a cross-section
of a glass pipette.

74
00:06:04 --> 00:06:10
So, it goes around like that.
And I could bring it up really

75
00:06:10 --> 00:06:16
tight up against the membrane.
And suppose I did it in such a way

76
00:06:16 --> 00:06:22
that I could get a really great
seal and I just have a teeny patch of

77
00:06:22 --> 00:06:28
membrane. Suppose that teeny
patch of membrane had just

78
00:06:28 --> 00:06:35
one channel in it. And
now, so this is a pipette,

79
00:06:35 --> 00:06:41
suppose I were to rip off that
patch of membrane from the cell,

80
00:06:41 --> 00:06:48
poor cell, and have a glass pipette
with a little patch of membrane on

81
00:06:48 --> 00:06:54
its end with a single
isolated ion channel. Now,

82
00:06:54 --> 00:07:01
if I measured the current through
this channel by putting it in an

83
00:07:01 --> 00:07:07
appropriate solution,
maybe I ripped off a resting

84
00:07:07 --> 00:07:13
potassium channel, OK? If
I put this in a potassium

85
00:07:13 --> 00:07:18
solution and I apply a current,
I apply a voltage difference, I

86
00:07:18 --> 00:07:23
should be able to see a current.
And you can actually measure a

87
00:07:23 --> 00:07:28
current. Even more cool, if I
do this and I've ripped off a

88
00:07:28 --> 00:07:33
voltage-gated sodium channel, then
it turns out that I ought to be

89
00:07:33 --> 00:07:38
able to study its properties by
changing the voltage on it and

90
00:07:38 --> 00:07:44
measuring the current as
a function of the voltage.

91
00:07:44 --> 00:07:49
And, well, it turns out that if I do
this I'm able to measure in resting

92
00:07:49 --> 00:07:55
or in these voltage-gated channels
current flows conductivities,

93
00:07:55 --> 00:08:01
actually, what I'm really measuring
is the conductivity of the channel

94
00:08:01 --> 00:08:07
like this, I can see the channel
opening and closing and opening and

95
00:08:07 --> 00:08:12
closing quantily. I
can measure quantily the

96
00:08:12 --> 00:08:18
conductivity. That's not quantum
mechanics. It's just quanta

97
00:08:18 --> 00:08:23
measurements of the conductivity.
What would happen if I had two

98
00:08:23 --> 00:08:29
channels that had been ripped
off? Now I'd see it go like this.

99
00:08:29 --> 00:08:32
Well, maybe another one opens.
Oops, now one closes. Now the

100
00:08:32 --> 00:08:36
other one closes. And
quite remarkably you can get

101
00:08:36 --> 00:08:39
this. So, you can study single
molecule, single molecular channels.

102
00:08:39 --> 00:08:43
You want to know how this channel
opens and at what voltage it opens?

103
00:08:43 --> 00:08:46
Just dial in the voltage and see if
it's open. Do you want to know how

104
00:08:46 --> 00:08:50
long it stays open? Just
turn it on and see how long it

105
00:08:50 --> 00:08:53
stays open. It's really cool.
You want to see if any other

106
00:08:53 --> 00:08:57
chemicals could affect it, any
ions, any other intracellular or

107
00:08:57 --> 00:09:01
extra cellular
chemicals? You can do it.

108
00:09:01 --> 00:09:05
So, the ability to study isolated
single channels came along with

109
00:09:05 --> 00:09:09
patch clamping. And what
it allows is a tremendous

110
00:09:09 --> 00:09:14
study of the biophysics
of individual channels.

111
00:09:14 --> 00:09:18
And, whereas, before people had to
look at the total conductivity of an

112
00:09:18 --> 00:09:22
entire axon. Now they're able,
and from that infer the behavior of

113
00:09:22 --> 00:09:26
single channels, now what
they can do is study the

114
00:09:26 --> 00:09:31
behavior of single channels and
synthetically build up a picture of

115
00:09:31 --> 00:09:35
the total conductivity of an axon
from its individual components and

116
00:09:35 --> 00:09:39
see if the components we've
identified are sufficient to explain

117
00:09:39 --> 00:09:45
the behavior that we see.
Anyway, that's patch clamping.

118
00:09:45 --> 00:09:51
Lots of fun. So, now, what I
want to turn now to is signaling

119
00:09:51 --> 00:09:59
at the synapse.

120
00:09:59 --> 00:10:04
So, we have our cell body here.
It's got its dendrites on it.

121
00:10:04 --> 00:10:10
Here's our axon. We've
managed to get an action

122
00:10:10 --> 00:10:15
potential started on it and
it moves all the way down.

