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CHAPTER
5
How Do Neurons
Communicate?
A Chemical Message
Neurotransmitter Systems
The Structure of Synapses
Focus on Disorders: Parkinson’s Disease
Stages in Neurotransmitter Function
Types of Synapses
The Evolution of a Complex Neural
Transmission System
Excitatory and Inhibitory Messages
Neurotransmission in the Skeletal Motor System
Neurotransmission in the Autonomic Nervous
System
Neurotransmission in the Central Nervous System
Focus on Disorders: The Case of the Frozen
Addict
The Kinds of Neurotransmitters
Identifying Neurotransmitters
Neurotransmitter Classification
The Types of Receptors for Neurotransmitters
Focus on Disorders: Awakening with L-Dopa
The Role of Synapses in Learning
and Memory
Learning and Changes in Neurotransmitter
Release
Synaptic Change with Learning in the
Mammalian Brain
Long-Term Learning and Associative Learning
Learning and the Formation or Loss of Synapses
Patrisha Thomson/Stone
Micrograph: Dr. Dennis Kunkel/Phototake
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T
he sea bird called the puffin (genus Fratercula,
the puffin’s body, imposes greater resistance to movement
which is Latin for “little brother”) exhibits remark-
than air does.
able behavior during its breeding season. It digs a
To meet its nutrient and oxygen needs during its vari-
burrow as deep as 4 feet into the earth, in which to lay its
ous behaviors, the puffin’s heart rate changes to match its
single egg. While on the ground, the puffin is relatively
energy expenditure. The heart beats slowly on land and in-
inactive, sitting on its egg or in front of its burrow. But,
creases greatly in flight. When the puffin dives beneath the
after the egg hatches, the puffin begins a period of Her-
surface of the water, however, its heart stops beating. This
culean labors. It must fly constantly back and forth
response is called diving bradycardia (brady meaning
between its burrow and its fishing ground to feed its rav-
“slow”; cardia meaning “heart”). Bradycardia is a strategy
enous young. It fishes by diving underwater and pro-
for conserving oxygen under water, because the circulatory
pelling itself by flapping its short stubby wings as if it
system expends no energy when the heart ceases pumping.
were flying. One by one it catches as many as 30 small
Your heart rate varies in the same way as the puffin’s
fish, all of which it holds in its beak to be carried back to
to meet your energy needs, slowing when you are at rest
its chick (Figure 5-1). The chick may eat as many as 2000
and increasing when you are active. Even exciting or re-
fish in its first 40 days of life. When flying to its fishing
laxing thoughts can cause your heart to increase or de-
ground, the puffin exerts a great deal of effort to maintain
crease its rate of beating. And, yes, like the puffin and all
its momentum. It also expends much energy as it “flies”
other diving animals, when you submerge your head in
through the water, because the water, although it supports
water, you, too, display diving bradycardia. What regulates
all this turning up, down, and off of heart-
Kevin Schafer
beat as behavior requires?
Because the heart has no knowledge
about how quickly it should beat, it must be
told to adjust its rate of beating. These commands consist of at least two different messages: an excitatory message that says
“speed up” and an inhibitory message that
says “slow down.” What is important to our
understanding of how neurons interact is
that it was an experiment designed to study
how heart rate is controlled that yielded an
answer to the question of how neurons communicate with one another. In this chapter,
we explore that answer in some detail. First,
Figure 5-1
we consider the chemical signals that neurons use to in-
A puffin is returning with food for its chick. Its heart rate varies to
match its energy needs, slowing down on land, increasing during
flight, and stopping completely when the puffin dives below the
surface of the water to fish.
hibit or excite each other. Then, we examine the function
of excitatory and inhibitory synapses and excitatory and
inhibitory receptors. Finally, we investigate the changes
that synapses undergo during learning.
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154 ■
CHAPTER 5
A CHEMICAL MESSAGE
Otto Loewi
(1873–1961)
In 1921, Otto Loewi conducted a now well-known experiment on the control of heart
rate, the design of which came to him in a dream. One night, having fallen asleep while
reading a short novel, he awoke suddenly and completely, with the idea fully formed.
He scribbled the plan of the experiment on a scrap of paper and went back to sleep.
The next morning, he could not decipher what he had written, yet he felt it was important. All day he went about in a distracted manner, looking occasionally at his notes,
but wholly mystified about their meaning. That night he again awoke, vividly recalling
the ideas in his previous night’s dream. Fortunately, he still remembered them the next
morning. Loewi immediately set up and successfully performed the experiment.
Loewi’s experiment involved electrically stimulating a frog’s vagus nerve, which leads
from the brain to the heart, while at the same time channeling the fluid in which the stimulated heart had been immersed to a second heart that was not electrically stimulated, as
shown in Figure 5-2. The fluid traveled from one container to the other through a tube.
Loewi recorded the rate of beating of both hearts. The electrical stimulation decreased the
rate of beating of the first heart, but, more important, the fluid transferred from the first
to the second container slowed the rate of beating of the second heart, too. Clearly, a message about the speed at which to beat was somehow carried in the fluid.
But where did the message originally come from? The only way in which it could
have gotten into the fluid was by a chemical released from the vagus nerve. This
chemical must have dissolved into the fluid in sufficient quantity to influence the second heart. The experiment therefore demonstrated that the vagus nerve contains a
EXPERIMENT
Question: How does a neuron pass on a message?
Stimulating
device
Recording
device
1
Vagus nerve of frog
heart 1 is stimulated.
2
Fluid is transferred
from first to
second container.
Figure 5-2
Otto Loewi’s 1921 experiment
demonstrating the involvement of a
neurochemical in controlling heart rate.
He electronically stimulated the vagus
nerve going to a frog heart that was
maintained in a salt bath. The heart
decreased its rate of beating. Fluid from
the bath was transferred to a second
bath containing a second heart. The
electrical recording from the second
heart shows that its rate of beating also
decreased. This experiment demonstrates
that a chemical released from the vagus
nerve of the first heart can reduce the
rate of beating of the second heart.
Follow the main steps in the experiment
to arrive at the conclusion that
neurotransmission is chemical.
Vagus
nerve
Fluid transfer
Frog heart 1
Frog heart 2
Rate of
heartbeats
Stimulation
3
Recording from frog heart
1 shows decreased rate of
beating after stimulation…
4
…as does the recording
from frog heart 2 after
the fluid transfer.
Conclusion
The message is a
chemical released
by the nerve.
HOW DO NEURONS COMMUNICATE?
chemical that tells the heart to slow its rate of beating. Loewi subsequently identified
that chemical as acetylcholine (ACh).
In further experiments, Loewi stimulated another nerve, called the accelerator
nerve, and obtained a speeding-up of heart rate. Moreover, the fluid that bathed the
accelerated heart increased the rate of beating of a second heart that was not electrically stimulated. Loewi identified the chemical that carried the message to speed up
heart rate as epinephrine (EP). Together, these complementary experiments showed
that chemicals from the vagus nerve and the accelerator nerve modulate heart rate,
with one inhibiting the heart and the other exciting it.
Chemicals that are released by a neuron onto a target are now referred to as chemical
neurotransmitters. Neurons that contain a chemical neurotransmitter of a certain type
are named after that neurotransmitter. For example, neurons with terminals that release
ACh are called acetylcholine neurons, whereas neurons that release EP are called epinephrine neurons. This naming of neurons by their chemical neurotransmitters helps to
tell us whether those particular neurons have excitatory or inhibitory effects on other
cells. It also helps to tell us something about the behavior in which the neuron is engaged.
In the next section, we will look at the structure of a synapse, the site where
chemical communication by means of a neurotransmitter takes place. We will also examine the mechanisms that allow the release of a neurotransmitter into a synapse, as
well as the types of synapses that exist in the brain. You will learn how a group of neurons, all of which use a specific neurotransmitter, can form a system that mediates a
certain aspect of behavior. Damage to such a system results in neurological disorders
such as Parkinson’s disease (described in “Parkinson’s Disease” on page 156).
The Structure of Synapses
Otto Loewi’s discovery about the regulation of heart rate was the first of two important findings that provided the foundation for our current understanding of
how neurons communicate. The second
had to wait for the invention of the electron microscope, which enabled scientists to see the structure of a synapse.
The electron microscope uses some
of the principles of both an oscilloscope
and a light microscope. As Figure 5-3
shows, it works by projecting a beam of
electrons through a very thin slice of tissue that is being examined. The varying
structure of the tissue scatters the beam
of electrons and, when these electrons
strike a phosphorus-coated screen, they
leave an image, or shadow, of the tissue.
The resolution of an electron microscope
is much higher than that of a light microscope because electron waves are smaller
than those of light and so there is much
less scatter of the beam when it strikes the
tissue. If the tissue is stained with substances that reflect electrons, very fine details of structure can be observed.
Light microscope
Acetylcholine (ACh)
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155
Epinephrine (EP)
Figure 5-3
In a light microscope, light is reflected
through the specimen and into the eye
of the viewer. In an electron microscope,
an electron beam is directed through the
specimen and onto a reflectant surface,
where the viewer sees the image.
Because electrons scatter less than do
light particles, an electron microscope
can show finer details than a light
microscope can show. Whereas a light
microscope can be used to see the
general features of a cell, an electron
microscope can be used to examine the
details of a cell’s organelles.
Electron microscope
Electron gun
Specimen
Specimen
Light
Image
R. Roseman/Custom Medical Stock
Superstock
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CHAPTER 5
Parkinson’s Disease
Focus on Disorders
Case VI: The gentleman who is the subject of
symptoms, Jean Charcot named them Parkinson’s disease in
[this case] is seventy-two years of age. He has
recognition of the accuracy of Parkinson’s observations.
led a life of temperance, and has never been
Three major findings have helped researchers under-
exposed to any particular situation or circum-
stand the neural basis of Parkinson’s disease. The first came
stance which he can conceive likely to have
in 1919 when C. Tréatikoff studied the brains of nine Parkin-
occasioned, or disposed to this complaint:
son patients on autopsy and found that an area of the mid-
which he rather seems to regard as incidental
brain called the substantia nigra (meaning “dark substance”)
on his advanced age, than as an object of
had degenerated. In the brain of one patient who had expe-
medical attention. He however recollects that
rienced symptoms of Parkinson’s disease on one side of the
about twenty years ago he was troubled by
body only, the substantia nigra had degenerated on the side
lumbago, which was severe and lasted some
opposite that of the symptoms. These observations clearly
time. About eleven or twelve, or perhaps
implicated the substantia nigra in the disorder.
more, years ago, he first perceived weakness
The other two major findings about the neural basis of
in the left hand and arm, and soon after found
Parkinson’s disease came almost half a century later when
the trembling to commence. In about three
methods for analyzing the brain for neurotransmitters had
years afterwards the right arm became affect-
been developed. One was the discovery that a single neuro-
ed in a similar manner: and soon afterwards
transmitter, dopamine, was related to the disorder, and the
the convulsive motions affected the whole
other was that axons containing dopamine connect the sub-
body and began to interrupt speech. In about
stantia nigra to the basal ganglia. In 1960, when examining
three years from that time the legs became
the brains of six Parkinson patients during autopsies,
affected. Of late years the action of the bow-
H. Ehringer and O. Hornykiewicz observed that, in the basal
els had been very much retarded. (James
ganglia, the dopamine level was reduced to less than
Parkinson, 1817/1989)
10 percent of normal. Confirming the role of dopamine in
this disorder, U. Ungerstedt found in 1971 that injecting a
In his 1817 essay from which this case study is taken,
neurotoxin called 6-hydroxydopamine into rats selectively
James Parkinson reported similar symptoms in six patients,
destroyed neurons containing dopamine and produced the
some of whom he observed only in the streets near his clinic.
symptoms of Parkinson’s disease as well.
Shaking was usually the first symptom, and it typically began
The results of these studies and many others, including
in a hand. Over a number of years, the shaking spread to in-
anatomical ones, show that the substantia nigra contains
clude the arm and then other parts of the body. As the dis-
dopamine neurons and that the axons of these neurons pro-
ease progressed, the patients had a propensity to lean for-
ject to the basal ganglia. The death of these dopamine neu-
ward and walk on the forepart of their feet. They also tended
rons and the loss of the neurotransmitter dopamine from their
to run forward to prevent themselves from falling forward. In
terminals create the symptoms of Parkinson’s disease. Re-
the later stages of the disease, patients had difficulty eating
searchers do not yet know exactly why dopamine neurons
and swallowing. Being unable to swallow, they drooled,
start to die in the substantia nigra of patients who have the
and their bowel movements slowed as well. Eventually,
idiopathic form of Parkinson’s disease (idiopathic refers to a
the patients lost all muscular control and were unable to
condition related to the individual person, not to some exter-
sleep, because of the disruptive tremors. More than 50 years
nal cause such as a neurotoxin). Discovering why idiopathic
after James Parkinson first described this debilitating set of
Parkinsonism arises is an important area of ongoing research.
HOW DO NEURONS COMMUNICATE?
The first good electron micrographs, made in the 1950s, revealed many of the
structures of a synapse. In the center of the micrograph in Figure 5-4 is a typical
chemical synapse. The synapse is in color and its parts are labeled. The upper part of
the synapse is the axon and terminal; the lower part is the dendrite. Note the round
granular substances in the terminal, which are vesicles containing the neurotransmitter. The dark band of material just inside the dendrite provides the receptors for
the neurotransmitter. The terminal and the dendrite are separated by a small space.
The drawing in Figure 5-4 illustrates the three main parts of the synapse: the
axon terminal, the membrane encasing the tip of an adjacent dendritic spine, and the
very small space separating these two structures. That tiny space is called the synaptic
cleft. The membrane on the tip of the dendritic spine is known as the postsynaptic
membrane. It contains many substances that are revealed in micrographs as patches
of dark material. Much of this material consists of protein receptor molecules that
receive chemical messages. Micrographs also reveal some dark patches on the presynaptic membrane, the membrane of the axon terminal, although these patches are
harder to see. Here, too, the patches are protein molecules, which in this case serve
largely as channels and pumps, as well as receptor sites. Within the axon terminal
are many specialized structures, including both mitochondria (the organelles that
supply the cell’s energy needs) and what appear to be round granules. The round
granules are synaptic vesicles that contain the chemical neurotransmitter. Some axon
terminals have larger compartments, called storage granules, which hold a number of
synaptic vesicles. In the micrograph, you can also see that this centrally located
synapse is sandwiched by many surrounding structures, including glial cells, other axons and dendritic processes, and other synapses.
Chemical synapses are not the only kind of synapses in the nervous system. A second
type is the electrical synapse, which is rare in mammals but is found in other animals. An
(A) The parts of this synapse are
characteristic of most synapses. The
neurotransmitter, contained in vesicles, is
released from storage granules and
travels to the presynaptic membrane
where it is expelled into the synaptic cleft
through the process of exocytosis. The
neurotransmitter then crosses the cleft
and binds to receptors (proteins) on the
postsynaptic membrane. (B) An electron
photomicrograph of a synapse in which
an axon terminal connects with a
dendritic spine. Surrounding the centrally
located synapse are other synapses, glial
cells, axons, and dendrites. Within the
terminal, round vesicles containing
neurotransmitters are visible. The dark
material on the postsynaptic side of the
synapse includes receptors and
substances related to receptor function.
Presynaptic
neuron
Mitochondrion:
Organelle that provides
the cell with energy.
Presynaptic
terminal
Neurotransmitter
Synaptic cleft: Small
space separating
presynaptic terminal
and postsynaptic
dendritic spine.
Postsynaptic membrane:
Contains protein
molecules that receive
chemical messages.
Storage granule:
Large compartment that holds
synaptic vesicles.
Channel
Dendritic
spine
Postsynaptic
receptor: Site to
which a neurotransmitter
molecule binds.
(B)
Axon
Presynaptic
terminal
Presynaptic
membrane
Synaptic
vesicles
Synaptic
cleft
Postsynaptic
membrane
Dendritic
spine
Glial cell
Courtesy Jeffrey Klein
Presynaptic membrane:
Contains protein
molecules that
transmit chemical
messages.
Synaptic vesicle:
Round granule
that contains
neurotransmitter.
157
Figure 5-4
(A)
Dendrite of
postsynaptic
neuron
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CHAPTER 5
Figure 5-5
Synaptic transmission generally consists
of four steps. (1) Synthesis: Using chemical
building blocks imported into the axon
terminal, a neurotransmitter is
synthesized and packaged in vesicles.
(2) Release: In response to an action
potential, the transmitter is released
across the presynaptic membrane by
exocytosis. (3) Receptor action: The
transmitter crosses the synaptic cleft and
binds with a receptor on the postsynaptic
membrane. (4) Inactivation: After use,
the transmitter is either taken back into
the terminal or inactivated in the
synaptic cleft.
electrical synapse has a fused presynaptic and postsynaptic membrane that allows an action potential to pass directly from one neuron to the next. This mechanism prevents the
brief delay in information flow—on the order of about 5 milliseconds per synapse—of
chemical transmission. For example, the crayfish has electrical synapses to activate its tail
flick, a response that allows it to escape quickly from a predator.
Why, if chemical synapses transmit messages more slowly, do mammals depend
on them almost exclusively? There must be some benefits that outweigh the drawback
of slowed communication. Probably the greatest benefit is the flexibility that chemical
synapses allow in controlling whether a message is passed from one neuron to the
next. This benefit is discussed later in this chapter.
Stages in Neurotransmitter Function
The process of transmitting information across a synapse includes four basic steps.
1. The transmitter molecules must be synthesized and stored in the axon terminal.
2. The transmitter must be transported to the presynaptic membrane and released
in response to an action potential.
3. The transmitter must interact with the receptors on the membrane of the target
cell located on the other side of the synapse.
4. The transmitter must somehow be inactivated or it would continue to work
indefinitely.
These steps are illustrated in Figure 5-5. Each requires further explanation.
NEUROTRANSMITTER SYNTHESIS AND STORAGE
1
Synthesis: Building
blocks of a transmitter
substance are imported
into the terminal…
Precursor
chemicals
Neurotransmitter
… where the
neurotransmitter
is synthesized and
packaged into
vesicles.
2
Release: In response
to an action potential,
the transmitter is
released across the
membrane by
exocytosis.
3
Receptor action: The
transmitter crosses
the synaptic cleft and
binds to a receptor.
Neurotransmitters are manufactured in two general ways. Some are
manufactured in the axon terminal from building blocks derived
from food. Transporter proteins in the cell membrane absorb the
required precursor chemicals from the blood supply. (Sometimes these transporter proteins absorb the neurotransmitter
itself ready-made.) Mitochondria in the axon terminal provide the energy needed to synthesize precursor chemicals
into the neurotransmitter. Other neurotransmitters are
manufactured in the cell body according to instructions
contained in the neuron’s DNA. Molecules of these
transmitters are packaged in membranes on the
Golgi bodies and transported on microtubules to
the axon terminal.
In the axon terminal, neurotransmitters manufactured in either of these ways are wrapped in a
membrane to form synaptic vesicles, which can
usually be found in three locations within the terminal. Some vesicles are stored in granules, as
mentioned earlier. Other vesicles are attached to
the filaments in the terminal, and still others are
attached to the presynaptic membrane, where they
4
are ready for release into the synaptic cleft. After a
Inactivation: The
vesicle has been released from the presynaptic
transmitter is either
membrane, other vesicles move to that membrane
taken back into the
terminal or inactivated
location so that they, too, are ready for release
in the synaptic cleft.
when needed.
HOW DO NEURONS COMMUNICATE?
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159
THE RELEASE OF THE NEUROTRANSMITTER
What exactly triggers the release of a synaptic vesicle and the spewing of its neurotransmitter into the synaptic cleft? The answer is, an action potential. When an action
potential is propagated on the presynaptic membrane, the voltage changes on the
membrane set the release process in motion. Calcium ions (Ca2+) play an important
role in the process. The presynaptic membrane is rich in voltage-sensitive calcium
channels, and the surrounding extracellular fluid is rich in Ca2+. As illustrated in Figure 5-6, the arrival of the action potential opens these voltage-sensitive calcium channels, allowing an influx of calcium ions into the axon terminal.
Next, the incoming Ca2+ binds to a chemical called calmodulin, and the resulting
complex takes part in two chemical actions: one reaction releases vesicles bound to
the presynaptic membrane, and the other releases vesicles bound to filaments in the
axon terminal. The vesicles released from the presynaptic membrane empty their contents into the synaptic cleft through the process of exocytosis, described in Chapter 3.
The vesicles that were formerly bound to the filaments are then transported to the
presynaptic membrane to replace the vesicles that just emptied their contents.
Link to your CD and find the area
on synaptic transmission in the Neural
Communication module to better
visualize the structure and function of
the axon terminal. Watch the animation
and note how the internal components
work as a unit to release neurotransmitter
substances into the synapse.
THE ACTIVATION OF RECEPTOR SITES
After the neurotransmitter has been released from vesicles on the presynaptic
membrane, it diffuses across the synaptic cleft and binds to specialized protein molecules embedded in the postsynaptic membrane. These protein molecules are called
1
When an action
potential reaches the
terminal, it opens
calcium channels.
Complex
Figure 5-6
Calmodulin
Action
potential
Calcium
ions
2
Incoming calcium ions
bind to calmodulin,
forming a complex.
3
This complex binds to
vesicles, releasing some from
filaments and inducing
others to bind to the
presynaptic membrane and
to empty their contents.
When an action potential reaches an
axon terminal, it opens voltage-sensitive
calcium channels. The extracellular fluid
adjacent to the synapse has a high
concentration of calcium ions that then
flow into the terminal. The calcium ions
bind to synaptic vesicles in the free
vesicle pool, inducing these vesicles to
bind to the presynaptic membrane and
expel their contents into the synaptic
cleft. Calcium ions also bind to vesicles
that are bound to filaments, which frees
these vesicles so that they are available
for release.
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CHAPTER 5
Transmitter-activated receptor. In
the membrane of a cell, a receptor that
has a binding site for a neurotransmitter.
Transporter. A protein molecule that
pumps substances across a membrane.
Bernard Katz
(b. 1911)
transmitter-activated receptors (or just receptors, for short), because they receive the
transmitter substance. The postsynaptic cell may be affected in one of three ways, depending on the type of neurotransmitter and the kind of receptors on the postsynaptic membrane. First, the transmitter may depolarize the postsynaptic membrane and
so have an excitatory action on the postsynaptic cell; second, the transmitter may hyperpolarize the postsynaptic membrane and so have an inhibitory action on the postsynaptic cell; or, third, the transmitter may initiate other chemical reactions. The types
of receptors that mediate these three effects will be described later in this chapter.
In addition to interacting with the postsynaptic membrane’s receptors, a neurotransmitter may also interact with receptors on the presynaptic membrane. That is, it
may have an influence on the cell that just released it. The presynaptic receptors that a
neurotransmitter may activate are called autoreceptors (self-receptors) to indicate
that they receive messages from their own axon terminals.
How much neurotransmitter is needed to send a message? In the 1950s, Bernard
Katz and his colleagues provided an answer. Recording electrical activity from the
postsynaptic membranes of muscles, they detected small spontaneous depolarizations. They called these depolarizations miniature postsynaptic potentials. The potentials varied in size, but the sizes appeared to be multiples of the smallest potential.
The researchers concluded that the smallest potential is produced by releasing the
contents of just one synaptic vesicle. They called this amount of neurotransmitter a
quantum. To produce a postsynaptic potential that is large enough to propagate an
action potential requires the simultaneous release of many quanta.
The results of subsequent experiments showed that the number of quanta released from the presynaptic membrane in response to a single action potential depends on two factors: (1) the amount of Ca2+ that enters the axon terminal in response to the action potential and (2) the number of vesicles that are docked at the
membrane, waiting to be released. Keep these two factors in mind, because they will
become relevant when we consider synaptic activity during learning.
THE DEACTIVATION OF
THE NEUROTRANSMITTER
Chemical transmission would not be a very effective messenger system if a neurotransmitter lingered within the synaptic cleft, continuing to occupy and stimulate receptors.
If this happened, the postsynaptic cell could not respond to other messages sent by the
presynaptic neuron. Therefore, after a neurotransmitter has done its work, it must be
removed quickly from receptor sites and from the synaptic cleft.
This removal of a neurotransmitter is done in at least four ways. First, some of
the neurotransmitter simply diffuses away from the synaptic cleft and is no longer
available to bind to receptors. Second, the transmitter is inactivated or degraded by
enzymes that are present in the synaptic cleft. Third, the transmitter may be taken
back into the presynaptic axon terminal for subsequent reuse, or the by-products of
degradation by enzymes may be taken back into the terminal to be used again in the
cell. The protein molecule that accomplishes this reuptake is a membrane pump
called a transporter. Fourth, some neurotransmitters are taken up by neighboring
glial cells, which may contain enzymes that further degrade those transmitters. Potentially, the glial cells can also store a transmitter for reexport to the axon terminal.
Interestingly, an axon terminal has chemical mechanisms that enable it to respond to the frequency of its own use. If the terminal is very active, the amount of
neurotransmitter made and stored there increases. If the terminal is not often used,
however, enzymes located within the terminal may break down excess transmitter.
The by-products of this breakdown are then reused or excreted from the cell.
HOW DO NEURONS COMMUNICATE?
Types of Synapses
So far we have considered a generic synapse, with features that most synapses
possess. There actually is a wide range of
Dendrites
synapses, each with a relatively specialized location, structure, and function.
Figure 5-7 shows a number of different
kinds of synapses.
If you think back to Chapter 4, you
will realize that you have already encountered two different kinds of synapses. One is the kind in which the axon
terminal of a neuron ends on a dendrite
or dendritic spine of another neuron.
Cell
body
This kind of synapse, called an axodendritic synapse, is the kind shown in Figure 5-4. The other kind of synapse with
Axon
which you are already familiar is an axomuscular synapse, in which an axon
synapses with a muscle.
The other types of synapses include
Capillary
the axosomatic synapse, in which an
axon terminal ends on a cell body; the
axoaxonic synapse, in which an axon
terminal ends on another axon; and the
axosynaptic synapse, in which an axon terminal ends on another synapse—that is, a
synapse between some other axon and its target. There are also axon terminals that
have no specific targets but instead secrete their transmitter chemicals nonspecifically
into the extracellular fluid. These synapses are called axoextracellular synapses. In addition, there is the axosecretory synapse, in which an axon terminal synapses with a
tiny blood vessel called a capillary and secretes its transmitter directly into the blood.
Finally, synapses are not limited to axon terminals. Dendrites also may send messages
to other dendrites through dendrodendritic synapses.
This wide range of synaptic types makes synapses a very versatile chemical delivery system. Synapses can deliver chemical transmitters to highly specific sites or to
more diffuse locales. Through connections to the dendrites, cell body, or axon of a
neuron, chemical transmitters can directly control the actions of that neuron. Through
axosynaptic connections, they can also provide exquisite control over another neuron’s input onto a cell. And, by excreting transmitters into extracellular fluid or into
the blood, axoextracellular and axosecretory synapses can modulate the function of
large areas of tissue or even of the entire body. In fact, many of the hormones that circulate in your blood and have widespread influences on your body are transmitters
secreted by neurons.
The Evolution of a Complex Neural
Transmission System
If you consider all the biochemical steps required to get a message across a synapse, as
well as the many different kinds of synapses that exist in the body, you may wonder
why such a complex communication system ever developed. The answer must be that
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161
Dendrodendritic: Dendrites
send messages to other
dendrites.
Axodendritic: Axon terminal
of one neuron synapses on
dendritic spine of another.
Axoextracellular: Terminal
with no specific target.
Secretes transmitter into
extracellular fluid.
Axosomatic: Axon terminal
ends on cell body.
Axosynaptic: Axon terminal
ends on another terminal.
Axoaxonic: Axon terminal
ends on another axon.
Axosecretory: Axon terminal
ends on tiny blood vessel
and secretes transmitter
directly into blood.
Figure 5-7
Synapses in the central nervous system
are of various types. An axon terminal
can end on a dendrite, on another axon
terminal, on any cell body, or on an
axon. It may also end on a blood
capillary or end freely in extracellular
space. Dendrites may also make synaptic
connections with each other.
162
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CHAPTER 5
this arrangement makes up for its complexity by allowing the nervous system to be
flexible about the behavior that it produces. Puffins, after all, sometimes fish energetically and other times sit quietly to incubate an egg. These very different behaviors are
governed by the various ways in which messages sent across synapses are regulated. In
the following sections, you will see that there are also great varieties of neurotransmitters and receptor sites. They, too, add versatility to neural transmission, further increasing the flexibility of behavior.
But why chemical transmitters in this complex communication system? Why not
some other messenger with equal potential for flexibility? If you think about the behaviors of simple single-celled creatures, the start of the strategy of using chemical secretions for messages is not that hard to imagine. The first primitive cells secreted digestive juices onto bacteria to prepare them for ingestion. These digestive juices were
probably expelled from the cell body through the process of exocytosis, in which a
vacuole or vesicle attaches itself to the cell membrane and then opens into the extracellular fluid to discharge its contents. The mechanism of exocytosis for digestion parallels the use of exocytosis to release a neurotransmitter. Quite possibly the digestive
processes of a cell were long ago co-opted for processes of communication.
Visit the CD and find the area on
synaptic transmission in the Neural
Communication module. Go to the
sections on excitatory and inhibitory
synapses to learn more about type I
and type II synapses.
Figure 5-8
Type I synapses are found on the spines
and dendritic shafts of the neuron, and
type II synapses are found on the neuron’s
cell body. The structural features of type
I and type II synapses differ in the shape
of vesicles, in the density of material on
the presynaptic membrane, in cleft size,
and in the size of the postsynaptic active
zone. Type I synapses are usually
excitatory, and type II synapses inhibitory.
Dendritic
spine
Dendritic shaft
Type I
synapse
Cell body
Type II
synapse
Axon hillock
Excitatory and Inhibitory Messages
Despite all the different kinds of synapses, in the end, they convey only two types of
messages: excitatory or inhibitory. That is to say, a neurotransmitter either increases
or decreases the probability that the cell with which it comes in contact will produce
an action potential. In keeping with this dual message system, synapses can be divided
into type I and type II. Type I synapses are excitatory in their actions, whereas type II
synapses are inhibitory.
These two types of synapses vary both in location and in appearance. As shown in Figure 5-8, type I synapses are typically located on the
Large active
shafts or the spines of dendrites, whereas type II synapses are typically
zone
Wide cleft
located on a cell body. In addition, type I synapses have round synaptic
vesicles, whereas the vesicles of type II synapses are flattened. The material on the presynaptic and postsynaptic membranes is denser in a type I
synapse than it is in a type II, and the type I cleft is wider. Finally, the active zone on a type I synapse is larger than that on a type II synapse.
The different locations of type I and type II synapses divide a
neuron into two zones: an excitatory dendritic tree and an inhibitory cell body. With this arrangement, you can think of excitatory and inhibitory messages as interacting in two ways. First, you
Dense material
Round
can picture excitation coming in over the dendrites and spreading to
on membranes
vesicles
the axon hillock, where it may trigger an action potential that travels
Small active
down the length of the axon. If the message is to be stopped, it is
zones
Narrow cleft
best stopped by applying inhibition close to the axon hillock, the
origin of the action potential. This model of excitatory–inhibitory
interaction is viewed from an inhibitory perspective. Inhibition is a
blocking of excitation—essentially a “cut ’em off at the pass” strategy. Another way to conceptualize how these two kinds of messages
interact is to picture excitatory stimulation overcoming inhibition.
If the cell body is normally in an inhibited state, the only way for an
action potential to be generated at the axon hillock is for the cell
body’s inhibition to be reduced. This is an “open the gates” strategy.
Sparse material Flat vesicles
The excitatory message is like a racehorse ready to run down the
on membranes
track, but first the inhibition of the starting gate must be removed.
HOW DO NEURONS COMMUNICATE?
The English neurologist John Hughlings-Jackson recognized the role of inhibition and its removal in human neurological disorders. Many such disorders are characterized by symptoms that seem to be “released” when a normal inhibitory influence
is lost. Hughlings-Jackson termed this process “release of function.” An example is an
involuntary movement, such as a tremor, called a dyskinesia (from the Greek dys,
meaning “disordered,” and kinesia, meaning “movement”). Later in this chapter, other
examples of released behavior will be described.
■
163
John Hughlings-Jackson
(1835–1911)
In Review
Chemical transmission is the principal form of communication between neurons. When
an action potential is propagated on an axon terminal, a chemical transmitter is released
from the presynaptic membrane into the synaptic cleft. There the transmitter diffuses
across the cleft and occupies receptors on the postsynaptic membrane, after which the
transmitter is deactivated. The nervous system has evolved various kinds of synapses,
including those between axon terminals and dendrites, cell bodies, muscles, other
axons, and even other synapses, as well as those that release their chemical transmitters
into extracellular fluid or into the blood and those that connect dendrites to other dendrites. Together, these different types of synapses increase the flexibility of behaviors.
Even though synapses vary in both structure and location, they all do one of only two
things: either excite target cells or inhibit them.
Figure 5-9
The four criteria for determining
whether a chemical is a neurotransmitter
are summed up in this diagram.
THE KINDS OF NEUROTRANSMITTERS
In the 1920s, after Otto Loewi’s discovery that excitatory and inhibitory
chemicals control the heart’s rate of beating, many researchers thought
that the brain must work in much the same way. They assumed that
there must be excitatory and inhibitory brain cells and that epinephrine
and acetylcholine were the transmitters through which these neurons
worked. At that time, they could never have imagined what we know today: the human brain employs as many as 100 neurotransmitters to control our highly complex and adaptable behaviors. Although we are now certain of only about 50 1
Chemical must be
substances that act as transmitters, we are in the midst
synthesized or
of a research revolution in this field. Few scientists are
present in neuron.
willing to put an upper limit on the eventual number
of transmitters that will be found. In this section, you 2
When released,
will learn how these neurotransmitters are identified
chemical must
and examine the categories of those currently known.
produce response
in target cell.
Identifying Neurotransmitters
Chemical
Figure 5-9 shows four criteria for identifying neurotransmitters:
1. The chemical must be synthesized in the neuron
or otherwise be present in it.
2. When the neuron is active, the chemical must be
released and produce a response in some target cell.
3
Same response must be obtained
when chemical is experimentally
placed on target.
4
There must be a mechanism
for removal after chemical’s
work is done.
164
(A)
■
CHAPTER 5
3. The same response must be obtained when the chemical is experimentally placed on the target.
4. There must be a mechanism for removing the chemical from its site of action after its work is done.
By systematically applying these criteria, researchers can determine which of the many thousands of chemical moleMotor
neurons
cules that exist in every neuron is a neurotransmitter.
The criteria for identifying a neurotransmitter are
(B)
fairly easy to apply when examining the peripheral nervous
system, especially at an accessible nerve–muscle junction,
Acetylcholine
where there is only one main neurotransmitter, acetylInhibitory
choline. But identifying chemical transmitters in the ceninterneuron
(Renshaw cell)
tral nervous system is not so easy. In the brain and spinal
cord, thousands of synapses are packed around every neuron, preventing easy access to a single synapse and its acMotor neuron
+
tivities. Consequently, for many of the substances thought
to be central nervous system neurotransmitters, the four
criteria needed as proof have been met only to varying degrees. A chemical that is suspected of being a neurotrans– Renshaw
loop
mitter but has not yet been shown to meet all the criteria
for one is called a putative (supposed) transmitter.
Researchers trying to identify new CNS neurotransmitters use microelectrodes to stimulate and record from single
Axon
neurons. A glass microelectrode can be filled with the chemcollateral
ical being studied so that, when a current is passed through
Muscle
the electrode, the chemical is ejected into or onto the neuron. New staining techMain axon
niques can identify specific chemicals inside the cell. Methods have also been developed for preserving nervous system tissue in a saline bath while experiments are performed to determine how the neurons in the tissue communicate. The use of slices of
tissue simplifies the investigation by allowing the researcher to view a single neuron
through a microscope while stimulating it or recording from it.
+
Acetylcholine was the first substance identified as a neurotransmitter in the
central nervous system. This identification was greatly facilitated by a logical arguFigure 5-10
ment that predicted its presence even before experimental proof was gathered. All the
motor-neuron axons leaving the spinal cord contain acetylcholine, and each of these
The Renshaw loop is a circular set of
connections. (A) Cresyl violet–stained
axons has an axon collateral within the spinal cord that synapses on a nearby incross section of the spinal cord of a rat
terneuron that is part of the central nervous system. The interneuron, in turn,
showing the location of motor neurons
synapses back on the motor neuron’s cell body. This circular set of connections, called
that project to the muscles of the forea Renshaw loop after the researcher who first described it, is shown in Figure 5-10. Belimb. (B) A diagrammatic representation
cause the main axon to the muscle releases acetylcholine, investigators suspected that
of a motor neuron involved in a Renshaw
its axon collateral also might release acetylcholine. It seemed unlikely that two termiloop with its main axon going to a
nals of the same axon would use different transmitters. Knowing what chemical to
muscle and its axon collateral remaining
look for made it easier to find and obtain the required proof that acetylcholine was in
in the spinal cord to synapse with an
fact a neurotransmitter in this location, too. Incidentally, the loop made by the axon
interneuron there. The terminals of both
collateral and the interneuron in the spinal cord forms a feedback circuit that enables
the main axon and the collateral contain
the motor neuron to inhibit itself and not become overexcited if it receives a great
acetylcholine. The plus and minus signs
many excitatory inputs from other parts of the central nervous system. Follow the
indicate that, when the motor neuron is
highly excited, it can turn itself off
positive and negative signs in Figure 5-10 to see how the Renshaw loop works.
through the Renshaw loop.
Today the term “neurotransmitter” is used more broadly than it was when researchers first started trying to identify these chemicals. The term applies not only to
substances that carry a message from one neuron to another by influencing the volt-
HOW DO NEURONS COMMUNICATE?
age on the postsynaptic membrane, but also to chemicals that have little effect on
membrane voltage but instead induce effects such as changing the structure of a
synapse. Furthermore, not only do neurotransmitters communicate in the orthodox
fashion by delivering a message from the presynaptic side of a synapse to the postsynaptic side, but they can send messages in the opposite direction as well. To make
matters even more complex, different kinds of neurotransmitters can coexist within
the same synapse, complicating the question of what exactly each contributes in relaying a message. To find out, researchers have to apply various transmitter “cocktails” to
the postsynaptic membrane. There is the added complication that some transmitters
are gases that act so differently from a classic neurotransmitter such as acetylcholine
that it is hard to compare the two. Because neurotransmitters are so diverse and work
in such an array of ways, the definition of what a transmitter is and the criteria used
to identify one have become increasingly flexible in recent years.
■
165
Small-molecule transmitters. A class
of neurotransmitters that are manufactured
in the synapse from products derived from
the diet.
Visit the Web site to link to
current research on neurotransmitters
at www.worthpublishers.com/kolb.
Figure 5-11
This diagrammatic representation shows
how the neurotransmitter acetylcholine
is synthesized and broken down. Within
the cell, acetate combines with choline
to produce acetylcholine. The enzymes
acetyl coenzyme A (acetyl CoA) and
choline acetyltransferase (ChAT) are
catalysts in the reactions that combine
the molecules. Outside the cell, the
enzyme acetylcholinesterase (AChE)
takes the molecules apart again.
Neurotransmitter Classification
Some order can be imposed on the diversity of neurotransmitters by classifying them
into three groups on the basis of their composition: (1) small-molecule transmitters,
(2) peptide transmitters (also called neuropeptides), and (3) transmitter gases. Here
we look briefly at the major characteristics of each group and list some of the neurotransmitters that the groups include.
SMALL-MOLECULE TRANSMITTERS
The first transmitters to be identified were small-molecule transmitters, one of which is acetylcholine. As the name of this category suggests, these transmitters are made up of small molecules. Typically,
they are synthesized and packaged for use in axon terminals. When a
small-molecule transmitter has been released from an axon terminal,
it can be quickly replaced at the presynaptic membrane. Compared
with other transmitters, these transmitters act relatively quickly.
Small-molecule transmitters or their main components are derived from the food that we eat. Therefore, their level and activity in
the body can be influenced by diet. This fact is important in the design of drugs that affect the nervous system. Many of the neuroactive drugs are designed to reach the brain in the same way that
small-molecule transmitters or their precursor chemicals do.
Table 5-1 lists some of the best-known and most extensively
studied small-molecule transmitters. In addition to acetylcholine,
this list includes four amines (an amine is a chemical that contains
an amine [NH] in its chemical structure) and four amino acids. A
few other substances are sometimes also classified as small-molecule
transmitters. In the future, researchers are likely to find additional
ones as well.
Figure 5-11 illustrates how a small-molecule transmitter is made
and destroyed. The example used is acetylcholine, the transmitter
present at the junction of neurons and muscles, including the heart.
Acetylcholine is made up of two parts, choline and acetate. Choline
is a substance obtained from the breakdown of fats, such as egg
yolk, and acetate is a compound found in such substances as vinegar. One enzyme, acetyl coenzyme A (acetyl CoA), carries acetate to
the site where the transmitter is synthesized, and a second enzyme,
choline acetyltransferase (ChAT), transfers acetate to choline to
1
2
Acetyl CoA carries acetate to ChAT transfers
the transmitter synthesis site. acetate to choline…
…to form
ACh.
ChAT
Acetate
Acetyl CoA
Products
Choline
ACh
Intracellular fluid (presynaptic)
Presynaptic membrane
Synaptic cleft
AChE
Acetate
AChE
ACh
Choline
Postsynaptic membrane
Intracellular fluid (postsynaptic)
4
The products of the
breakdown can be
taken up and reused.
3
In the synaptic cleft,
AChE detaches acetate
from choline.
Table 5-1
Small-Molecule Neurotransmitters
Transmitter
Abbreviation
Acetylcholine
Amines
Dopamine
Norepinephrine
Epinephrine
Serotonin
Amino acids
Glutamate
Gamma-aminobutyric acid
Glycine
Histamine
Dopamine. A chemical neurotransmitter
released by dopamine neurons.
Glutamate. An amino acid neurotransmitter that excites neurons.
Gamma-aminobutyric acid (GABA).
An amino acid neurotransmitter that
inhibits neurons.
Neuropeptides. A class of chemical
neurotransmitters, manufactured with
instructions from the cell’s DNA; thus a
neuropeptide consists of a chain of amino
acids that act as a neurotransmitter.
Tyrosine
hydroxylase
Enzyme 1
L-Dopa
form acetylcholine (ACh). After ACh has been released into the synaptic cleft and diffuses to receptor sites on the postsynaptic membrane, a
ACh
third enzyme, called acetylcholinesterase (AChE), reverses the process
of synthesis, detaching acetate from choline. The products of the
DA
breakdown can then be taken back into the axon terminal for reuse.
NE
Some of the amines and amino acids included in Table 5-1 are synthesized by the same biochemical pathway and so are considered related
EP
to one another. They are grouped together in Table 5-1. One such group5-HT
ing consists of the amines dopamine, norepinephrine, and epinephrine
(which, as you already know, is the excitatory transmitter at the heart).
Figure 5-12 shows that epinephrine is the third transmitter produced by
Glu
a single biochemical sequence. The precursor chemical is tyrosine, an
GABA
amino acid that is abundant in food. The enzyme tyrosine hydroxylase
Gly
changes tyrosine into L-dopa, which is sequentially converted by other
H
enzymes into dopamine, norepinephrine, and, finally, epinephrine.
An interesting fact about this biochemical sequence is that the enzyme tyrosine
hydroxylase is in limited supply; consequently, so is the rate at which dopamine, norepinephrine, and epinephrine can be produced, regardless of how much tyrosine is
present or ingested. This rate-limiting factor can be bypassed by orally ingesting Ldopa, which is why L-dopa is a medication used in the treatment of Parkinson’s disease, as described in “Awakening with L-Dopa” on page 168.
Two of the amino acid transmitters, glutamate and gamma-aminobutyric acid
(GABA), also are closely related, because GABA is formed by a simple modification of
glutamate, as shown in Figure 5-13. These two transmitters are considered the workhorses of the nervous system because so
COOH
many synapses use them. In the forebrain and
COOH
cerebellum, glutamate is the main excitatory
CH2
transmitter and GABA is the main inhibitory
CH2
CH2
transmitter. (The amino acid glycine is a
CH2
much more common inhibitory transmitter
H2N
CH
in the brainstem and spinal cord). InterestH2N
CH
ingly, glutamate is widely distributed in neuCOOH
rons, but it becomes a neurotransmitter only
Glutamate
GABA
if it is appropriately packaged in vesicles in
the axon terminal.
Enzyme 2
PEPTIDE TRANSMITTERS
Dopamine
Enzyme 3
Norepinephrine
Enzyme 4
Epinephrine
Figure 5-12
A single biochemical sequence produces
three of the classical neurotransmitters—
dopamine, norepinephrine, and
epinephrine. A different enzyme (1–4) is
responsible for each synthetic step.
Figure 5-13
Glutamate, the major excitatory
neurotransmitter in the brain, and
GABA, the major inhibitory
neurotransmitter in the brain, are
related. The removal of the carboxyl
(COOH) group from glutamate produces
GABA. The space-filling models of the
two neurotransmitters show that their
shapes are different, thus allowing them
to bind to different receptors.
More than 50 short chains of amino acids
form the families of the neuropeptide transmitters listed in Table 5-2. As you learned in
Chapter 3, amino acid chains are connected
by peptide bonds, which accounts for the name
of this class of neurotransmitters. Neuropeptide transmitters are made from instructions contained in the cell’s DNA. Although
in some neurons these transmitters are made
in the axon terminal, most are assembled on
the neuron’s ribosomes, packaged in a membrane by Golgi bodies, and transported by
the microtubules to the axon terminals. The
entire process of synthesis and transport is
relatively slow, compared with that of other
HOW DO NEURONS COMMUNICATE?
■
167
types of nerotransmitters. Consequently, these transmitters
Table 5-2 Peptide Neurotransmitters
are not replaced quickly.
Family
Example
Peptides have an enormous range of functions in the nerOpioids
Enkephaline, dynorphin
vous system, as might be expected from the large number of
them that exist there. Peptides serve as hormones, are active in
Neurohypophyseals
Vasopressin, oxytocin
responses to stress, have a role in allowing a mother to bond to
Secretins
Gastric inhibitory peptide,
her infant, probably contribute to learning, help to regulate
growth-hormone-releasing peptide
eating and drinking, and help to regulate pleasure and pain.
Insulins
Insulin, insulin growth factors
For example, opium, obtained from seeds of the poppy flower,
Gastrins
Gastrin, cholecystokinin
has long been known to produce both euphoria and pain reSomatostatins
Pancreatic polypeptides
duction. Opium and its related synthetic chemicals, such as
morphine, appear to mimic the actions of three peptides: metenkephalin, leu-enkephalin, and beta-endorphin. (The term enkephalin derives from
Met-enkephalin
the phrase “in the cephalon,” meaning “in the brain or head,” whereas the term endorTyr Gly Gly Phe Met
phin is a shortened form of “endogenous morphine.”) A part of the amino acid chain in
Leu-enkephalin
each of these three peptide transmitters is structurally similar to the others, as shown in
Tyr Gly Gly Phe Leu
Figure 5-14. Presumably, opium mimics this part of the chain. The discovery of these
naturally occurring opium-like peptides suggested that one or more of them might take
part in the management of pain. Opioid peptides, however, appear to have a number of
Figure 5-14
locations and functions in the brain, so they may not be just pain-specific transmitters.
Chains of amino acids that act as neuroUnlike small-molecule transmitters, peptide transmitters do not bind to ion chantransmitters are called neuropeptides.
nels, so they have no direct effects on the voltage of the postsynaptic membrane. Instead,
The ones above are similar in structure;
peptide transmitters activate receptors that indirectly influence cell structure and functheir function is mimicked by opium.
tion. Because peptides are amino acid chains that are degraded by digestive processes,
they generally cannot be taken orally as drugs, as the small-molecule transmitters can.
TRANSMITTER GASES
Nitric oxide (NO). A gas that acts as a
The gases nitric oxide (NO) and carbon monoxide (CO) are the most unusual neurochemical neurotransmitter in many cells.
transmitters identified. As soluble gases, they are neither stored in nor released from
synaptic vesicles; instead, they are synthesized as needed. After synTransmitter binds
The pore opens, allowing the
thesis, each gas diffuses away from the site at which it was made, easto the binding site.
influx or efflux of ions.
ily crossing the cell membrane and immediately becoming active.
Nitric oxide is a particularly important neurotransmitter be- Extracellular
Ion
Transmitter
cause it serves as a messenger in many parts of the body. It controls fluid
Binding site
the muscles in intestinal walls, and it dilates blood vessels in brain regions that are in active use (allowing these regions to receive more
blood). Because it also dilates blood vessels in the sexual organs, NO
is active in producing penile erections. Unlike classical neurotransmitters, nitric oxide is produced in many regions of a neuron, inIntracellular
Pore
Pore
cluding the dendrites.
fluid
closed
open
The Types of Receptors for Neurotransmitters
Figure 5-15
When a neurotransmitter is released from a synapse, it crosses the synaptic cleft and
binds to a receptor. What happens next depends on the kind of receptor. There are
two general classes of receptors: ionotropic receptors and metabotropic receptors.
Each has a different effect on the postsynaptic membrane.
Ionotropic receptors allow the movement of ions across a membrane (the suffix
tropic in the word ionotropic means “to move toward”). As Figure 5-15 illustrates, an
ionotropic receptor has two parts: (1) a binding site for a neurotransmitter and (2) a
pore or channel. When the neurotransmitter attaches to the binding site, the receptor
Ionotropic receptors are proteins that
consist of two functional parts: a binding
site and a pore. When a transmitter
binds to the binding site, the shape of
the receptor changes, either opening the
pore or closing it. In the example shown
here, when the transmitter binds to the
binding site, the pore opens and ions are
able to flow through it.
168
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CHAPTER 5
Awakening with L-Dopa
Focus on Disorders
He was started on L-dopa in March 1969. The
The use of L-dopa to treat Parkinson’s disease began in
dose was slowly raised to 4.0 mg a day over a
1961, when two groups of investigators led by O. Horny-
period of three weeks without apparently pro-
kiewicz and A. Barbeau quite independently tried giving it to
ducing any effect. I first discovered that Mr. E.
Parkinson patients. They knew that L-dopa is a chemical that is
was responding to L-dopa by accident, chanc-
turned into dopamine at dopamine synapses, but they did not
ing to go past his room at an unaccustomed
know if it could relieve the symptoms of Parkinsonism. The
time and hearing regular footsteps inside the
L-dopa
room. I went in and found Mr. E., who had
muscular rigidity that the patients suffered, although it did not
been chair bound since 1966, walking up and
relieve their tremors. Since then, L-dopa has become a stan-
down his room, swinging his arms with con-
dard treatment for Parkinson’s disease. Its effects have been im-
siderable vigor, and showing erectness of pos-
proved by administering drugs that prevent L-dopa from being
ture and a brightness of expression completely
broken down before it gets to dopamine neurons in the brain.
new to him. When I asked him about the
turned out to have a dramatic effect in reducing the
L-Dopa
is not a cure for Parkinson’s disease. The disor-
effect, he said with some embarrassment:
der still progresses during treatment. As more and more
“Yes! I felt the L-dopa beginning to work three
dopamine synapses are lost, the treatment becomes less
days ago—it was like a wave of energy and
and less effective and eventually begins to produce invol-
strength sweeping through me. I found I could
untary movements called dyskinesia. When these side ef-
stand and walk by myself, and that I could do
fects eventually become severe, the L-dopa treatment must
everything I needed for myself—but I was
be discontinued.
Everett Collection, Inc.
afraid that you would see how well I was and
discharge me from the hospital.” (Sacks, 1976)
In this case history, neurologist Oliver Sacks describes
administering L-dopa to a patient who had acquired Parkinson’s disease as a result of getting severe influenza in the
1920s. This form of the disorder is called postencephalitic
Parkinsonism. The relation between the influenza and symptoms of Parkinsonism suggests that the flu virus entered the
brain and selectively attacked dopamine neurons in the substantia nigra. L-Dopa, by being able to increase the amount
of dopamine in remaining dopamine synapses, was able to
relieve the patient’s symptoms.
Ionotropic receptor. A receptor that has
two parts: a binding site for a neurotransmitter and a pore that regulates ion flow.
Metabotropic receptor. This receptor is
linked to a G protein and can affect other
receptors or act with second messengers
to affect other cellular processes.
The movie Awakenings gives a very accurate rendition of
the L-dopa trials conducted by Oliver Sacks and described in
his book of the same title.
changes its shape, either opening the pore and allowing ions to flow through it or
closing the pore and blocking the flow of ions. Because the binding of the transmitter
to the receptor is quickly followed by a single step (the opening or closing of the
receptor pore) that affects the flow of ions, ionotropic receptors bring about very
rapid changes in membrane voltage.
Structurally, ionotropic receptors are similar to voltage-sensitive channels, discussed
in Chapter 4. They are composed of a number of membrane-spanning subunits that
HOW DO NEURONS COMMUNICATE?
(A) Metabotropic receptor coupled to an ion channel
Transmitter
Ion
Binding site
Transmitter
Transmitter binds to
receptor in both
types of reaction.
Binding site
Receptor
β
γ
α
γ
α
Closed ion
channel
G protein
G protein
Receptor-bound
transmitter
β
169
(B) Metabotropic receptor coupled to an enzyme
Receptor
β
■
Enzyme
Receptor-bound
transmitter
The binding of the
transmitter triggers
activation of G protein
in both types of reactions.
γ
α
β
γ
α
The alpha-subunit of the G
protein binds to a channel,
causing a structural change
in the channel that allows
ions to pass through.
β
γ
Alpha-subunit
α
Open ion
channel
The alpha-subunit binds to
an enzyme, which activates
a second messenger.
β
γ
α
Alpha-subunit
Second messenger
The second messenger can
activate other cell processes.
form petals around the pore, which lies in the center. Within the pore is a
shape-changing segment that allows the pore to open or close, which regulates the flow of ions through the pore.
In contrast with an ionotropic receptor, a metabotropic receptor
lacks its own pore through which ions can flow, although it does have a
binding site for a neurotransmitter. Through a series of steps, metabotropic receptors produce changes in nearby ion channels or they bring
about changes in the cell’s metabolic activity (that is, in activity that requires an expenditure of energy, which is what the term metabolic means).
Figure 5-16A shows the first of these two effects. The metabotropic
receptor consists of a single protein, which spans the cell membrane.
The receptor is associated with one of a family of proteins called guanyl
nucleotide-binding proteins, or G proteins for short. A G protein consists of three subunits: alpha, beta, and gamma. The alpha-subunit
Activates
DNA
Activates
ion channel
Figure 5-16
(A) A metabotropic receptor coupled to an ion channel has a
binding site and an attached G protein. When a neurotransmitter binds to the binding site, the alpha-subunit of
the G protein detaches from the receptor and attaches to the
ion channel. In response the channel changes its
conformation, allowing ions to flow through its pore. (B) A
metabotropic receptor coupled to an enzyme also has a
binding site and an attached G protein. When a
neurotransmitter binds to the binding site, the alpha-subunit
of the G protein detaches and attaches to the enzyme. The
enzyme in turn activates a compound called a second
messenger. The second messenger, through a series of
biochemical steps, can activate ion channels or activate other
cell processes, including the production of new proteins.
170
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CHAPTER 5
Second messenger. A chemical that is
activated by a neurotransmitter (the first
messenger) and carries a message to initiate some biochemical process.
Click on your CD and find the section
on the membrane potential in the module
on Neural Communication. Review ionic
flow across the cell membrane. Imagine
this flow being associated with ionotropic
receptor stimulation to induce action
potentials and neural signals.
detaches from the other two subunits when a neurotransmitter binds to the G protein’s associated metabotropic receptor. The detached alpha-subunit can then bind to
other proteins within the cell membrane or within the cytoplasm of the cell. If the alpha-subunit binds to a nearby ion channel in the membrane, the structure of the
channel changes, modifying the flow of ions through it. If the channel is already open,
it may be closed by the alpha-subunit or, if already closed, it may become open. This
change in the channel and the flow of ions across the membrane influence the membrane’s electrical potential.
The binding of a neurotransmitter to a metabotropic receptor can also trigger
other cellular reactions that are more complicated than the one shown in Figure
5-16A. These other reactions are summarized in Figure 5-16B. They all begin when
the detached alpha-subunit binds to an enzyme, which in turn activates another
chemical called a second messenger (the neurotransmitter is the first messenger). A
second messenger, as the name implies, carries a message to other structures within
the cell. It can bind to a membrane channel, causing the channel to change its structure and thus alter ion flow through the membrane. It can initiate a reaction that
causes protein molecules within the cell to become incorporated into the cell membrane, resulting in the formation of new ion channels; or it can send a message to the
cell’s DNA instructing it to initiate the production of a new protein.
No one neurotransmitter is associated with a single kind of receptor or a single
kind of influence on the postsynaptic cell. At one location, a particular transmitter
may bind to an ionotropic receptor and have an excitatory effect on the target cell. At
another location, the same transmitter may bind to a metabotropic receptor and have
an inhibitory effect. For example, acetylcholine has an excitatory effect on skeletal
muscles, where it activates an ionotropic receptor, but it has an inhibitory effect on
the heart, where it activates a metabotropic receptor. In addition, each transmitter
may bind with a number of different kinds of ionotropic or metabotropic receptors.
Elsewhere in the nervous system, acetylcholine, for example, may activate a variety of
either type of receptor.
In Review
The three main classes of neurotransmitters are: small-molecule transmitters, peptide
transmitters, and transmitter gases. Each class of transmitter is associated with ionotropic
(excitatory) and metabotropic (mainly inhibitory) receptors. An ionotropic receptor contains a pore or channel that can be opened or closed to regulate the flow of ions through
it. This, in turn, brings about voltage changes on the cell membrane. Metabotropic receptors activate second messengers to indirectly produce changes in the function and structure of the cell. The more than 100 neurotransmitters used in the nervous system are
each associated with many different ionotropic and metabotropic receptors.
NEUROTRANSMITTER SYSTEMS
When researchers began to study neurotransmitters, they thought that any given neuron would contain only one transmitter at all its axon terminals. This belief was called
Dale’s law, after its originator. New methods of staining neurochemicals, however,
have revealed that Dale’s law is an oversimplification. A single neuron may use one
transmitter at one synapse and a different transmitter at another synapse, as David
HOW DO NEURONS COMMUNICATE?
Sulzer (1998) and his coworkers have shown. Moreover, different transmitters may
coexist in the same terminal or in the same synapse. For example, peptides have been
found to coexist in terminals with small-molecule transmitters, and more than one
small-molecule transmitter may be found in a single synapse. In some cases, more
than one transmitter may even be packaged within a single vesicle.
All this complexity makes for a bewildering number of combinations of neurotransmitters and the receptors for them. What are the functions of so many combinations? We do not have a complete answer. Very likely, however, this large number of
combinations is critically related to the many different kinds of behavior of which humans are capable.
Fortunately, the complexity of neurotransmission can be simplified by concentrating on the dominant transmitter located within any given axon terminal. The neuron and its dominant transmitter can then be related to a behavioral function. In this
section, we consider some of the links between neurotransmitters and behavior. We
begin by exploring the two parts of the peripheral nervous system: the skeletal motor
system and the autonomic system. Afterward, we investigate neurotransmission in the
central nervous system.
Neurotransmission in the Skeletal Motor System
The brain and spinal cord contain neurons that send their axons to the body’s
skeletal muscles (the muscles attached to bones). These muscles include those of the
eyes and face, the trunk, the limbs, and the fingers and toes. The neurons of the skeletal motor system are sometimes referred to as the final common path for movement
because, without them, movement would not be possible. These neurons are also
called cholinergic neurons because acetylcholine is their main neurotransmitter. (The
term cholinergic applies to any neuron that uses acetylcholine as its main transmitter.)
At a muscle, cholinergic neurons are excitatory and produce muscular contractions.
Not only does a single neurotransmitter serve as the workhorse for the skeletal
motor system, so does a single kind of receptor. The receptor on all skeletal muscles is
an ionotropic, transmitter-activated channel called a nicotinic ACh receptor (nAChr).
When ACh binds to this receptor, the receptor’s pore opens to permit ion flow, thus
depolarizing the muscle fiber. The pore of a nicotinic receptor is large and permits the
simultaneous efflux of potassium ions and influx of sodium ions. Nicotine, a chemical contained in cigarette smoke, activates a nicotinic ACh receptor in the same way
that ACh does, which is how this type of receptor got its name. In other words, the
molecular structure of nicotine is sufficiently similar to that of acetylcholine that
nicotine fits into an acetylcholine receptor “slot.”
Although acetylcholine is the primary neurotransmitter at skeletal muscles, other
neurotransmitters also are found in these cholinergic axon terminals and are released
onto the muscle along with acetylcholine. One of these other transmitters is a neuropeptide called calcitonin-gene-related peptide (CGRP), which acts through second
messengers to increase the force with which a muscle contracts.
Neurotransmission in the Autonomic
Nervous System
In Chapter 2, you learned that the autonomic nervous system has two divisions: the
sympathetic and the parasympathetic (see Figure 2-29). They work in complementary
fashion to regulate the body’s internal environment, preparing it for action or calming
it down. The sympathetic division is responsible for producing what is called the
■
171
Cholinergic neuron. A neuron that contains acetylcholine in its synapses.
172
■
CHAPTER 5
Figure 5-17
The autonomic nervous system is made
up of the sympathetic division, which
prepares the body for fight or flight,
and the parasympathetic system, which
prepares the body to rest and digest.
All the neurons leaving the spinal cord
have acetylcholine as a neurotransmitter.
In the sympathetic system, these
acetylcholine neurons activate
epinephrine neurons, which turn on
organs required for fight or flight and
turn off organs used to rest and digest.
In the parasympathetic nervous system,
the acetylcholine neurons of the spinal
cord activate other acetylcholine
neurons, which turn off organs used for
fight or flight and turn on organs used
to rest and digest.
Adrenergic neuron. A neuron containing epinephrine; the term adrenergic derives from the term adrenaline.
Sympathetic division
“fight or flight”
KEY
Acetylcholine
Epinephrine
Parasympathetic division
“rest and digest”
fight-or-flight response. In this response, heart rate is turned up, digestive functions are
turned down, and the body is made ready to run away or to fight. The parasympathetic division is responsible for producing an essentially opposite reaction called the
rest-and-digest response. Here digestive functions are turned up, heart rate is turned
down, and the body is made ready to lie back and digest dinner.
Figure 5-17 shows the neurochemical organization of the autonomic nervous
system’s sympathetic and parasympathetic divisions. The parasympathetic neurons
are cholinergic, whereas the sympathetic neurons are adrenergic, meaning that they
contain the chemical transmitter adrenaline, which is another name for epinephrine.
Cholinergic neurons in the spinal cord, in turn, control both the sympathetic and
the parasympathetic neurons. In other words, cholinergic neurons in the spinal cord
synapse with adrenergic neurons to prepare the body’s organs for fight or flight;
they also synapse with other cholinergic neurons to prepare the body’s organs to rest
and digest.
Whether cholinergic synapses or andrenergic synapses are excitatory or inhibitory on a particular body organ depends on the receptors of that organ. Epinephrine
turns up heart rate and turns down digestive functions because its receptors on the
heart and the digestive organs are different. Epinephrine receptors on the heart are
excitatory, whereas epinephrine receptors on the gut are inhibitory. Similarly, acetylcholine turns down heart rate and turns up digestive functions because its receptors
on these organs are different. Acetylcholine receptors on the heart are inhibitory,
whereas those on the gut are excitatory. The ability of neurotransmitters to be excitatory in one location and inhibitory in another allows the sympathetic and parasympathetic divisions to form a complementary system for regulating the body’s internal
environment.
HOW DO NEURONS COMMUNICATE?
Neurotransmission in the Central Nervous System
Some neurotransmitters in the central nervous system have very specific functions.
For instance, a variety of chemical transmitters specifically prepare female white-tail
deer for the fall mating season. Then, come winter, a different set of biochemicals
takes on the new specific function of facilitating the development of the fetus in the
mother deer. The mother gives birth in the spring and is subjected to yet another set
of biochemicals with highly specific functions, such as the chemical influence that enables her to recognize her own fawn and another one that enables her to nurse. The
transmitters in these very specific functions are usually neuropeptides.
In contrast, other neurotransmitters in the central nervous system have more
general functions, helping an organism carry out routine daily tasks. These more
general functions are mainly the work of small-molecule transmitters. For example,
the small-molecule transmitters GABA and glutamate are the most common neurotransmitters in the brain, with GABA having an inhibitory effect and glutamate an
excitatory one.
In addition, each of four small-molecule transmitters—acetylcholine, dopamine, norepinephrine, and serotonin—participates in its own general system, the
purpose of which seems to be to ensure that neurons in wide areas of the brain act
in concert by being stimulated with the same neurotransmitter. For example,
Figure 5-18 shows a cross section of a rat brain that is stained for the enzyme
acetylcholinesterase, which breaks down ACh. The darkly stained areas of the neocortex have high acetylcholinesterase concentrations, indicating the presence of
cholinergic terminals. These terminals, which are clearly located throughout the
neocortex, belong to neurons that are clustered in a rather small area just in front of
the hypothalamus. There also are high concentrations of ACh in the basal ganglia
and basal forebrain, which renders these structures very dark in Figure 5-18.
An anatomical organization such as this one, in which a few neurons send axons to
widespread brain regions, suggests that these neurons play a role in synchronizing
activity throughout the brain. These general-purpose systems are commonly called
ascending activating systems. They can be envisioned as something like the power
supply to a house, in which a branch of the power line goes to each room of the
house but the electrical appliance powered in each room differs, depending on
the room.
Referred to by the transmitters that their neurons contain, the four ascending
activating systems are the cholinergic, dopaminergic, noradrenergic, and serotonergic
Neocortex
Basal ganglia
Basal ganglia
Acetylcholine
synapses
Basal forebrain
neurons
■
173
Ascending activating system. A group
of neurons, each of which contains a
common neurotransmitter, that have their
cell bodies located in a nucleus in the basal
forebrain or brainstem and their axons
distributed to a wide region of the brain.
CNS: The brain
and spinal cord.
PNS: Neurons outside
the brain and spinal cord.
Figure 5-18
This micrograph shows the localization
of acetylcholinesterase, the enzyme that
breaks down acetylcholine, in the brain
of a rat. The drawing (left) shows the
location at which the transverse section
(right) was taken. The cholinergic neurons
of the basal forebrain are located in the
lower part of the section, adjacent to
the two white circles, which comprise
fibers in the anterior commissure. The
basal forebrain neurons project to the
neocortex, and the darkly stained bands
in the cortex show areas that are rich in
cholinergic synapses. The dark central
parts of the section are the basal ganglia,
which also are rich in cholinergic neurons.
■
174
CHAPTER 5
Cholinergic system
(acetylcholine): Active in
maintaining waking electroencephalographic (EEG) patterns of
the neocortex. Thought to play a
role in memory by maintaining
neuron excitability. Death of
acetylcholine neurons and
decrease in acetylcholine in the
neocortex are thought to be
related to Alzheimer’s disease.
Basal
forebrain
nuclei
Midbrain nuclei
Frontal
cortex
Corpus
callosum
Caudate nucleus
Substantia nigra
Thalamus
Dopaminergic system
(dopamine): Active in maintaining
normal motor behavior. Loss of
dopamine is related to Parkinson’s
disease, in which muscles are rigid
and movements are difficult to
make. Increases in dopamine
activity may be related to
schizophrenia.
Cerebellum
Noradrenergenic system
(norepinephrine): Active in
maintaining emotional tone.
Decreases in norepinephrine
activity are thought to be related
to depression, whereas increases
in it are thought to be related to
mania (overexcited behavior).
Locus coeruleus
Serotonergic system
(serotonin): Active in maintaining
waking EEG patterns. Increases in
serotonin activity are related to
obsessive-compulsive disorder,
tics, and schizophrenia. Decreases
in serotonin activity are related
to depression.
Raphé nuclei
Figure 5-19
For all four major nonspecific ascending systems, the cell bodies are located in
nuclei (large round circles) in the brainstem. The axons of these neurons project
diffusely to the forebrain, cerebellum, and spinal cord, where they synapse with
most neurons of the target structure. Each system has been associated with one
or more behaviors or nervous system diseases.
systems. Figure 5-19 shows the location of neurons in
each of these four systems, with arrow shafts indicating the pathways of axons and arrow tips indicating
axon terminals. The four ascending activating systems
are similarly organized in that the cell bodies of their
neurons are clustered together in only a few nuclei in
or near the brainstem, whereas the axons of the neurons are widely distributed in the forebrain, brainstem, and spinal cord.
Figure 5-19 summarizes the behavioral functions
as well as the brain disorders in which each of the four
ascending activating systems has been implicated. The
ascending cholinergic system contributes to the EEG
activity of the cortex and hippocampus in an alert,
mentally active person, and so seems to play a role in
normal wakeful behavior. People who suffer from
Alzheimer’s disease, which starts with minor forgetfulness and progresses to major memory dysfunction,
show a loss of these cholinergic neurons at autopsy.
One treatment strategy currently being pursued for
Alzheimer’s is to develop drugs that stimulate the
cholinergic system to enhance behavioral alertness. The
brain abnormalities associated with Alzheimer’s disease
are not limited to the cholinergic neurons, however.
There is also extensive damage to the neocortex and
other brain regions. As a result, it is not yet clear what
role the cholinergic neurons play in the progress of
the disorder. Perhaps their death causes degeneration in
the cortex or perhaps the cause-and-effect relation is
the other way around, with cortical degeneration being
the cause of cholinergic cell death. Then, too, it may be
that the loss of cholinergic neurons is just one of many
neural symptoms of Alzheimer’s disease.
One function of the ascending dopaminergic system is involvement in motor behavior. If dopamine
neurons in the brain are lost, the result is a condition of
extreme rigidity, in which opposing muscles are contracted, making it difficult for an affected person to
move. Patients also show rhythmic tremors of the limbs.
This condition, called Parkinson’s disease, is discussed in
“Focus on Disorders” throughout this chapter. Although
Parkinson’s disease usually arises for no known cause, it
can also be triggered by the ingestion of certain drugs,
as described in “The Case of the Frozen Addict” on page
175. Those drugs may act as selective poisons, or neurotoxins, that kill the dopamine neurons. Another function of the dopaminergic system is involvement in reward or pleasure, inasmuch as many drugs that people
abuse seem to act by stimulating this system. In addition, this system has a role in a condition called schizophrenia, one of the most common and debilitating psychiatric disorders. One explanation of schizophrenia is
that the dopaminergic system is overactive.
HOW DO NEURONS COMMUNICATE?
■
175
The Case of the Frozen Addict
jection of MPTP into monkeys produced symptoms similar
a 42-year-old man used 4 ⁄2 grams of a “new
to those produced in humans and a similar selective loss of
synthetic heroin.” The substance was injected
dopamine neurons in the substantia nigra. Thus, the com-
intravenously three or four times daily and
bined clinical and experimental evidence indicates that
caused a burning sensation at the site of injec-
Parkinson’s disease can be induced by a toxin that selec-
tion. The immediate effects were different from
tively kills dopamine neurons in this part of the brain.
1
heroin, producing an unusual “spacey” high as
Is there any hope of a cure for this selective cell destruc-
well as transient visual distortions and halluci-
tion? In 1988, Patient 1 was taken to University Hospital in
nations. Two days after the final injection, he
Lund, Sweden, to receive an experimental treatment. The
awoke to find that he was “frozen” and could
treatment consisted of implanting into the caudate and puta-
move only in “slow motion.” He had to “think
men of his brain dopamine neurons taken from human fetal
through each movement” to carry it out. He
brains. Extensive work with rodents and nonhuman primates
was described as stiff, slow, nearly mute, and
had demonstrated that fetal neurons, which have not yet de-
catatonic during repeated emergency room
veloped dendrites and axons, can survive transplantation
visits from July 9 to July 11. He was admitted
and grow into mature neurons that can secrete neurotrans-
to a psychiatric service on July 15, 1982, with
mitters. The patient had no serious postoperative complica-
a diagnosis of “catatonic schizophrenia” and
tions. Twenty-four months after the surgery, he was much
was transferred to our neurobehavioral unit the
improved and could function much more independently. He
next day. (Ballard et al., 1985, p. 949)
could dress and feed himself, visit the bathroom with help,
This patient was one of seven young adults who were hospitalized at about the same time in California. All the patients
showed symptoms of severe Parkinson’s disease, which is extremely unusual in people their age. The symptoms, which had
and make trips outside his home. He also responded much
better to the medication that he received. The transplantation
of fetal neurons to treat Parkinson’s disease continues to be
an area of active research.
appeared very suddenly after drug injection, were similar to
Dr. Hakan Widner, M.D., PhD.,
Lord University, Sweden
Focus on Disorders
Patient 1: During the first 4 days of July 1982,
those displayed by patients who have had Parkinson’s disease
for many years. All appeared to have injected a synthetic heroin
that was being sold on the streets in the summer of 1982. What
was the link between the heroin and the Parkinson’s symptoms?
An investigation by J. William Langston and his colleagues (1992) found that the heroin contained a contaminant called MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). The contaminant resulted from poor preparation of
the heroin during its synthesis. The results of experimental
studies in rodents showed that MPTP was not itself responsible for the patients’ symptoms, but it was metabolized into
MPP+ (1-methyl-4-phenylpyridinium), which is a neurotoxin.
In one autopsy of a suspected case of MPTP poisoning, the
victim suffered a selective loss of dopamine neurons in the
substantia nigra, with the rest of the brain being normal. In-
Positron emission tomographic images of Patient 1’s brain
comparing levels of fluoro-dopa (a weakly radioactive form
of L-dopa) before the implantation of fetal dopamine
neurons (left) and 12 months after this operation (right).
The increased size of the red and gold area indicates that
transplanted dopamine neurons are present and producing
dopamine in the patient’s brain.
From “Bilateral Fetal Mesencephalic Grafting in Two Patients with
Parkinsonism Induced by 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyradine
(MPTP),” by H. Widner, J. Tetrud, S. Rehngrona, B. Snow, P. Brundin,
B. Gustavii, A. Bjorklund, O. Lindvall, and W. J. Langston, 1992, New
England Journal of Medicine, 327, p. 151.
176
■
CHAPTER 5
Learn more about Parkinson’s disease
at the Web site (www.worthpublishers.
com/kolb/chapter5) with links to current
research and foundations devoted to
investigating this disorder.
Behaviors and disorders related to the noradrenergic ascending system have been
very difficult to identify. Some of the symptoms of depression may be related to decreases in the activity of noradrenergic neurons, whereas some of the symptoms of
manic behavior (excessive excitability) may be related to increases in the activity of
these same neurons.
The serotonergic ascending system has a role in producing a waking EEG in the
forebrain, as does the cholinergic system. But behavioral functions for serotonin
are not well understood. It may be that some of the symptoms of depression are related to decreases in the activity of serotonin neurons. Consequently, there may be
two forms of depression, one related to norepinephrine and the other related to serotonin. Some research suggests that some of the symptoms of schizophrenia also may
be related to serotonin, which, again, implies that there may be different forms of
schizophrenia.
In Review
Although axon terminals can contain more than one kind of neurotransmitter, neurons
are usually identified by the principal neurotransmitter in their terminals. Many neurotransmitters take part in rather specific behaviors that may occur only once each month
or year, whereas other neurotransmitters take part in behavioral functions that occur continuously. Neurons containing a specific neurotransmitter may be organized into functional systems that mediate some aspect of behavior. For instance, acetylcholine is the
main neurotransmitter in the skeletal motor system, and acetylcholine and epinephrine
are the main neurotransmitters in the autonomic system. The central nervous system contains not only widely dispersed glutamate (excitatory) and GABA (inhibitory) neurons,
but also systems of neurons that have acetylcholine, norepinephrine, dopamine, or serotonin as their neurotransmitter. These systems are associated both with specific aspects of
behavior and with specific kinds of neurological disorders.
THE ROLE OF SYNAPSES IN LEARNING AND MEMORY
Donald O. Hebb
(1904–1985)
Clearly, synapses are very versatile in structure and function, but are they also capable
of change? The question of change asks about the plasticity of synapses. Can the experiences that an organism has as it functions in the world bring about long-lasting alterations in synapses? If such change is possible, synapses provide a potential site for
the neural processes of learning. After all, learning is usually defined as a relatively
permanent change in behavior as a result of experience. That change in behavior
must somehow be linked to a change in the structure and function of the nervous system. Does the synapse lie at the heart of this nervous system change?
In 1949, Donald O. Hebb, in his book titled The Organization of Behavior, suggested that learning is mediated by structural changes in synapses. He was not the first
person to make this suggestion, but the change that he envisioned was novel. According to Hebb, “When an axon of cell A is near enough to excite a cell B and repeatedly
or persistently takes part in firing it, some growth process or metabolic change takes
place in one or both cells such that A’s efficiency, as one of the cells firing B, is increased” (Hebb, 1949, p. 62).
When Hebb proposed this idea, there were no methods available to test it. But
through the years, as such methods have been developed, Hebb’s proposal has been
HOW DO NEURONS COMMUNICATE?
supported. Learning does often require the joint firing of two neurons, which increases the efficiency with which their synapse functions. This increased efficiency
provides the structural basis for new behavior. A synapse that undergoes this kind of
change is commonly called a Hebb synapse.
In the following sections, you will discover that synapses are capable of change
and mediate a number of different kinds of learning, including habituation, sensitization, and associative learning. We will explore three different ways that synapses can
be altered in response to an organism’s experiences. First, they can change in the release of a neurotransmitter; second, they can grow new synaptic connections; and,
third, they can modify their structures. We will also see that channels and receptors,
structures critical to the action potential and neurotransmitter release, can also participate in learning.
■
Hebb synapse. A synapse that can
change with use so that learning takes
place.
Habituation. A form of learning in
which a response to a stimulus weakens
with repeated stimulus presentations.
NEUROTRANSMITTER RELEASE AND HABITUATION
Habituation is a simple form of learning in which the strength of a response to a certain stimulus becomes weaker with repeated presentations of that stimulus. For example, if you are accustomed to living in the country and then move to a city, you might
at first find the sounds of traffic and people extremely loud and annoying. With time,
however, you stop noticing most of the noise. You have habituated to it. Similar habituation develops with our other senses. When you first put on an item of clothing,
such as a shoe, you “feel” it on your body, but very shortly it is as if the shoe is no
longer there. The reason? Habituation. You have not become insensitive to sensations,
however. When people talk to you on a city street, you still hear them; when someone
steps on your foot, you still feel the pressure. It is the customary, “background” sensations that your brain has learned to screen out.
Aplysia also displays habituation. One example is habituation to waves in the
shallow tidal zone in which it lives. These snails are constantly buffeted by the flow
of waves against their bodies, and they learn that waves are just the background
“noise” of daily life. They do not flinch and withdraw every time a wave passes over
them. They habituate to this stimulus. But a sea snail that is habituated to waves is
not insensitive to other touch sensations. If the snail is touched with a novel object,
it responds by withdrawing its siphon and gill. The animal’s reaction to repeated
presentations of the same novel stimulus forms the basis for studying its habituation response.
Jeff Rotman
Learning and Changes in
Neurotransmitter Release
The marine snail Aplysia californica, shown in Figure 5-20, is slightly larger than a
softball and has no shell. When threatened, it defensively withdraws its more vulnerable body parts—the gill (through which it extracts oxygen from the water) and the
siphon (a spout above the gill used to expel seawater and waste). Some of the
roughly 20,000 neurons that mediate the snail’s behaviors are quite accessible to researchers, and circuits with very few synapses can be isolated for study. This makes
Aplysia extremely useful for experiments on learning. By touching or shocking the
animal’s appendages, researchers can produce a number of enduring changes in its
defensive responses. These behavioral changes can then be used to study underlying
changes in the nervous system. Eric Kandel (1976) and many other neuroscientists
have conducted just such studies to try to explain the neurological basis of simple
kinds of learning.
177
Figure 5-20
The sea snail Aplysia californica.
■
178
CHAPTER 5
EXPERIMENT
Question: What happens to gill response after repeated stimulation?
Procedure
1
Gill withdraws
from water jet.
2
Gill no longer
withdraws
from water jet,
demonstrating
habituation.
Siphon
Ca2
1
With habituation,
the influx of calcium
ions in response to
an action potential
decreases…
+
Minutes
later
Presynaptic
membrane
Water jet
Results
Postsynaptic
membrane
The sensory neuron stimulates
the motor neuron to produce gill
withdrawal before habituation.
Ca2
Sensory neuron
Skin of
siphon
2
…resulting in less
neurotransmitter
released at the
presynaptic
membrane...
Motor neuron
Gill
muscle
+
3
…and less depolarization
of the postsynaptic
membrane.
Conclusion
Withdrawal response weakens with repeated presentation
of water jet (habituation) due to decreased Ca2+ influx and
subsequently less neurotransmitter release.
Figure 5-21
The neural basis of habituation. A jet of
water is sprayed on the siphon of Aplysia
while movement of the gill is recorded.
The gill withdrawal response weakens
with repeated presentations of the water
jet. As a result, a sensory neuron from
the skin of the siphon forms a
connection with a motor neuron that
contracts the gill muscle. Recordings
from the sensory neuron and motor
neuron after habituation show that
neither has lost its sensitivity to electrical
stimulation. Measures of transmitter
release at the sensory–motor synapse
show that less neurotransmitter is
released after habituation. This decrease
in neurotransmitter occurs because
calcium channels have become less
responsive to the voltage changes
associated with action potentials, causing
a reduction in the influx of calcium
needed to release neurotransmitter.
The procedure section of Figure 5-21 shows the experimental setup for studying the
withdrawal response of Aplysia to a light jet of water. If the jet of water is presented as
many as 10 times, the withdrawal response is weaker some minutes later when the animal
is again tested with the water jet. The decrement in the strength of the withdrawal is habituation. This habituation can last as long as 30 minutes. What is its neural basis?
The results section of Figure 5-21 starts by showing a simple representation of the
pathway that mediates Aplysia’s gill-withdrawal response. For purposes of illustration,
only one sensory neuron, one motor neuron, and one synapse are shown, even though,
in actuality, about 300 neurons may take part in this response. The jet of water stimulates
the sensory neuron, which in turn stimulates the motor neuron that is responsible for the
gill withdrawal. But exactly where do the changes associated with habituation take place?
In the sensory neuron? In the motor neuron? Or in the synapse between the two?
Habituation is not a result of an inability of either the sensory or the motor neuron to produce action potentials. In response to direct electrical stimulation, both the
sensory neuron and the motor neuron retain the ability to generate action potentials
even after habituation. Electrical recordings from the motor neuron show that, accompanying the development of habituation, the excitatory postsynaptic potentials in
the motor neuron become smaller. The most likely way that these EPSPs (excitatory
postsynaptic potentials) decrease in size is that the motor neuron is receiving less neurotransmitter across the synapse. And, if less neurotransmitter is being received, then
the changes accompanying habituation must be taking place in the presynaptic axon
terminal of the sensory neuron.
Kandel and his coworkers measured neurotransmitter output from a sensory
neuron and verified that less of it is in fact released from a habituated neuron than
from a nonhabituated one. Recall that the release of a neurotransmitter in response to
an action potential requires an influx of calcium ions across the presynaptic membrane. As habituation takes place, that calcium ion influx decreases in response to the
HOW DO NEURONS COMMUNICATE?
voltage changes associated with an action potential. Presumably, with repeated use,
calcium channels become less responsive to voltage changes and more resistant to the
passage of calcium ions. Why this happens is not yet known. At any rate, the neural
basis of habituation lies in the presynaptic part of the synapse. Its mechanism, which
is summarized in the right-hand close-up of Figure 5-21, is a reduced sensitivity of
calcium channels and a consequent decrease in the release of a neurotransmitter. This
reduced sensitivity of calcium channels in response to voltage changes produces habituation, a form of learning and memory about an organism’s experiences.
■
179
Sensitization. A process by which the
response to a stimulus increases with repeated presentations of that stimulus.
NEUROTRANSMITTER RELEASE AND SENSITIZATION
Aplysia is capable of other forms of learning as well. One is sensitization, an enhanced
response to some stimulus. Sensitization is the opposite of habituation. The organism becomes hyperresponsive to a stimulus rather than accustomed to it. For instance, a
sprinter crouched in her starting blocks is often hyperresponsive to the starter’s gun; its
firing triggers in her a very rapid reaction. The stressful, competitive context in which the
race takes place helps to sensitize her to this sound. Sensitization occurs in other contexts,
too. Sudden and novel forms of stimulation often heighten our general awareness and
result in larger-than-normal responses to all kinds of stimulation. If you are suddenly
startled by a loud noise, you become much more responsive to other stimuli in your
surroundings, including some of those to which you had previously become habituated.
The same thing happens to Aplysia. Sudden novel stimuli can heighten a snail’s
responsiveness to familiar stimulation. For example, if the snail is attacked by a predator, it becomes acutely aware of other changes in its environment and hyperresponds
to them. In a laboratory, a small electric shock to the tail mimics a predatory attack
and is effective in producing this kind of sensitization, which is illustrated in the procedure section of Figure 5-22. In fact, a single electric shock to the tail of Aplysia enhances its gill-withdrawal response for a period that lasts from minutes to hours.
EXPERIMENT
Question: What happens to gill response in sensitization?
Figure 5-22
The neural basis of sensitization. A
shock is delivered to the tail of Aplysia
before the siphon is stimulated with a
jet of water, resulting in an enhanced
gill-withdrawal response. As a result, a
serotonin interneuron that makes a
presynaptic connection with the sensory
neuron releases serotonin. Serotonin
reduces K+ efflux through potassium
channels, thus prolonging the action
potential. The prolonged action
potential results in a greater calcium
influx and therefore increased release
of transmitter.
1
Procedure
Serotonin reduces K+ efflux through
potassium channels, prolonging an action
potential on the siphon sensory neuron.
Interneuron
Gill withdrawal
Serotonin
A shock to the tail enhances
the gill withdrawal
response (sensitization).
Water jet
Sensory
neuron
Second
messenger
Shock
Results
An interneuron receives input from a “shocked”
sensory neuron in the tail and releases serotonin
onto the axon of a siphon sensory neuron.
Skin of
siphon
Motor
neuron
2
The prolonged
action potential
results in more
+
Ca2 influx and
increased
transmitter
release…
3
…causing greater
depolarization of
the postsynaptic
membrane after
sensitization.
Interneuron
Sensory
neuron
+
K
+
Motor
neuron
Gill
muscle
Ca2
Conclusion
Reinstatement of the withdrawal response after a shock is due to
increased K+ influx and subsequently more neurotransmitter release.
180
■
CHAPTER 5
In addition to studying the neurological basis of habituation, Kandel and his
coworkers studied the neurological basis of sensitization. In this case, the neural circuits are a little more complex than those taking part in habituation. To simplify the
picture, the results section of Figure 5-22 shows only one of each kind of neuron. An
interneuron that receives input from a sensory neuron in the tail (and so carries information about the shock) makes an axoaxonic synapse with a siphon sensory neuron. The interneuron contains the neurotransmitter serotonin in its axon terminal.
Consequently, in response to a tail shock, the tail sensory neuron activates the interneuron, which in turn releases serotonin onto the axon of the siphon sensory neuron. Information from the siphon still comes through the siphon sensory neuron to
activate the motor neuron leading to the gill muscle. This last link you already know
about from the discussion of habituation.
Now let us see what happens at the molecular level. The serotonin released from
the interneuron binds to a metabotropic serotonin receptor on the axon of the siphon
sensory neuron. This binding causes second messengers to be activated in the sensory
neuron. Specifically, the serotonin receptor is coupled though its G protein to the
enzyme adenyl cyclase. This enzyme increases the concentration of the second messenger cyclic adenosine monophosphate (cAMP) in the presynaptic membrane of the
siphon sensory neuron, the membrane that forms one side of a synapse with the
motor neuron leading to the gill. Through a number of chemical steps, cAMP attaches a phosphate (PO4) to potassium (K+) channels, and the phosphate renders the
K+ channels relatively unresponsive. The close-up of the results section of Figure 5-22, on the right, sums up the result. In response to an action potential traveling
down the axon of the siphon sensory neuron (such as one generated by a touch to the
siphon), the K+channels on that neuron are slower to open. Consequently, potassium
ions cannot repolarize the membrane as quickly as is normal, so the action potential
lasts a little longer than it usually would. The longer-lasting action potential prolongs
the inflow of Ca2+ into the membrane. In turn, the increased concentration of Ca2+
results in more neurotransmitter being released from the sensory synapse onto the
motor neuron that leads to the gill muscle, which produces a larger-than-normal gillwithdrawal response. The gill withdrawal may also be enhanced by the fact that the
second messenger cAMP may mobilize more synaptic vesicles, making more neurotransmitter ready for release into the sensory– motor synapse.
Sensitization, then, is the opposite of habituation at the transmitter level as well
as at the behavioral level. In sensitization, more calcium influx results in more transmitter being released, whereas, in habituation, less calcium influx results in less neurotransmitter being released. The structural basis of memory in these two forms of
learning is different, however. In sensitization, the change takes place in potassium
channels, whereas, in habituation, the change takes place in calcium channels.
Synaptic Change with Learning
in the Mammalian Brain
The studies of habituation and sensitization in Aplysia show that changes in synapses
do underlie simple forms of learning. In this section, we look at experiments that
demonstrate that synapses participate in learning in the mammalian brain.
We begin our exploration of synaptic change in learning in the forebrain structure called the hippocampus. The hippocampus of mammals is relatively simple cortex that has only three layers, rather than the six layers in the neocortex. The neurons
in one of these layers are packed closely together to form a bandlike line. This linear
arrangement of the neurons aligns their dendrites and cell bodies, and so summed
HOW DO NEURONS COMMUNICATE?
Amplitude of EPSP
EPSPs from many of them—sums known as (A)
Stimulate
Record
field potentials—can be recorded quite easily
with extracellular electrodes. Both the relatively simple circuitry of the hippocampus
Postsynaptic
and the ease of recording large field potenEPSP
tials there make the hippocampus a very popPresynaptic
Postsynaptic
ular structure for studying the neural basis
neuron
neuron
of learning.
(B)
In 1973, Timothy Bliss and Terje Lomo
Each dot represents
the amplitude of the
demonstrated that repeated electrical stimulaEPSP in response to one
tion of the perforant pathway entering the hipweak test stimulation.
pocampus produces a progressive increase in
0.4
the size of the field potentials recorded from
hippocampal cells. This enhancement in the
0.2
size of the field potentials lasts for a number
of hours to a number of days or even weeks.
0.0
Bliss and Lomo called it long-term enhancement (LTE). Long-term enhancement can be
30
0
60
90
120
obtained at many synapses of the nervous sysTime (minutes)
tem, but the hippocampus, because of its simBurst of
ple structure, continues to be a favorite locastrong stimulation
tion for LTE studies. The fact that LTEs last for
days or months suggests two things. First, some change must have taken place at the
synapse that allowed the field potential to become larger. Second, the change in the
synapse might be related to the kinds of learning that we experience each day.
Because LTE can be recorded at many different locations in the brain, Figure
5-23A illustrates the experimental procedure for a typical synapse. The presynaptic
neuron is stimulated electrically while the electrical activity produced by the stimulation is recorded from the postsynaptic neuron. The insert in Figure 5-23A shows the
excitatory postsynaptic potential produced by a single pulse of electrical stimulation.
In a typical experiment, a number of test stimuli are given to estimate the size of the
induced EPSP. Then a strong burst of stimulation, consisting of a few hundred pulses
of electrical current per second, is administered. Then the test pulse is given again.
Figure 5-23B illustrates the fact that the amplitude of the EPSP has increased and remains larger for as long as 90 minutes after the high-frequency burst of stimulation.
The high burst of stimulation has produced a long-lasting change in the response of
the postsynaptic neuron. In other words, LTE has occurred. In order for the EPSP to
increase in size, more neurotransmitter must be released from the presynaptic membrane or the postsynaptic membrane has to become more sensitive to the same
amount of transmitter. So the question is, What is the mechanism that enables this
change?
To examine the possible synaptic changes underlying LTE, we will turn to the results of some experiments in which glutamate is the chemical transmitter at the terminals of the neurons being stimulated. Glutamate acts on two different types of glutamate receptors located on the postsynaptic membrane, called N-methyl-D-aspartate
(NMDA) and alpha-amino-3-hydroxy-5-methylisoazole-4-proprionic acid (AMPA)
receptors. As Figure 5-24A shows, AMPA receptors ordinarily mediate the responses
produced when glutamate is released from a presynaptic membrane. NMDA receptors usually do not respond to glutamate, because their pores are blocked by magnesium ions (Mg2+) .
Under appropriate circumstances, however, NMDA receptors can open to allow the
passage of calcium ions. For them to open requires two events to take place at approxi-
■
181
Figure 5-23
(A) In this experimental setup for
demonstrating long-term enhancement,
the presynaptic neuron is stimulated
with a test pulse and the EPSP is
recorded from the postsynaptic neuron.
(B) Each test pulse of stimulation
produces an EPSP, the amplitude of
which is indicated by a dot on a graph.
After a period of intense stimulation, the
amplitude of the EPSP produced by the
test pulse increases.
Long-term enhancement (LTE). A
change in the amplitude of an excitatory
postsynaptic potential that lasts for hours
to days in response to stimulation of a
synapse; may play a part in learning.
Sometimes referred to as long-term or
long-lasting potentiation (LTP or LLP).
182
■
CHAPTER 5
(B) Strong electrical stimulus
(depolarizing EPSP)
(A) Weak electrical
stimulus
Glutamate
Calcium ions
Magnesium ion
Presynaptic
neuron
NMDA receptor
NMDA
receptor
AMPA receptor
AMPA
receptor
Postsynaptic
neuron
Because the NMDA receptor
pore is blocked by a
magnesium ion, release of
glutamate by a weak
electrical stimulation activates
only the AMPA receptor.
Figure 5-24
The synaptic change that underlies LTE.
(A) A weak electrical stimulus (test
stimulus) releases glutamate from the
presynaptic terminal, and the glutamate
binds to the AMPA receptor. The NMDA
receptor is insensitive to glutamate and
is blocked by a magnesium ion. (B) An
intense burst of strong stimulation is
sufficient to depolarize the postsynaptic
membrane to the point at which the
magnesium block is removed from the
NMDA receptor. (C) Now, in response to
a test stimulus, glutamate binds to the
NMDA receptor, and the receptor pore
opens to allow the influx of calcium ions.
Calcium ions, acting through second
messengers, produce a number of
changes that include an increase in the
responsiveness of AMPA receptors to
glutamate, the formation of new AMPA
receptors, and even retrograde messages
to the presynaptic terminal to enhance
glutamate release.
Doubly gated channel. A membrane
channel containing a pore that opens to
allow entry of calcium into the cell only
when the membrane is depolarized and
is stimulated by the appropriate neurotransmitter.
A strong electrical stimulation
can depolarize the postsynaptic
membrane sufficiently that the
magnesium ion is removed
from the NMDA receptor pore.
(C) Weak electrical
stimulus
Calcium
ions
Second
messenger
NMDA
receptor
AMPA receptor
Now glutamate, released by
weak stimulation, can activate
the NMDA receptor to allow
Ca2+ influx, which, through a
second messenger, increases
the function or number of
AMPA receptors, or both.
mately the same time, which is why NMDA receptors are called doubly gated channels.
The two required events are illustrated in Figure 5-24B and C. First, as shown in Figure
5-24B, the postsynaptic membrane must be depolarized by strong electrical stimulation.
When the membrane is depolarized, the Mg2+ ion is displaced from the pore. Second, as
shown in Figure 5-24C, the NMDA receptors must be activated by glutamate from the
presynaptic membrane. If these two changes take place at roughly the same time, Ca2+
ions are able to enter the postsynaptic neuron through the NMDA receptor pore. This
entry of Ca2+ into the cell initiates the cascade of events associated with the long-lasting
increase in the size of the field potential, which is long-term enhancement.
What happens when Ca2+ enters a postsynaptic neuron? There are three proposals.
The first has calcium acting through a second messenger to improve current flow
through the AMPA receptor. The second has calcium acting through a second messenger to stimulate the formation of new AMPA receptors. In both cases, the same amount
of neurotransmitter therefore produces a larger field potential because of a change in
the AMPA receptors. The third proposal is a little more complex. In this case, Ca2+ is
suggested to trigger the production of a substance called retrograde plasticity factor.
Retrograde plasticity factor diffuses back into the presynaptic membrane and reacts
with second messengers there. One of the functions of the presynaptic second mes-
HOW DO NEURONS COMMUNICATE?
sengers is to enhance the release of glutamate in response to presynaptic stimulation.
Accordingly, this increase in the release of glutamate results in LTE. The results of
some experiments suggest that retrograde plasticity factor may be the gaseous transmitter NO.
The novel part of this story is that hippocampal NMDA receptors thus mediate a
change that in every way meets the criteria of a Hebb synapse. The synapse changes
with use. The familiar part of the story is that calcium ions take part, just as in learning in Aplysia.
Long-Term Enhancement and
Associative Learning
Associative learning involves learning associations between stimuli, such as learning
that A goes with B. This form of learning is very common. Learning that a certain
telephone number goes with a certain person, that a certain odor goes with a certain
food, or that a certain sound goes with a certain musical instrument are all everyday
examples of associative learning. Your learning that NMDA receptors take part in
mammalian learning is another example of associative learning.
The NMDA receptor change just described is not associative, because one stimulus
is not linked with another. There was only the initial strong electrical stimulation—no
pairing of this stimulation with another stimulus. But this mechanism may mediate associative learning. Remember that the NMDA receptor is doubly gated. In order for
calcium ions to pass through its pore, the magnesium block must be removed by depolarization of the membrane, and then glutamate must bind to the receptor. If one of
the two stimuli in the associative pair depolarized the membrane and the other released glutamate, then that would provide the basis for associative learning.
The demonstration of LTE occurring at a synapse when a weak stimulus is paired
with a stronger one provides a model for how associations might be learned between
two different events that take place together in time. But is this neural change actually
related to learning in an organism’s natural environment? And, if this change does
underlie real-life associative learning, what are the natural equivalents of the weak
and the strong stimulation?
The strong source of stimulation comes from an interesting feature of the action
potentials produced by certain neurons. When these neurons fire, the nerve impulse
travels not only down the axon, but also back up the dendritic tree. This dendritic action potential creates a depolarization of the postsynaptic membrane that is adequate
to remove the Mg2+ block in NMDA receptors. When the Mg2+ blocks are removed,
the release of glutamate into any synapse on the dendrite can activate NMDA receptors and thus produce LTE. This is where the weak stimulation comes in. The weak
stimulation is any environmental event that triggers glutamate-releasing activity into
a synapse at the same time as the postsynaptic membrane is being depolarized. Initially, this transmitter input onto the dendritic tree of the postsynaptic neuron would
not be strong enough to produce LTE. With repeated pairing of the glutamate release
and a depolarization of the postsynaptic membrane caused by dendritic action potentials, however, LTE could eventually occur. Potentially, then, if one behavioral event
causes the hippocampal cells to discharge at the same time as some other event causes
the release of glutamate onto those cells’ dendrites, LTE would result in response to
the second event.
A specific example will help you see how this process relates to associative learning. Suppose that, as a rat walks around, a hippocampal cell fires when the rat reaches a
certain location. The stimulus that produces this firing may be the sight of a particular
■
183
Associative learning. A form of learning in which two or more unrelated stimuli become associated with each other to
elicit a behavioral response.
184
■
CHAPTER 5
object, such as a red light. The signal about the light would presumably be carried by
the visual system to the neocortex and then from the visual neocortex to the hippocampal cell. Now suppose that, during an excursion to this place where the light is
located, the rat encounters a novel object—say, a tasty piece of food. Input concerning
that food could be carried from the taste area of the neocortex to the same hippocampal cell that fires in response to the light. As a result, the taste and odor input associated
with the food would arrive at the cell at the time that it is firing in response to the light.
Because the cell is firing, the Mg2+ block is removed, so LTE can take place. Subsequently, the sight of the red light will fire this hippocampal cell, but so will the odor of
this particular food. The hippocampal cell, in other words, stores an association between the food and the light.
You may be wondering how this association could be useful to a rat, or even
yourself. Let us use the rat as an example. If the rat were to smell the odor of this
food on the snout of another rat that had eaten it, the hippocampal cell would discharge. Because the discharge of this cell is also associated with a particular light and
location in the environment, the rat might know (or think) that, if it goes to that location, it will once again find food there. Jeff Galef and his coworkers (1990) in fact
demonstrated that a rat that smells the odor of a particular food on the breath of a
demonstrator rat will go to the appropriate location to obtain some of the food. This
example of the social transmission of food-related information is an excellent example of associative learning. Although this behavior can be disrupted by brain lesions
in the hippocampus, it has not yet been demonstrated that learning this food-andplace association is mediated by LTE in synapses, because it is technically difficult to
locate the appropriate synapses and record from them in a freely moving animal.
Learning and the Formation or Loss of Synapses
When we view pictures of neurons, dendrites, and synapses, they are inanimate and
static, but living neurons are not like this. Living neurons are constantly changing.
Maria Fischer and her coworkers (1998) video-recorded the behavior of living hippocampal neurons that were maintained in a culture. They labeled the neurons with a
green fluorescent dye that binds to actin, a contractile protein that is found in the cell
and is responsible for dendritic movement. As the dye bound to the actin, each neuron could be seen to have numerous fluorescent protuberances. Many were filopodia—small fingerlike extensions that continuously projected from and retracted back
into the dendrites. These filopodia are presumed to be precursors of dendritic spines.
Other protuberances were clearly dendrites with well-developed heads and narrow
shafts. These dendrites were continuously changing their size, shape, and length over
periods of seconds. A cultured neuron in a dish has no axon connections, and the absence of such connections may have contributed to much of the dendritic movement
observed. Nevertheless, the results of the experiment show that dendrites and their
spines can be formed or lost or change their shape rapidly enough to be responsible
for the neural changes associated with learning.
The neural changes associated with learning must be long-lasting enough to account for a relatively permanent change in an organism’s behavior. The changes at
synapses described in the preceding sections develop quite quickly, but they do not last
indefinitely, as memories often do. How, then, can synapses be responsible for the relatively permanent changes in behavior that we call long-term memory and learning?
If the procedures that produce habituation and sensitization or associative
learning are repeated a number of times, the behavioral changes that result, instead
of lasting for hours or days, can last for months. In other words, a brief period
of training produces learning that lasts only a short time, whereas a longer period of
training produces more enduring learning. You can probably think of instances in
■
HOW DO NEURONS COMMUNICATE?
Figure 5-25
Motor
neuron
Habituation and sensitization in Aplysia
can be accompanied by structural
changes in the sensory neuron in which
the number of synapses with the motor
neuron decline as a result of habituation
and increase as a result of sensitization.
These structural changes may underlie
enduring memories.
Sensory
neuron
Control
185
Habituated
Sensitized
your own life. If you cram for an exam the night before, you usually forget the material quickly; but, if you study a little each day for a week, your learning tends to endure. What underlies this more persistent form of learning? It seems that the basis of
it would be more than just a change in the release of a neurotransmitter, and, whatever the change is, it must be a relatively permanent one.
Craig Bailey and Mary Chen (1989) have helped to answer this question. They
found that the number and size of sensory synapses and the amount of transmitter
that they contain are changed in well-trained habituated and sensitized Aplysia. The
number and size of synapses are decreased in habituated animals and increased in
sensitized animals, as shown in Figure 5-25. Apparently, the synaptic events associated
with habituation and sensitization can also trigger processes in the sensory cell that
result in the loss or formation of new synapses. A mechanism through which these
processes can take place begins with calcium ions. These calcium ions can mobilize
second messengers to send instructions to nuclear DNA. The nuclear DNA, in turn,
can initiate changes that result in the increase or decrease of various structural aspects
of the synapse, including the number of synapses.
The second messenger cAMP probably plays an important role in carrying these
instructions to nuclear DNA. The evidence for cAMP’s involvement comes from studies of fruit flies. In the fruit fly Drosophila, two genetic mutations can occur that produce the same learning deficiency. One mutation, called dunce, produces a lack of the
enzymes needed to degrade cAMP, so the fruit fly has abnormally high levels of cAMP.
These high levels of cAMP, which are outside the normal range for Drosophila neurons,
render the cAMP second messenger inoperative. The other mutation, called rutabaga,
also renders the cAMP second messenger inoperative, but it does so by producing levels of cAMP so low that they, too, are outside the normal range for Drosophila neurons.
Significantly, fruit flies with either of these two mutations are impaired in their ability
to acquire habituated and sensitized responses. It seems that new synapses are required
in these types of learning and that the second messenger cAMP is needed to carry instructions to form them. Figure 5-26 summarizes the findings of this research.
To confirm that the growth and loss of synapses underlie relatively permanent
changes in behavior requires not only studies of fruit flies and sea snails, but also studies of mammalian brains. Such studies are difficult to do, however. There are many
more neurons and connections in a mammalian brain than in a snail ganglion, and it
is almost impossible to know where a learning-related change may take place. Even in a
simplified experimental condition that uses the hippocampus and a known pathway,
there are far too many synaptic connections to be certain of which synapse or synapses
are changing to mediate learning. But many of these methodological difficulties can be
overcome if the experiment is conducted in a dish, as the following experiment was.
The German researchers Florian Engert and Tobias Bonhoffer (1999) took slices
of the hippocampus from the brains of rats and maintained them in a culture for 2 to
4 weeks before beginning their study. When hippocampal slices are initially cultured,
there is a large increase in the number of dendritic spines on certain neurons, but,
Craig Bailey
Mary Chen
Drosophila
cAMP
No learning
High levels
Dunce
Learning
Normal levels
No mutation
No learning
Low levels
Rutabaga
Figure 5-26
Two genetic mutations can disrupt
learning in the fruit fly Drosophila. The
mutation dunce increases the amount of
the second messenger cAMP, moving it
above the concentration range at which
it can be regulated. The mutation
rutabaga decreases the amount of the
second messenger cAMP, moving it
below the concentration range at which
it can be regulated.
EXPERIMENT
Question: Does the development of new synapses underlie learning?
Procedure
AP5, a chemical that blocks
NMDA receptors on the
postsynaptic neuron, was added
to the hippocampal neurons…
Postsynaptic
cell
AP5
Stimulating
electrode
Presynaptic
cell
Recording
electrode
…and washed off where
presynaptic axon meets
postsynaptic dendrite.
The presynaptic cell
was stimulated.
After a strong burst of stimulation, the EPSP from
the postsynaptic cell was recorded in response to
weak test stimulation. LTE had resulted.
Figure 5-27
To demonstrate the formation of new synapses in the mammalian hippocampus,
a slice of hippocampus is maintained in a dish. A recording electrode is
placed in a presynaptic neuron and a stimulating electrode is placed in a
postsynaptic neuron. A fluorescent dye is injected into the postsynaptic
neuron through the recording electrode so that the neuron can be visualized
through a microscope. A chemical that blocks receptors on the postsynaptic
neuron (AP5) is placed over the preparation but is washed away from the
zone in which the presynaptic and postsynaptic neurons have synapses. A
weak test stimulation of the presynaptic neuron produces low-amplitude
EPSPs in the postsynaptic neuron. After an intense burst of stimulation, the
test stimulus produces a larger EPSP. Each dot represents the size of an EPSP
in response to a single test stimulus. About 30 minutes after LTE, two new
dendritic spines appear on the dendrite of the postsynaptic neuron. The
finding that new dendritic spines grow in conjunction with LTE suggests that
they support long-term changes in interneuron communication and may
provide the neural substrate for new learning in behaving animals.
Voltage (mV)
after 2 weeks of incubation, the neurons become stabilized. The experimental setup is illustrated in Figure 5-27. A glass microelectrode was
9
inserted into a hippocampal neuron. Through the electrode, the fluorescent molecule calcein was injected into the cell to color it green. The
7
cell was also stimulated through this electrode, which sufficiently deLTE
5
polarized the cell membrane to remove the Mg2+ block from NMDA
receptors. A drug called AP5 (2-amino-5-phosphonovaleric acid),
3
which blocks NMDA receptors, was then added to the bath surround1
ing the neuron, and a second microelectrode was inserted into the ax–20 –10 0 10 20 30 40 50 60 70
ons of other neurons that had synapsed with the first cell. Next, the
Time (min)
Stimulation
area of the dendrite adjacent to the second stimulating electrode was
Results
washed to remove AP5 from just this region of the postsynaptic neuDendrite before stimulation
ron. The axons were then stimulated electrically, and the EPSPs produced by that stimulation were recorded from the postsynaptic cell.
Structural changes on the stimulated dendrite were observed
About 30 minutes
with the use of a confocal microscope. A confocal microscope is simiafter stimulation…
Dendrite 30 minutes after stimulation
lar to a light microscope except that the light that shines through
the tissue comes from a laser. Light from a laser does not scatter, so
a small object can be viewed clearly. In addition, changing the focal
point of the laser makes it possible to see through the dendrite and
then reconstruct a three-dimensional picture of it. The fluorescent
…two new spines
molecule calcein that was injected into the neuron makes its denhad appeared on
the dendrite in the
drites readily observable through the confocal microscope.
area where the AP5
The graph in Figure 5-27 shows the changes in the size of the
was washed off.
EPSPs recorded from the postsynaptic neuron. First, a number of
test stimuli are given to determine the size of the EPSP, followed by
Conclusion
10 minutes of electrical stimulation. Then, EPSPs with a larger amNew dendritic spines can grow in conjunction with LTE.
plitude, indicating that LTE has occurred, are recorded in response
to test stimuli. The results section of Figure 5-27 shows that, about
30 minutes after stimulation, two new spines appeared on the dendrite.
No
spines
appeared
on other parts of the neuron that were still subject to the
Learn more about the confocal microscope in the Research Methods section
AP5 block. Consequently, this experiment demonstrates that new dendritic spines can
on your CD. You’ll see a diagram of the
grow in conjunction with LTE. In this experiment, it was not possible to see the axon
apparatus and video clips of cells taken
terminals, but presumably new terminals arose to connect the stimulated axons to the
with a confocal microscope.
new dendritic spines, thus forming new synapses. Note that the new synapses appeared about 30 minutes after LTE, so these new connections were not required for
LTE. The new synapses, however, are probably required for LTE to endure.
HOW DO NEURONS COMMUNICATE?
■
187
In Review
Are synapses required for learning? The answer is, Yes, in a number
of different ways. In Aplysia, changes in synaptic function can
mediate two forms of learning: habituation and sensitization. Presynaptic voltage-sensitive calcium channels mediate habituation by
becoming less sensitive with use. Presynaptic serotonin metabotropic receptors can change the sensitivity of potassium channels
and so increase Ca2+ influx to mediate sensitization. At the same
time, these same receptors can produce fewer or more synapses to
provide a structural basis for long-term habituation and sensitization. Mammals provide an example of synaptic change related to
associative learning. Here learning occurs only if certain events
take place at the same time. Clearly, many changes in the synapses
of neurons can mediate learning. Because learning can have a
structural basis, measurements of different structures within a
synapse can be a source of insight into the relations between synaptic change and behavioral experience. Figure 5-28 summarizes the
areas of a synapse that can be measured and related to behavior.
Increased
transport
Increase in size or
area of terminal
Increase in number
of synaptic vesicles
Increase in density
of contact zones
Change in size
of synaptic cleft
Increase in size
or area of spine
Change in stem
length and width
Increase in protein
transport for spine
construction
SUMMARY
1. What early experiments provided the key to understanding how neurons communicate with each other? In the 1920s, Otto Loewi suspected that nerves secrete a
chemical onto the heart, which regulates its rate of beating. His subsequent
experiments showed that acetylcholine slows heart rate, whereas epinephrine
increases it. This observation provided the key to understanding the basis of
chemical neurotransmission.
2. What is the basic structure of a synapse that connects one neuron to another neuron?
A synapse between two neurons consists of the first neuron’s axon terminal
(which is surrounded by a presynaptic membrane), a synaptic cleft (a tiny gap
between the two neurons), and a postsynaptic membrane on the second neuron.
Systems for manufacturing the chemical neurotransmitter used in communicating between the two neurons are located in the first neuron’s axon terminal or
cell body, whereas systems for storing the neurotransmitter are in its axon terminal.
Receptor systems on which that neurotransmitter acts are located on the postsynaptic membrane.
3. What are the major stages in the function of a neurotransmitter? There are four
major stages in neurotransmitter function: (1) synthesis and storage of the
neurotransmitter, (2) its release from the axon terminal, (3) action of the neurotransmitter on postsynaptic receptors, and (4) processes for inactivating the
neurotransmitter. After its manufacture, the neurotransmitter is wrapped in a
membrane to form synaptic vesicles, which become attached to the presynaptic
membrane of the axon terminal. When an action potential is propagated on the
presynaptic membrane, voltage changes set in motion the release of the neurotransmitter. Exocytosis of the contents of one synaptic vesicle releases a quantum
of neurotransmitter into the synaptic cleft. This quantum produces a miniature
postsynaptic potential on the postsynaptic membrane. To generate an action
potential on the postsynaptic cell requires the simultaneous release of many
Figure 5-28
A summary of locations on a synapse
where changes may subserve learning.
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CHAPTER 5
neuroscience interactive
4.
There are many resources available for
expanding your learning on-line:
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www.worthpublishers.com/kolb/
chapter5
Try some self-tests to reinforce your
mastery of the material. Look at some
of the news updates reflecting current
research on the brain. You’ll also be able
to link to other sites which will reinforce
what you’ve learned.
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5.
6.
www.pdf.org
Link to this site to learn more about
Parkinson’s disease and current research
to find a cure.
On your CD-ROM you’ll be able to
quiz yourself on your comprehension
of the chapter. The module on Neural
Communication also provides important reinforcement of what you’ve
learned. In addition, the Research
Methods module includes coverage of
some of the technological techniques
referred to in this chapter, including the
confocal microscope.
7.
8.
quanta of transmitter. After a transmitter has done its work, it is inactivated by
such processes as diffusion out of the synaptic cleft, breakdown by enzymes, and
uptake of the transmitter or its components into the axon terminal (or sometimes into glial cells).
What are the three major types of neurotransmitters, and in what kinds of synapses
do they participate? There may be as many as 100 neurotransmitters, including
small-molecule transmitters, neuropeptides, and gases. Neurons containing these
transmitters make a variety of connections with various parts of other neurons,
as well as with blood vessels and extracellular fluid. Functionally, neurons can be
both excitatory and inhibitory, and they can participate in local circuits or general brain systems. Excitatory synapses, known as type I, are usually located on a
dendritic tree, whereas inhibitory synapses, known as type II, are usually located
on a cell body.
What are the two general classes of receptors for neurotransmitters? Most neurotransmitters act on one of two receptors: ionotropic or metabotropic. An ionotropic
receptor contains a pore that can be opened or closed to regulate the flow of ions
through it, thereby producing voltage changes on the cell membrane. Metabotropic
receptors activate second messengers to indirectly produce changes in the function
and structure of the cell. Each of the numerous neurotransmitters used in the nervous system is associated with many different ionotropic and metabotropic receptors.
What are some of the systems into which neurons that employ the same principal
neurotransmitter are organized, and how are these systems related to behavior? Systems of neurons that employ the same principal neurotransmitter govern various
aspects of behavior. For instance, the skeletal motor system controls movement of
the skeletal muscles, whereas the autonomic system controls the body’s internal
organs. Acetylcholine is the main neurotransmitter in the skeletal motor system,
and acetylcholine and epinephrine are the main transmitters in the autonomic
system. The central nervous system contains not only widely dispersed glutamate
and GABA neurons, but also systems of neurons that have either acetylcholine,
norepinephrine, dopamine, or serotonin as their main neurotransmitter. These
systems ensure that wide areas of the brain act in concert, and each is associated
with its own behavioral functions and disorders.
How do changes in synapses effect learning? Changes in synapses underlie learning
and memory. In habituation, a form of learning in which a response becomes
weaker as a result of repeated stimulation, calcium channels become less responsive to an action potential and, consequently, less neurotransmitter is released
when an action potential is propagated. In sensitization, a form of learning in
which a response becomes stronger as a result of stimulation, changes in potassium channels prolong the duration of the action potential, resulting in an
increased influx of calcium ions and, consequently, a greater release of a neurotransmitter. With repeated training, new synapses can develop, and both these
kinds of learning can become relatively permanent.
What structural changes in synapses may be related to learning? In Aplysia, in response to repeated sessions of habituation, the number of synapses connecting
the sensory neurons and the motor neurons decreases. