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Okay let's get started
so in our last episode what we managed to do was get from the dendritic
end of a neuron to the axon terminal end of the same neuron.
You know what goes on by now.
Nervous system, unbelievably fast, unbelievably facile, and
thus the repetitively drummed into your head
contrast, screaming your head off when you
have something to say, being screamingly silent otherwise.
The massive, expensive process neurons put in to
contrast between signal and noise as part of that.
The deep resting potential.
Negatively charged the critical role of potassium your life determined by
the Nernst equation except that it's not right thus the Goldman equation.
Then seeing once there is excitation at the dendritic
end, depolarization pebble in the pond ripple dissipates no single
input is ever going to convince the axon hillock.
To pass threshold with enough temporal and spatial summation, you get your
action potential thanks to the first voltage-gated sodium channel opening up.
At that point, action potential shoots into
the positive range, and then that big,
exciting process of saying, it is all
over with, open the potassium channels, delayed rectification,
and hyperpolarize so that nobody on earth can think
that you're still saying you're having an action potential.
Then we saw the critical point plasticity.
The axon hillock being able to change its threshold in
response to all sorts of interesting things, hormones, et cetera.
Okay, so, what we have now managed to do is have
that action potential saltate all the way down to the axon terminals.
And at this point the neuron
has to speak to the next one in line.
And thanks to the dramatic foreshadowing on Friday,
what we know is, it releases a chemical messenger.
A neurotransmitter which goes from the first neuron and goes to the second
one in line and causes all the dendritic stuff we had on Friday.
So the critical point of all of that is there is a space in
between the neurons there is a gap in between
the axon terminal of this neuron and the dendritic spine
of the other and what we have up on top
is our schematic of one neuron talking to the next.
Its axon terminals reaching out and dramatically magnified on
the bottom, what we see is they don't actually touch.
There's a gap between the two neurons played out
10,000 times for each neuron. They're a gap known as the synapse.
We synapse a little space in between and
here produced the major challenge of neurobiology for
a period there which was so how does the first neuron talk to the second one.
Because what we saw on Friday was the first neuron is doing
all of its internal dialogue in its head in terms of electrical charge.
The excitation sweeping from the dendrites to
the axon hillock turning into the action potential.
And the big problem with that
yawning synaptic space there filled with extracellular
fluid is the action potential can't jump from one neuron to the next.
The electrical excitation can't spread
from the, important jargon, presynaptic neuron,
to the postsynaptic one.
And if the presynaptic neuron was going to be able to talk to the postsynaptic, it
had to translate its electrical excitation into something different.
A chemical messenger.
And the release of neurotransmitters, these chemical
messengers, that go from left to right.
Go from the presynaptic neuron across the synapse
and then get to latter half of Friday's lecture.
Does the excitation of the dendritic and massively important subject.
So massively important in part because people didn't
use to think there were such things as synapses.
What was your basic idea as to how neurons were wired up if you were a 19th
century paleoneurobiologist which clears during fetal development you've got
a gazillion neurons and they grow out these processy
things that people were just sorting out with microscopes
and axon terminals and reaching out to the dendrites.
And what was the obvious thing going on in everybody's mind, was, as the axon
terminal and the dendritic spine developed and
came towards each other, they merged into one.
They formed a continuous connection between the two neurons and then that
few all of the neurons in your brain, with all of their connections
there, were merged into one gigantic neural net.
And this was a view called the sinctitial view of how the
nervous system worked, because everybody knew
there was something electrical going on.
They had known that for a couple of centuries.
What they didn't know was how you could do anything other than have just
electrical signals smoothly go from one neuron
to the next, because they were all interconnected.
They had all merged together.
So this was the dominant view at the time. Way out in left field there was a
lunatic fringe that was instead saying the neurons don't actually touch each other.
There are gaps in between and somehow
they've got to communicate with each other chemically.
This was the cell hypothesis, the neuron
doctrine, that neurons were independent versus the synticium.
Huge conflict,
always under sort of appreciated by historians.
This was the major geopolitical conflict of the 19th
century between the syncticial people and the neuron doctrine people.
Peasants slaughtered, brother turned against brother in a bloodbath
and finally, finally it was all solved around 1905 in
one of those painful ironies that brought down the synctitial
people who were extremely arrogant because they actually knew how
to spell synctition.
But what happened was one of the leading synctitionists invented
some new type of stain which allowed people to stain individual neurons.
At the time, and his arch enemy on Earth, the
king grand poobah of the neuron doctrine people, used it
to show the dye didn't go from one neuron to
the next and form one whole glob of brain network.
It was
individual neurons. They were separated.
And this produced a much gloried, sort of Nobel Prize for the two
of them, where the guy who had used it to prove the neuron doctrine.
Someone who, if you become a neurobiologist,
you will name your children after this man.
It's required by law. Santiago Ramón y Cajal.
Spanish scientist, and he's the one who showed
it, and his opponent, Luigi Golgi, who invented
the stain, so they both got the Nobel Prize and Cajal was very noble about it.
And Golgi sort of said, you ***, that
was basically his Nobel Prize address of this
guy showing that, but the neuron doctrine came
to dominate everything, because the neurons didn't actually touch.
And this brought in this whole challenge now of so how do
they talk to each other if you have this massive yawning microscopic river
in between the two neurons.
And when you look at it in retrospect in makes perfect sense that
the synctitial people thought these folks were
lunatics because nobody could see the synapses.
And soon after, the stains came along, came along, microscopes finally
powerful enough to show they didn't actually talk to each other.
And what you had to have instead was
some means of translating the electrical signal intraneuronally and
to a chemical signal interneuronally.
And thus was born this whole field of neurotransmitterology the ways in
which the presynaptic neuron releases chemical
messengers to talk to the postsynaptic one.
Okay, so here's the basic picture of what happens.
So we've got our axon terminal here, blown up by scale.
The cell body is in the American Great
Plains, and this is a single axon terminal, and
what you've got there, drawn, actually this is
a satellite photograph of what it does look like.
So you've got little microtubules coming down the axon
terminals, and then we have, of course, obligatory organelles
like mitochondria there, lots of them, high density, because
what we're about to see is a hugely expensive process.
And then we've got these little iconic
water balloon things there, tethered to the
very end of the cell membrane, these
little vesicles, these little vessels filled with neurotransmitters.
Our schematic little dots there.
Neurotransmitters, so they sit there, in these storage
vesicles tethered to the membrane at the very end.
So we have an action potential that got started about four miles
to the left, and along it comes, and you know by now how
it works.
Voltage-gated sodium channel opens up, all hell breaks loose.
You pull, next one opens, next one opens,
it's sodium channels all the way down until you
get to the very end, til you get to
the axon terminal on the membrane facing out there.
And suddenly instead you've got a voltage-gated calcium channel.
So, suddenly, something very different is happening.
It's calcium that rushes in.
And calcium starts an insanely complex process.
Old model, simplistic one that we will use for our purposes here,
is that the vesicles are these little balloons tethered to the axon terminal.
The membrane there by a little bit of dental floss actin.
Calcium comes in, causes the actin to curl up on itself, pulls the vesicle towards
the pl, the membrane there, and the vesicle, being a lipid
bilayer merges into it perfectly clean
process, exocytosis, out comes your neurotransmitter.
In actuality, there is an unbelievably complex process.
The vesicles are tethered inside a skeletal matrix there, and the
calcium activates enzymes that machete their way through the matrix and move
the vesicle towards the wall. And there's docking proteins.
And every single one of the players in that is like a five-syllable word.
It's an incredibly complicated process.
A large part of which was worked out by Thomas Sudhof over in
the med school who got the Nobel Prize this year for this amazing work.
You dump your neurotransmitter.
We've just translated the electrical signal,
this thing, okay, I'm staying over here.
We've translated the electrical signal that has now
come down in the form of the action potential.
And, thanks to calcium rushing in, we have now dumped neurotransmitter.
We have dumped a neurotransmitter into the synapse, just to help a little bit here.
Again, a synapse is this wild,
extracellular environment where, in principle, you
dump the neurotransmitters in there and they will be flushed out to sea
by the fluid movement there.
You've got little bits of glia surrounding the synapse as a
breakwater just to stabilize this as an internal liquid environment there, these
are not the same glial cells that are making the myelin
all the way down there but just a local way of stabilizing.
Okay, so you have dumped your neurotransmitter.
It goes floating across the synapse and straight out of Friday's
lecture binds to receptors on the postsynaptic side
and thus we've got Friday's receptor-gated sodium channels
there that open up and we have our
depolarizing event and its Friday all over again.
So neurotransmitter floats across and binds to its receptor and
lock and key cliche in hand, everything goes normally after that.
We know what happens
at this point. Okay, so that is the basic process.
We've got one important thing now which is we gotta clean up after ourselves.
We gotta get rid of the neurotransmitter.
At that point it comes floating off the receptor and
you got one of two options if you're a neuron.
You can be a total slob and throw out your neurotransmitter at that point
you have an enzyme out there in the synaptic space which
degrades the neurotransmitter, breaks it down so it is now inactive.
And flushes it down the toilet.
Down the toilet, out into the extra-cellular space where it
eventually gets in your cerebral spinal fluid, your blood, your urine.
As we'll see in a while, in terms of clinical sort of
approaches to this, a lot of the time you're trying to figure
out what's going on in people's brains.
By measuring levels of breakdown products of neurotransmitters in their urine.
This is really imprecise.
Okay, so you can flush the stuff down the toilet, or
when it comes floating off the receptor, you can be ecologically minded.
You can recycle your neurotransmitter.
You can have a reuptake pump sitting there which grabs the neurotransmitter and
the synapse takes it back up again and
repackages it into another vesicle and recycles it.
And you see neurons and different neurotransmitter
types differ as to how much they do
recycling route versus the breaking it out and breaking it down and flushing it out.
In some weirdo pathways, the recycling is first taken up
in the glia that then send it back to the neuron.
This is our basic
picture, though.
Neurotransmitter is dumped, thanks to exocytosis, triggered
by the calcium influx, goes floating across, binds
to the receptor, does Friday's lecture all over
again, and then is either degraded or recycled.
Okay, so that's our basic picture.
So time to start making it messier.
So, we've got from Friday our iconic picture of neurotransmitter
binds to the receptor and as a result the sodium channel opens up, sodium comes in
and you begin to depolarize the membrane, you begin
to depolarize the dendritic spine there. And what do we've got?
We've got one neuron exciting the other, we know, not exciting it a
whole lot, but none the less in that little local provincial dendritic spine,
that is an excitatory event. Now, we do something different, and here.
We've got in this case instead of opening that sodium channel
and depolarizing a little bit now what you do is there's
a neurotransmitter that comes floating across and binds to its receptor
and as a result of that the sodium channel closes more.
Wait a second you should be saying in
an outraged voice what's it doing it's closed.
It's in a closed
state until you excite it with a neurotransmitter, it
opens up, we're just dealing with probabilistic physical chemistry stuff.
You got a channel that's closed most of the time but every now and then it hiccups
and opens up and most of the time it's
closed and that sort of statement is just statistical.
Suppose you got a neurotransmitter that makes sure
it's closed a larger percentage of the time.
Instead of 98%, we're up to 99% of the time
it's closed. What's the result of that?
You're going to ever so slightly
hyperpolarize the inside of that dendritic spine
a little bit more because there's a little bit less sodium leaking it.
You're making it a little bit
more negatively charged, a little bit hyperpolarized.
It's now a little bit less likely to be able to have an action potential.
What have we just
identified here?
A theoretical potential for an inhibitory neurotransmitter.
An excitatory neurotransmitter depolarizes and by
doing so from Friday increases the likelihood
of this neuron having an action potential
an inhibitory neurotransmitter doing exactly the opposite.
Okay from what I just described an inhibitory neurotransmitter that makes
a sodium channel that's closed most of the time be closed
even more of the time that's not accomplishing a whole lot.
So let's design something else now we have in the third line what we've got
is a neurotransmitter binds to its receptor
and what happens now with it receptor-gated channel.
It opens up and what it allows to flow is chloride.
Chloride can flow where's
the negatively charged chloride its out in the synapse and what's
it going to do it has to figure out its own feelings
about the Goldman equation but the net result is chloride is going
to rush in and you make the area there even more negative.
What we've just identified is a very potent way of hyperpolarizing
a dendritic spine, a very potent way in which a neurotransmitter
can be inhibitory.
And as we'll see, a huge percentage of the inhibitory
neurotransmitters in the brain work by opening up chloride channels.
Conversely, we can now come up with the same theoretical thing.
The chloride channel is just a statistical state.
So now you got a neurotransmitter that does exactly the up.
You can walk through the rest of the steps here.
What we've come up with are three hypothetical
ways in which a neurotransmitter can be excitatory.
Can open up some channel or other,
change ionic stuff, depolarize, make it more likely
to have an action potential, three different ways
in which you can hyperpolarize, have inhibitory neurotransmitter.
And most of the excitatory neurotransmitters are
working by way of opening sodium channels.
Most of the inhibitory neurotransmitters as I said, work on
the chloride system, with some interesting exceptions, that will come next week.
Okay, so we've now gotten this fact that
neuro transmitters, can come in two different flavors.
They can be excitatory or inhibitory.
And what we've also seen here is its then all these local events that happen you've
got a little bit of ionic whatever and
you've got in this local little dendritic spine
something very, very unexciting to the entire neuron
occurs, but then you see a slight complication.
So we have our schematic diagram on top
from Friday of a receptor, coupled to its channel.
And we've got a thus receptor gated channel.
But what you know by now from how cells really work is
what goes on is there's a second messenger system that they're not
actually coupled and tertiary messengers.
And suddenly what that allows you to do is how this
world of second messengers getting to third messengers getting to umpteen.
And beginning to get into phosphorylation cascades inside the cell.
Beginning to have effects on transcription factors.
Suddenly this classical picture where neurotransmitters do is
cause some little ionic hiccup going on right in that little dendritic spine.
What also became clear was they can
also access phosphorylation [INAUDIBLE] they can turn genes
on and off, they've got power to reach in in a much more substantial way there.
Nonetheless, even though this garnered a whole bunch of Nobel prizes
showing how they can tap into genomic effects, the vast majority
of what the neurotransmitters are doing are these very little local ionic events.
Either depolarizing hyperpolarizing the excitory inhibitor.
Okay so with that in hand we can now ask a critical
question which is how many different types of neurotransmitters do you need?
And we've already seen, in principle, we've got
to have at least two different types one
that says get excited one that says get inhibited.
And the classic way to see this is
you know, take somebody's heart and stick it on
a table and you're going to see something surprising
which is it keeps beating all on its own.
The heart has an endogenous rhythm.
It is an organ that beats on its own, and all your
nervous system does is to tell it to speed up or slow down.
[COUGH] And as you might expect, and what
we will see is, in a couple of lectures, there are two different projections going
to the heart of axons sending them and
one releases an excitatory neurotransmitter related to adrenaline.
One releases inhibitory one that's the entire
world of neural regulation of the heart.
You need two flavors of neurotransmitters, one says
yes, one says no, that's all you need.
But then we get into our world of what the brain is
like, and the fact that that projection doesn't do calculus for you.
By the time you get to the fancy stuff in the brain, we got one neuron
talking to a gazillion others, suddenly, you want to
have much more subtlety going on in there.
And what you see is a vast number of different types of neurotransmitters.
That are a whole bunch of them excitatory and a whole bunch of them inhibitory,
why then you need all these different kinds?
They differ as to how excitatory, how long they work for, how inhibitory, do they
do it in some contingent manner, do they
suddenly you've got a lot more complexity there.
Amid that, two hard and fast rules in neurotransmitterology, and this
came from this guy who was like the law-giver of all
of this stuff, Dale, Dale's two
principles of neurotransmitters, released in the 1930s.
I've never known if that was his first name or last name or both names.
But nonetheless, everybody gets raised on Dale's two principles.
First one.
[COUGH] A neuron starts to have an action potential at its axon hillock, and the
first law is it is going to propagate down to every single one of the 10,000
axon terminals.
So all of them are going to be dumping neurotransmitter.
Second of Dale's laws within that neuron when it's dumping neurotransmitter from
all of those axon terminals at the same time, it's the same neurotransmitter.
One neuron can be characterized as releasing only flavor A neurotransmitter.
That's what it does.
That's the
only thing it does.
So the two rules, you're dumping
neurotransmitter from all the axon terminals in
response to an action potential starting and
it's always the same kind of neurotransmitter.
And of course what turns out to be is Dale
was totally wrong and there's exceptions to all of that.
But most of us will still live under the tyranny of
Dale's laws for our purposes one flavor of neurotransmitter per neuron and
all the neuron all the axon terminals release at the same time.
Okay I can't resist so here's where Dale gets violated in some neurons.
You don't have, oh my god, this is so
confusing, release one neurotransmitter from some of the axon terminals,
a different one from what you get in some cases
are two different types of neurotransmitters in the same vesicle.
And that winds up giving you vast
subtlety because what typically occurs there is one of
them works a whole lot faster than the other.
But the slower one works a longer time you begin to have more shaping
of the way in which you can talk to the next neuron in line.
[COUGH] Okay so given that by now there's a whole bunch of chemicals that
have been identified as neurotransmitters and we will get to them what the criteria
are but at this point what comes up is
so what's the chemistry, what's the biochemistry of these neurotransmitters?
And at this point something awful is going to
happen to lots of you about three years from now.
Those of you who just happened by chance to stumble into medical school.
And at this point in your intro neuro class what they
are going to do is torture you beyond description by now forcing
you to memorize biosynthetic pathways for the neurotransmitters.
And it is god awful because it's totally confusing and
there's all these synthetic steps and umpteen enzymes with a gazillion
names and what we're going to do now is see how
that's totally stupid and superfluous
for understanding what neurotransmitters are about.
Here let me demonstrate this to you okay. How many of you speak a foreign language?
Okay somebody tell me in the language they speak what the word is for mother.
>> Alma.
>> Alma what language. >> Tunnel.
>> Okay what else. >> [INAUDIBLE]
>> Okay what language. >> [INAUDIBLE]
>> What else? >> Sign language.
>> okay. That doesn't count.
>> [LAUGH] >> He didn't really say that.
Don't listen to.
Okay, what else? >> Mama.
>> What language?
>> Chinese. >> What else?
>> [INAUDIBLE] >> What else, what language?
What do you notice something going on here?
Which is with the exception of that trouble-maker back
there, they all have this M sound in them.
The huge percentage of Earth's languages have an M sound for
mother in there, and they're only one or two syllables long.
Why is this?
Because of vicious selection, because when you got a 10-month-old, mostly what they
make is sounds like Mm, and at some point or other that turns,
because of the utility, when you were 10 months old and you were
suddenly hungry, you don't say please, I'm
feeling a bit hypoglycemic, is it possible?
[NOISE] Trust me, what you say at that point is mm, and in all these
languages, it turns into an M sound with mama in some way or other and that's
virtually universal.
So that explains the biochemistry of, what the hell am I talking about?
How did we get there?
Okay, what we see here is a very, very critical point
remarkably enough as I try to get out of this tangent.
If you got something important to say you use a very simple way of saying it.
You don't say mama with an 18 syllable
word involving dipthongs or whatever those things are.
What you say is an incredibly simple state
that is derived readily from your
emotional state and doesn't involve anything fancy.
This is exactly what you see with the neurotransmitters.
It's Friday's theme all over again.
Oh, if you've got incredibly important stuff to say, and you scream your head
off, you want to have a neurotransmitter system
that is transparent, simple, and easy to make.
And that's a theme that comes through with every one of the neurotransmitter systems,
because the last thing on Earth you want is when the
lion is chasing you and you're about to try to run
for your life, oh, what a bummer, you've run out of
precursor to make the neurotransmitter
that's going to make your muscles contract.
Or, oh, they need to go look up what steps
18 and 19 are in the biosynthetic pathway, because they forgot.
You're screwed at that point.
What you see with all of the
neurotransmitters are a bunch of simple rules.
They are all made from
plentiful precursors.
They are all made with a few biosynthetic steps.
They are all made with really
simply arbitrary biochemistry, and whenever possible
you're cheap and you squeeze multiple
messengers out of the same synthetic pathway.
Okay, let's start off with each of those steps.
Cheap, plentiful.
What you have by definition as the
starting point for most of the neurotransmitters
is something or other where no organism on earth has ever run out of the stuff.
You make neurotransmitters from some plentiful
amino acid that you're never short of.
You make as a starting point of neurotransmitter
from something like a lipid in your cell membranes.
You're never going to run out of that stuff.
A very simple, small molecule, nothing that's going to be expensive,
something that's going to be very, very plentiful.
You don't want to suddenly have a shortage
of neurotransmitter because you ran out of precursor.
Next thing, next thing as promised is, you just
do a couple of biosynthetic steps so that you
tell the world, okay if you started off with
an amino acid, it's not an amino acid anymore.
Don't even dream of trying to use this thing as part of a protein.
It's not an amin, it's on its
way to becoming one of these neurotransmitter things.
Instead, some very simple small number of steps.
What do you then do with those small
number of steps is totally mindless, simplistic biochemistry.
There's absolutely no reason why it is implicitly the case that by having
this being one letter and this having this slight biochemical modification.
There's no way you can look at it and say oh it is implicitly the case to me
its totally obvious that this should be telling something
about queens and this should be telling something about homotidia.
Okay there's no, there's no relationship between the mechanical just
pure physical nature of the messenger and the message itself.
The biochemistry is totally arbitrary,
and we will see that shortly.
[COUGH] So just a few biosynthetic steps
and at that point, you've made a neurotransmitter.
Final principle of being totally cheap about this stuff
is whenever possible, make multiple neurotransmitters from the same precursor.
So you can piggyback large parts of
the synthetic pathways, and generate multiple messengers.
Over and over and over the neurotransmitter biochemistry is built
around, start with something really cheap and easy and plentiful.
Just do a couple of simple steps get your messenger
exocytosis send the message get it all over with go
back to sleep its done its nothing fancy and its
not for nothing that newspapers are printed on like cheap paper.
That's only useful for puppies the
next day and they're not on like illustrated manuscripts.
Because they have a very short half-life of relevance.
The neurotransmitterology, all of the biochemistry of it is
really fast and cheap and obsolete before you know it.
Okay, so with those principles [COUGH] in hand, let's look at the two
most, sort of well-studied early defined neurotransmitter systems.
And here
is where they will pummel you with the structures
and these things and the names of the enzymes
you're going to be overwhelmed and it's the exact
same principles as asking your mother to nurse you.
I say we're returning to that disturbing image but what we have here is it's the
same economic features of communication, plentiful precursors et cetera, et cetera.
First example on the left,
a class of neurotransmitters called catecholamines, these
are the most famous and most studied neurotransmitters.
Maybe.
But they're important.
They're very well understood, and what we see
here is the synthetic pathway for making them.
You already see the foreshadowing of
one of those rules in neurotransmitter cheapness.
I'm not saying the pathway for making the
catecholamine neurotransmitter.
This is the pathway for making catecholamine.
Neurotransmitters, multiple ones.
We will see that principle. Okay, so what do you start off with.
You have, as the starting point, tyrosine. Tyrosine.
No one on Earth has ever run out of tyrosine.
It is the most boring, innocuous man on the street amino acid you can get.
You start off with tyrosine.
This is not something fancy.
This does not require like, digging in the
ground to get rare minerals and having to smelt
the stuff to get, this is like, you got,
like, let's just grab something we got tons of.
Tyrosine, who cares, fine. We're going to start with tyrosine.
Totally simple there. Okay.
So at that point, the first step you need to do
is communicate to the world that tyrosine is no longer tyrosine.
Don't try to stick it in a protein, it's not an amino acid anymore.
I know, what can we do?
What can we do there?
Let's put on a plastic mustache on the tyrosine.
Let's hydroxylate it.
Good, that's fine.
You could've done anything, it's totally arbitrary.
Just stick something on it so that it's no
longer tyrosine, and you get a completely arbitrary first step.
You have tyrosine hydroxylase, the famed critical
rate-limiting step.
All it's doing is, you gotta do something
to distinguish it from your previous amino acid.
See you stuck on a hydroxyl group and you've got something that's not
yet a neurotransmitter it's a precursor l-dopa, l-dopa.
Okay so now you gotta do something else to
finally turn it into a transmitter, something else totally arbitrary.
I know, we've got some enzyme handy for
some other purpose, let's have it multi-use now.
Let's decarboxylate the thing.
because it's got a carboxyl group and so what you've done is, you
put on the plastic mustache and you've taken off one of the socks.
Completely arbitrary, again, there's nothing
particularly impressive about these steps there.
All you gotta do is come up with something that distinguishes it.
And what you've now generated
is the first of the catecholamine neurotransmitters dopamine.
Dopamine which we will hear a lot about in a little while.
Okay dopamine hooray so look at what you've accomplished.
You start with a plentiful precursor and two biosynthetic
steps that are as easy as any, you're moving around
a hydroxyl group a carboxyl group and it's completely
arbitrary and hooray for you two steps and you have
a chemical messenger that talks to neurons it is
completely arbitrary tiny simple molecule that's easy to make.
So that's great that shows a bunch of our principles.
Now at this point we see our next
cheapness principle in action here, which is, so
you're a neuron and you've been able to
make dopamine, let's make another neurotransmitter at this point.
Let's take the dopamine and
if you're the right type of neuron you will
have an enzyme who could take things one step further.
Dopamine beta hydroxylase and what do you do you hydroxylate
some place else you've now put on two plastic mustaches
it looks ridiculous but the main point is it looks
different from dopamine you've now made a second neurotransmitter norepinephrine.
Again, a completely arbitrary step, and,
you've now generated two different messengers in three different steps from
a plentiful precursor and it's really cheap and easy to do this.
But oh, that is not enough.
Let's do the same thing one more step, and in a subset of neurons, you can now have a
phenylalanine and methyltransferase let's transfer a methyl group just
once again now the shoe is on the left elbow
just arbitrary and you've created a third neurotransmitter epinephrine.
You've got the catecholamines and look at this just
out of a few steps three different chemical messengers
three different neurotransmitters and as we'll see they do
wildly different things in different parts of the brain.
Cheap synthesis.
Okay, so on the right, we see our second
system, and it's going to be the exact same story,
a class of neurotransmitters called indolamines.
Same thing.
Starting point, tryptophan.
Tryptohan, the only amino acid on Earth that isn't
as innocuous and boring as tyrosine, same deal again.
Plentiful amino acid and what you now have to do is
make sure its not mistaken and what are we going to do
to it to make it look different let's do the same
exact thing as their doing next door over in the catecholamine
county there.
Let's just do something with a hydroxyl group.
Tryptophan hydroxylase, the same arbitrary thing, and you better bet that
the tryptophan hydroxylase gene and the tyrosine hydroxylase gene were once
one gene before they duplicated and evolved somewhat separately.
It's the same exact system, so you've now
made something 5-HTP, and that's not yet a neurotransmitter.
Same deal as with l-dopa, precursor, do one more
step, one more step there, and what's the step?
It's the same exact thing you did over
at the catecholamine, and you've got a decarboxylase.
And you've now created your first indolamine neurotransmitter serotonin.
Same exact deal, same exact lessons to be learned.
Same vicious cheapness and then you do the same
trip all over again, you've got another enzyme
that can do a methyl transferase thing and.
You got a second neurotransmitter out of the system melatonin same
principles nothing creative here the
indolomines and the catecholamines are each
convinced the other ripped off the other one because its the
same exact principle and its the same thing for all these neurotransmitters.
Cheap, plentiful way of getting a lot of messengers
that you have to release real fast and which
are going to be obsolete in a tenth of a second.
But, you pay a price.
You pay a price as follows.
[COUGH] And one that is all about this sort of no free lunch dictum.
So, you have
your neurotransmitter queen and your neurotransmitter,
what did I come up with before?
Ocelots.
Okay, ocelots. I say free associating indefensively.
And you've got a receptor here and what it does
it it's lock and key cliche there in complementarity of structure.
And what you see is both of these guys can float in and bind to it.
Oh,
no, the receptor can't distinguish between
these two neurotransmitters that are structurally
similar, because they're first cousins, but
which may have totally different functions.
What you've gotta have there is a receptor that is keyed in on what's
unique about, there you go, perfect, about what's unique about that one.
It's gotta be, I hate this screen.
This thing is, okay. I'm going to impale myself.
>> [LAUGH]
>> And what we have I'm free associating to the
snowman in Frozen if any of you have seen that movie.
Oh my god, he's going off the rails.
Anyway, so, what we have here is you gotta
have a receptor that can distinguish between the two.
Again it's totally arbitrary.
But, if you want to tell the difference between epinephrine and
norepinephrine, you gotta have a receptor that can
keep track of where the methyl group is.
It's gotta be taking advantage so we see this dictum, if you're going to be
cheap in your neurotransmitter synthesis, you're going to
have to have some very fancy receptors.
And yes indeed there are some spectacularly
fancy ones that could distinguish between the two.
[COUGH] Themes of things to come,
when we look at the hormone section you
are going to see, for example, that two hormones that
are structurally almost identical and you sure as
hell want receptors that could distinguish between the two.
Estrogen and testosterone because we will
see the same cheapness principle and they're
almost i, and you'd better want your receptors to be able to distinguish them.
If you're going to be cheap with your messenger,
you're going to have to have some very fancy receptors.
So you have different neurotransmitter receptors
that could respond to multiple of the
neurotransmitters in the pathway that respond to
only one of them with different affinities.
The receptorology is extremely fancy.
There's no free lunch.
Okay.
So given those rules, what are some of the neurotransmitters out there?
First question derived from that is, so
how do you prove something's a neurotransmitter?
And there are four carved in stone rules for telling this.
And they're all totally obvious except for the fourth one.
First one, you are speculating that some chemical is a neurotransmitter.
What's the first requirement?
It's got to be in the axon terminal, duh! That makes perfect sense.
Yeah, right.
If it's not in the axon terminal, it can't be released from the terminal in response
to an action potential.
You got to be able to demonstrate it in a vesicle, in an axon terminal.
So that's reasonable.
Second requirement is when the neuron has
an action potential its gotta release the stuff.
That doesn't seem like an outrageous demand
for a neurotransmitter to qualify okay, so its
gotta be present and its gotta be
released exocytosed in response to an action potential.
Third requirement is also perfectly reasonable, which is
it's gotta do something to the postsynaptic neuron.
Something goes differently in that neuron at that point when this
thing goes floating across, and does
something biochemical there with the receptor.
In other words, it's gotta do something to the next neuron.
Otherwise this could just be arbitrary junk
that's being dumped by the presynaptic nerve.
So it's gotta be there it's
gotta be released at the logical time and
it's gotta have an effect on the postsynaptic neuron.
The fourth requirement is the killer.
[COUGH] What number three shows is it can do something to the postsynaptic neuron.
The number four requirement to showing that
it does do that under normal circumstances.
That this isn't just some circus trick you came up with by accidentally putting
on 100 zillion times more of the stuff than you ever see.
And what do you know, it does something to the dendritic spine at the other end.
You've gotta show that under normal
conditions of brain function the things you
identified in number three, it does
something or other to the postsynaptic neuron.
You've got to be able to show that it actually does do that.
And what that requires is finding a way to block the receptor.
Finding a way to make sure the stuff doesn't get released.
Finding a way to get rid of it and, if the thing that happens in number three now no
longer occurs under normal circumstances, you've just shown that
it has that physiological function that it normally does that.
And that fourth one is the killer criteria.
So at this point, there's like dozens of
different things out there that have met three
of the criteria for neurotransmitters that have met four.
You go away for a three-day weekend, and there's seven new
molecules that are potential ones that are found in the axon terminal.
There's a whole bunch that are established by now.
These guys that are very famous, in addition, acetylcholine,
Glutamates. What are other ones? Substance P, neurophysin. We're going to
hear about a whole bunch of these but they all
show these same exact principles in terms of these criteria.
Okay so what I've just alluded to is probably sort of the most dynamic realm of
this research, which is being able to now manipulate neurotransmitter systems.
[COUGH] And what I just said was sort of an
experimental technique, ooh, how do you show criteria number four?
Find a way to screw up and block the
receptor for this imaginary putative neurotransmitter?
And if number three's events don't occur,
you've just implicated that a normal function.
What am I talking about there? Finding ways to manipulate these pathways
with drugs using ways to have pharmacological interventions to have
neuropharmacological interventions and what we'll see is this is a good research
tool but this is also a huge amount of what goes on in clinical neurology.
First trying to figure out what
the neurotransmitter problem is somewhere up there.
Second, then trying to do something about it.
Okay, so what are ways in which
you can manipulate neurotransmitter systems with drugs?
So back to our iconic synapse and we have a first possibility.
Okay, suppose the neuron on the left,
our presynaptic neuron, hasn't released any neurotransmitters.
It hasn't had a thought in two weeks, it's been
completely silent just sitting there, it has not released anything.
And thus, it has not done anything
excitedly or inhibitorially to the postsynaptic neuron.
It's completely silent. Now, you take a drug.
A drug which structurally is really close
to the neurotransmitter that would be released there.
That is structurally very similar.
You take it, and it gets in your
stomach and your blood and your cerebrospinal fluid, and
eventually, some of it wanders into the synapse
and binds to the receptor on the postsynaptic side.
And it's
structurally close enough that it's just as effective.
It's keying in on a part of the receptor that
can't distinguish between the neurotransmitter
and this very close structural analogue.
What does it do then?
It triggers the receptor to do its normal thing.
What is it doing?
The postsynaptic neuron is responding as if
the presynaptic neuron has released a neurotransmitter.
What's going on? The postsynaptic neuron is hearing voices.
It's hearing voices that nobody else is
hearing because the presynaptic neuron isn't saying anything.
What have we just defined?
These are what hallucinogens do.
What they do is activate pathways that are not actually being stimulated with drugs
that neurochemically, structurally, are close enough to fake out the receptors.
And to give you a sense of that,
here on the left is the structure of serotonin, do not memorize that.
But the main point here being, that look on
the right, we have one of the main hallucinogens, psilocybin.
It's virtually the same structure.
Psilocybin, LSD, mescaline, all of them look just like serotonin.
And fit into the receptor and
thus neurons with serotonin receptors have hallucinations.
They hear voices,
they are getting messages that the presynaptic neuron isn't sending.
Okay, so that's a first thing we could do.
What next can we do in terms of a neurochemical manipulation?
Okay.
So what we've just done is by using a drug, we activate the
receptors when there's really nothing being
said to them by the presynaptic neuron.
Let's try the opposite strategy.
What if we have a drug that blocks the receptor?
One that I sort of hypothetically talked
about a few minutes ago, a receptor blocker.
A receptor blocker. Here's one example of one.
You've got a drug for
example one called Haldol other name for a close relative it
is called thorazine and what it does is it blocks dopamine receptors.
Same deal, you take it, it eventually gets into the brain, and gets into
synapses all over the brain, where it does absolutely nothing in most of the parts.
But any of the synapses that have
dopamine receptors, it will block the dopamine receptor.
Okay, anyone know,
recognize sort of how Haldol, thorazine, what it's used for?
To treat yeah?
>> [INAUDIBLE]
>> Psychosis, exactly.
Every television program where somebody's gone psychotic in the hallway of a
hospital and they yell for help and they pull the person down.
And somebody, usually the med student wandering
through there grabs the syringe and pokes
it into the guy's ***, and what they're always using at that point is
Haldol, thorazine, blocking the dopamine receptors.
It is the most effective class of drugs for treating schizophrenics.
Okay, so let's observe that now.
Here you have this horrible, horrible
disease, schizophrenia, and what you've got
is hallucinations, tangential thought, a whole
bunch of cognitive social changes, awful disease.
And you throw in a drug that blocks
dopamine receptors, and the person starts looking less psychotic.
What's your hypothesis have to be?
Ooh, I betcha the problem is that there's too much dopamine in the first place.
And thus circa 1950s, we've got the dopamine hypothesis for
schizophrenia, which remains the most convincing connection with the disease.
Up until the 1950s, if you had
schizophrenia, the greatest experts on Earth would sit
down and tell your mother that she caused the schizophrenia by giving
you conflicting signals, and her mothering
style, schizophrenogenic mothering, That destroyed endless
mothers of schizophrenics, and suddenly in the 1950s, people got this drug
instead, and everybody said, oh, it's
not the mothering, it's a biochemical disorder.
It's a biochemical disorder, 90% of the
psychiatric hospital beds in this country were emptied
out within a couple of years when people were finally able to treat.
Oh it must be too much dopamine. The dopamine hypothesis
so what we've just done in this case is number 1
get some insights into what's going on in the disease
number 2 actually be able to treat it a little bit.
Okay so what else can you do another type of
drug that will block another receptor and will block it permanently.
In the case here with the dopamine blockers, comes on these antipsychotics.
Another name for the class, neuroleptics.
They bind for what.
That's why you need to take some every day or so.
But then there's a class of receptor blockers that stay permanently there.
And what happens if they happen to
be receptors for a neurotransmitter that tells
your diaphragm to do whatever diaphragms do
and you don't breathe and you suffocate?
That's what curare does as a poison
it blocks acetylcholine receptors in the diaphragm.
Okay so lots of ways now the strategy of blocking the receptor.
What else can you do?
You can have a drug that blocks the release of
a neurotransmitter, and there's ones out there that are used.
There is one called Reserpine, which was used to
decrease blood pressure, when too much of a neurotransmitter that
increases heart rate was being released, blocked this.
This drug would disintegrate vesicles for this neurotransmitter.
That's great, okay. How about inverse to that?
nah. I won't go into that.
Okay inverse of that.
How about a drug which instead of blocking neurotransmitter release, it
triggers neurotransmitter release and makes you dump more of the stuff?
It triggers the fusion of the vesicle tube and suddenly you
are getting more potent signals than, what class of drugs do?
That's what amphetamines do.
That what, that's what *** does in terms of dopamine pathways.
It triggers more
of that. Okay, what did we just see?
Something important.
Dopamine's got something to do with logical sequential
thought and when it's wacky, you've got schizophrenia.
Dopamine in another part of the brain has
to do with perception of pleasure and reward.
And *** is working on that system.
What it does is it triggers a dump of dopamine in those reward pathways.
It triggers a dump a thousand-fold
higher than any natural stimulus has been found to release dopamine.
Okay, so a drug that can do that.
Now, what else can you do?
Let's go to our after the neurotransmitter's been released.
We just saw ways to manipulate that after it interacts with the receptor.
We just saw ways of manipulating there [INAUDIBLE].
Now we've got the cleaning up after your self phase.
So what about drugs that can manipulate that?
Okay.
First off, now we've got a neurotransmitter that
comes floating off, and this is one of those
where there's a degradative enzyme that grabs onto it,
rips it up into little pieces, flushes it down.
That's how it's inactivated.
Suppose you throw in a drug that blocks that degradative enzyme.
It inhibits it.
It doesn't work anymore.
What's going to happen now? The neurotransmitter doesn't get degraded.
So it's got nothing else to do in the synapse,
so it hits the receptor a second time and a
third time and an eleventieth time, and you get more
of the neurotransmitter signal going through there because it persists longer.
And this is a drug that was developed in the 60s, targeting an enzyme called MAO,
monoamine oxidase, and what that does is rip apart norepinephrine.
So somebody came up with a drug that inhibited MAO, an
MAO-inhibitor, and that was the first effective drug for clinical depression.
So you get somebody who's depressed and you give
them a drug that causes there to be more
norepinephrine signaling in pathways in the brain and they
get less depressed what's your hypothesis have to be
there's too little norepinephrine in depression and that was the
leading hypothesis at the time using a drug to manipulate it.
Okay so you recall our second way of
cleaning up the mess in the synapse afterward the
recycling step the reuptake step so let's get a
drug now that blocks reuptake of the neurotransmitter serotonin.
Serotonin. So you block
the reuptake pump. What happens?
Same deal ias just now with those MAO inhibitor things.
The serotonin sticks around and hits the receptor a second
time and a thousandth time and you potentiate the signal and
what that does is it turns out to be the
most effective drug out there for helping people with clinical depression.
A selective serotonin reuptake inhibitor an SSRI
most famous of which is Prozac.
Prozac works by blocking serotonin reuptake.
So now suddenly you got two things on your hands here.
One is, oh, so how do we reason through this?
So you take a drug that blocks the reuptake of serotonin and thus
serotonin sticks around longer and is more potentiated and people get less depressed.
Oh, I bet what's going on in depression is too little serotonin.
And thus
you have the too little serotonin people who
hate the guts of the too little norepinephrine people.
Our second point here is there's multiple neurotransmitters involved in this stuff.
And at this point, depression for example, appears
to involve deficits in serotonin, norepinephrine, and dopamine.
And different of the antidepressant drugs work on different
components of them, but they all have the same effects.
They all block either the breakdown or the re-uptake.
So in all cases, what you have to conclude is the
problem is too little of the neurotransmitter in the first place.
Okay, for those who care about this, and probably statistically 10-20% of you
will have to care about this at some point or other in your lives.
In terms of where depression and neurochemistry works, dopamine,
a shortage of that seems to play a role in
the loss of pleasure in depression. Clinical term anhedonia,
hedonism, the pursuit of pleasure, anhedonia, inability to feel pleasure.
Norepinephrine and its shortage seems to play a role in what is called psychomotor
retardation which is when people are depressed, everything is exhausting.
Getting up and getting dressed is exhausting,
finding the change to do the laundry, brushing anything
it's all it's exhausting to do, it's exhausting to think.
That appears to be the norepinephrine component, serotonin seems to play
a role in the perseverative thinking that you get in depression.
Which is people who are depressed will have the same
depressing thoughts and just perseverate on them and just get stuck.
And Velcro and
sticky tape with these disturbing, depressing thoughts, and they can't stop
them, serotonin reuptake inhibitors, Prozac and others, seem to work on that.
The serotonin component seems to have something to do with this
perseverative thinking about things that evoke grief and all of that.
Okay, so given what I just described what other
psychiatric disorder could you use Prozac for, if Prozac
is working on this perseverative feature of thought in depressives where they just
can't stop thinking about depressing stuff, what
other disease could you use Prozac for?
What? OCD, obsessive compulsive disorder.
What does that have in common with depression?
Totally different world views, what does it have in common.
You're thinking all the time about how your loved ones
are going to die someday and there goes the ozone layer.
You're thinking all day long about keeping the fork and
the knife perfectly parallel and did you really mail that letter.
In both cases, it's this perseverative, sticky, viscous thinking
stuff, so serotonin reuptake hibit, inhibitors work on both, ways
to begin to piece apart what these different neurotransmitter systems do.
Okay.
Next thing you could manipulate, and this shows us something very interesting.
So suppose you've got one of the truly awful neurological diseases out there.
If you get a choice in the matter, do not get this one Parkinson's disease.
Parkinson's disease, you lose the ability to easily initiate motions.
Motions are slowed down, fine motor control is impaired.
You get a tremor having to do with really complicated stuff.
In terms of normal muscular contraction rates bad disease.
So in the 1960s people began to figure out what Parkinson's disease was about.
They started doing postmortems on brains of
Parkinson's patients and expected to see all parts of the brain
blown out of the water and all of the brain was
fine except for this one tiny, little, obscure area that three
and half people had ever studied an area called the substantia nigra.
This one part of the brain and like 90% of the neurons
there were carpet bombed and dead in Parkinson's disease a-ha something very
wrong goes on there and it's now understood the biochemistry
of that and it's got to do with oxygen radical stuff.
But the main thing at that point was okay, so what neurotransmitter
is used by the substantia nigra to talk to other muscle pa?
It uses dopamine.
Dopamine, and that suddenly triggered this idea, okay.
So if in Parkinson's disease, 90% of those dopamine-releasing
neurons are lost, maybe we can help by replacing some of the dopamine.
Let's perk up the dopamine levels.
Turns out, you can't really get dopamine into the brain very easily.
Let's do one step earlier. Let's give that precursor stuff, l-dopa.
And in the 60's people started giving l-dopa to people with Parkinson's disease
and what that would do is the remaining 10% of the neurons would
suddenly have more dopamine to release and people got better.
And I grew up in this era of sort of reading Reader's Digest articles in
the 60s and there would be articles with names like l-dopa has set me free.
Parkinsonian patients who hadn't be able to take
a step in decades and this drug absolutely miraculous
although bummer of an ending it turns out
about three, four years later it makes the Parkinson's
worse than before hand but everybody had a great time at the beginning there.
>> [LAUGH]
>> Okay, so we have here a drug manipulation that's
increasing the amounts of dopamine and thus Parkinson's gets better.
Okay, I know every single one of your are thinking this right now.
There is a huge confusing contradiction that's just come up
here, and it just challenges the credibility of all this.
Okay, back to schizophrenia.
So the problem in schizophrenia seems to be in some part
of the brain that has to do with logical sequential thinking.
There's too much dopamine.
So give a drug that's dopamine receptor blocker, and things get wonderful.
Meanwhile, 17 counties over in the substantia
nigra, in Parkinson's disease, there seems to be
a problem with too little dopamine, of these
neurons that helped to initiate smooth motor control.
So you give a drug, then boosts up dopamine levels, and people get better.
Wait a second.
There's a problem here.
So what's the prediction you could make at this point?
What happens when you treat
a schizophrenic with dopamine receptor blockers?
Or what happens when you treat a Parkinson's patient with l-dopa?
Any predictions?
Yeah.
>> The schizophrenics who takes these drugs
start to like show some Parkinson's syndromes.
>> Yep.
You treat somebody with the antipsychotics and they begin to get Parkinsonia.
And you treat somebody with l-dopa, with Parkinson's disease, and
they often become psychotic when the doses get too high.
Go into any state hospital and go
way back in the back ward of the psychiatric
unit, and there's somebody sitting there trembling like this.
That person is a schizophrenic who's been taking
dopamine receptor blockers for 20 years or so.
And the fancy term for it is tardive
dyskinesia kinesia kinetics dyskinesia abnormal movement you try
to fix up the schizophrenia and you get Parkinsonian symptoms if you go to high on
the dose.
Meanwhile over in the Parkinsonian realm you give them
l-dopa and if the doses get too high the person
starts looking psychotic on you what's the punchline here
you're using the same neurotransmitter in a gazillion different places.
You can have this arbitrary neurotransmitter that
has like two things like this and one
horizontal line, and you stick it with a C and T and you're talking about stuff
with whiskers, and you stick it with
some other letters and you're talking about existentialism.
You use the same neurotransmitter in lots of
different roles in different parts of the brain.
More of that economy stuff.
So you throw in a drug, and it's not just going to go
to that one part of the brain that's lost 90%, it goes all over.
And over and over, so that the
challenge in clinical neuropharmacology is, you throw a
drug into this whole vat of the brain and it affects stuff all over.
You got too little of something here and it's normal everywhere
else, you fix up the problem and you get the side effects.
Or you get exactly the opposite.
Enormously messy challenge in the field how do you ZIP
code the drugs so they go exactly where they're needed?
Okay.
So what we've gotten to now are two neurons at a time.
And what we will do next on Wednesday is now leap into the world of
three neurons and begin to see how neural
networks work, and computational stuff out of that.
So we will resume.