123
00:10:15 --> 00:10:21
Now we get here to one
of the synaptic terminals.

124
00:10:21 --> 00:10:26
The electrical signal makes it all
the way to the synaptic terminal,

125
00:10:26 --> 00:10:32
but how does it affect
the post-synaptic cell?

126
00:10:32 --> 00:10:40
Well, let's get a
close-up of that.

127
00:10:40 --> 00:10:46
Here we go. Here's the synaptic
terminal. We've got our action

128
00:10:46 --> 00:10:52
potential coming.
Action potential coming.

129
00:10:52 --> 00:10:59
And then it gets here.
Action potential's arrived.

130
00:10:59 --> 00:11:05
I would like to release
chemicals into the synaptic cleft,

131
00:11:05 --> 00:11:12
the space between the pre
and the post-synaptic cell.

132
00:11:12 --> 00:11:20
I'd like to spill out chemicals
that are neurotransmitters.

133
00:11:20 --> 00:11:28
So, the pre-synaptic cell
conveniently has vesicles,

134
00:11:28 --> 00:11:37
little membrane-bound vesicles
with prepackaged neurotransmitters.

135
00:11:37 --> 00:11:42
OK? These prepackaged
neurotransmitters have been

136
00:11:42 --> 00:11:47
conveniently synthesized by the
cell and they're just sitting there

137
00:11:47 --> 00:11:52
waiting to be released in
response to an action potential.

138
00:11:52 --> 00:11:57
When the action potential comes,
it causes these synaptic vesicles to

139
00:11:57 --> 00:12:08
fuse --

140
00:12:08 --> 00:12:15
-- with the membrane. And
in fusing the insides become

141
00:12:15 --> 00:12:22
continuous with the outsides,
here's a little fusion picture here,

142
00:12:22 --> 00:12:30
and the neurotransmitters
leak out. OK?

143
00:12:30 --> 00:12:35
How does it do that,
though, mechanistically?

144
00:12:35 --> 00:12:40
How in the world does an action
potential cause these vesicles to

145
00:12:40 --> 00:12:46
fuse with the membrane? Well,
somehow it's got to read out

146
00:12:46 --> 00:12:51
electrical activity into some
kind of a chemical activity

147
00:12:51 --> 00:12:57
intracellularly.
Here's what it does.

148
00:12:57 --> 00:13:02
When the electrical signal comes
down, remember originally the

149
00:13:02 --> 00:13:08
membrane potential is negative,
but when an action potential comes

150
00:13:08 --> 00:13:13
by what does it do to the
membrane potential? It reverses it.

151
00:13:13 --> 00:13:19
It makes it positive inside briefly.
OK? So, this is the sign of an

152
00:13:19 --> 00:13:24
action potential,
an AP coming down.

153
00:13:24 --> 00:13:30
In this membrane we have us
another voltage-sensitive channel.

154
00:13:30 --> 00:13:35
This voltage sensitive channel is
a voltage sensitive calcium channel.

155
00:13:35 --> 00:13:40
OK? Who would like to design a
voltage-sensitive calcium channel?

156
00:13:40 --> 00:13:46
What should it do? What would you
like to have its opening and closing

157
00:13:46 --> 00:13:51
properties be?
When does it open?

158
00:13:51 --> 00:13:57
At a positive charge. So,
when you get to a positive

159
00:13:57 --> 00:14:02
membrane potential it swings
open. And then what does it do?

160
00:14:02 --> 00:14:07
Lets calcium move. Which
way does calcium want to go?

161
00:14:07 --> 00:14:11
In because it's more out. So,
what's going to happen is in

162
00:14:11 --> 00:14:16
response to the action
potential calcium will rush in.

163
00:14:16 --> 00:14:21
Now, calcium, you will recall,
was in vanishingly small traces

164
00:14:21 --> 00:14:26
inside, 0.1 micromolar we said.
And influx of calcium is a very

165
00:14:26 --> 00:14:31
serious matter and it is
sensed by variety of proteins.

166
00:14:31 --> 00:14:38
In particular, there is,
floating around in the

167
00:14:38 --> 00:14:45
cell, a protein here called a
calcium-dependent protein kinase.

168
00:14:45 --> 00:14:52
The calcium-dependent
protein kinase

169
00:14:52 --> 00:14:56
is a protein that is capable
of putting a phosphate group.

170
00:14:56 --> 00:15:00
Its kinase puts a phosphate
group on other proteins.

171
00:15:00 --> 00:15:04
So, the calcium-dependent protein
kinase over here will go along and

172
00:15:04 --> 00:15:08
catalyze the addition of a
phosphate group to other proteins.

173
00:15:08 --> 00:15:12
So, it will enzymaticly catalyze
this. But it only does so in the

174
00:15:12 --> 00:15:16
presence of calcium. So,
when there's calcium in the

175
00:15:16 --> 00:15:20
cell, the calcium-dependent kinase
is activated and it runs around and

176
00:15:20 --> 00:15:24
sticks phosphate groups on
specific target proteins.

177
00:15:24 --> 00:15:28
You know where one of those target
proteins lives? In the vesicles.

178
00:15:28 --> 00:15:32
The vesicles happen to
be a target for this. So,

179
00:15:32 --> 00:15:36
the vesicles have a protein on them.
And in one of these extraordinary

180
00:15:36 --> 00:15:40
coincidences in molecular biology,
the protein on the synaptic vesicle

181
00:15:40 --> 00:15:44
happens to be called,
coincidently, synapsin.

182
00:15:44 --> 00:15:48
OK? It's not actually entirely
a coincidence that it's called

183
00:15:48 --> 00:15:52
synapsin. It was named synapsin
because it was found on the synaptic

184
00:15:52 --> 00:15:56
vesicles, obviously. And
so what happens is when the

185
00:15:56 --> 00:16:00
action potential comes down it
causes the calcium channel to open

186
00:16:00 --> 00:16:03
in response to positive
voltage. Calcium comes in,

187
00:16:03 --> 00:16:07
actives at the kinase. The
kinase phosphorilates synapsin.

188
00:16:07 --> 00:16:11
And now the phosphorilated form of
synapsin likes to bind to something

189
00:16:11 --> 00:16:15
in the membrane. That's
it. How many of you still

190
00:16:15 --> 00:16:19
know what a Rube Goldberg machine
is? Good. OK. This is one of these

191
00:16:19 --> 00:16:23
just great, well, others
of you should look it up on

192
00:16:23 --> 00:16:27
the Web because they're just great
cartoons, the Rube Goldberg cartoons

193
00:16:27 --> 00:16:31
about the machine where the rooster
crows startling the cat which tugs

194
00:16:31 --> 00:16:35
the thing with causes this to flop
which causes the eggs to go in the

195
00:16:35 --> 00:16:39
pan which causes the thing
to cook which causes whatever.

196
00:16:39 --> 00:16:42
And I always think about these
in terms of great molecular Rube

197
00:16:42 --> 00:16:46
Goldberg machines. So,
this is the Rube Goldberg

198
00:16:46 --> 00:16:49
machine that gets this
synaptic vesicle to fuse there.

199
00:16:49 --> 00:16:53
OK? Good. Every bit of
neurobiology has a molecular

200
00:16:53 --> 00:16:57
mechanism to be explained like
this. So, now let's go onto the next

201
00:16:57 --> 00:17:01
bit. How does this
signal gets sensed at

202
00:17:01 --> 00:17:06
the next cell?
What are we up to?

203
00:17:06 --> 00:17:11
Number three. So, let's
look at a specific junction.

204
00:17:11 --> 00:17:16
Instead of looking at the
junction between two nerve cells,

205
00:17:16 --> 00:17:22
let me start with the junction
between a nerve cell and a muscle

206
00:17:22 --> 00:17:27
cell, the neuromuscular junction.
OK? So, I've now replaced my

207
00:17:27 --> 00:17:32
post-synaptic neuron by a
muscle fiber here. This is

208
00:17:32 --> 00:17:38
a muscle fiber. So, when
it spritzes out the stuff

209
00:17:38 --> 00:17:44
the neurons that innervate
muscle fibers, actually,

210
00:17:44 --> 00:17:51
I'm going to expand that a bit,
the neurons that innervate muscle

211
00:17:51 --> 00:17:57
fibers, here's the muscle, and
I'll put it at some distance

212
00:17:57 --> 00:18:03
here, muscle, spray out a
particular transmitter in response

213
00:18:03 --> 00:18:10
to the calcium influx. And
that transmitter is called

214
00:18:10 --> 00:18:17
acetylcholine,
henceforth ACH.

215
00:18:17 --> 00:18:24
Acetylcholine is spritzed out into
the synaptic cleft and comes out.

216
00:18:24 --> 00:18:32
And what do you think
acetylcholine is going to do?

217
00:18:32 --> 00:18:35
I've got to send the chemical
signal to the next cell.

218
00:18:35 --> 00:18:39
I've got to somehow send
that signal to the surface.

219
00:18:39 --> 00:18:43
It's going to bind to
something on the next cell.

220
00:18:43 --> 00:18:47
You know the deal, right?
So, it's going to have to

221
00:18:47 --> 00:18:51
bind to a protein on this cell.
And, remarkably, what it binds to

222
00:18:51 --> 00:18:55
is called an acetylcholine receptor.
OK? Very reasonable stuff. An

223
00:18:55 --> 00:19:00
acetylcholine receptor. The
acetylcholine receptor happens

224
00:19:00 --> 00:19:06
to be an ion channel, but
it's not a voltage-gated ion

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

226
00:19:12 --> 00:19:18
voltage. It's an ion channel that
opens in response to acetylcholine.

227
00:19:18 --> 00:19:24
It's what we'd call a ligand-gated
ion channel because it's gated by a

228
00:19:24 --> 00:19:31
ligand, acetylcholine. So,
this guy here is a ligand-gated

229
00:19:31 --> 00:19:39
ion channel which, when
acetylcholine binds to it,

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

231
00:19:47 --> 00:19:55
Bingo. Now, when sodium comes in
what happens? Action potential.

232
00:19:55 --> 00:20:04
But what a second.
This is a muscle.

233
00:20:04 --> 00:20:12
All membranes have
the machinery to

234
00:20:12 --> 00:20:16
have an action potential? Nah,
liver cells are pretty passive.

235
00:20:16 --> 00:20:21
You do this to a liver
cell it kind of sits there.

236
00:20:21 --> 00:20:25
But muscle cells do have an
action potential mechanism.

237
00:20:25 --> 00:20:30
They do respond here like a neuron,
an action potential. And so what

238
00:20:30 --> 00:20:34
happens when I open up some sodium
channels to the resting potential

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

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

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

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

243
00:20:49 --> 00:20:52
What does that do? It triggers
an action potential spreading

244
00:20:52 --> 00:20:56
throughout the muscle. And
because the muscle has an

245
00:20:56 --> 00:21:04
action
potential --

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

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

248
00:21:14 --> 00:21:19
One neuromuscular synapse will be
sufficient to activate the muscle,

249
00:21:19 --> 00:21:24
in principle, because you have
this action potential mechanism.

250
00:21:24 --> 00:21:29
And then when the action potential
fires in the muscle it actually

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

252
00:21:34 --> 00:21:38
The calcium channels cause calcium
to come in. The calcium causes your

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

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

255
00:21:47 --> 00:21:51
That's this Rube Goldberg machine.
All right. So, let's get ready.

256
00:21:51 --> 00:21:55
Let's fire. Let's send a
neuromuscular signal down.

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

258
00:22:00 --> 00:22:05
sitting around in my synapse
activating the ligand-gated sodium

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

260
00:22:10 --> 00:22:16
please. What are we
going to do about this?

261
00:22:16 --> 00:22:24
I could trigger
another channel,

262
00:22:24 --> 00:22:28
and maybe it could be a delayed
acetylcholine activated yeah,

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

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

265
00:22:36 --> 00:22:41
and we're going to refer them
to the engineering committee.

266
00:22:41 --> 00:22:45
What else? You could get rid of
the acetylcholine some other way.

267
00:22:45 --> 00:22:49
It turns out the latter
is the solution here.

268
00:22:49 --> 00:22:53
We would like to have some enzyme
that chews up the acetylcholine.

269
00:22:53 --> 00:22:59
How about acetylcholinesterase?
So, let's put acetylcholinesterase,

270
00:22:59 --> 00:23:06
ACHE, acetylcholinesterase
in the synaptic cleft.

271
00:23:06 --> 00:23:13
Then when I spritz acetylcholine
it gets to the other side,

272
00:23:13 --> 00:23:19
but very rapidly the
acetylcholinesterase is degrading it.

273
00:23:19 --> 00:23:26
And so it has a very short time
of persistence in the synaptic

274
00:23:26 --> 00:23:32
cleft. OK?
That works. So,

275
00:23:32 --> 00:23:37
that's how I run a
neuromuscular junction. OK?

276
00:23:37 --> 00:23:42
So, acetylcholinesterase
is very important. Now,

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

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

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

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

281
00:24:03 --> 00:24:11
different processes.
Anybody ever have fugu?

282
00:24:11 --> 00:24:18
Does anybody know what fugu is?
What's fugu? It's a blowfish.

283
00:24:18 --> 00:24:26
Right. It's a puffer fish eaten
in sushi, and it's an extraordinary

284
00:24:26 --> 00:24:32
delicacy. And why is that? Right.
Because it's one of the only

285
00:24:32 --> 00:24:36
sushis where you really have to
worry about improper preparation,

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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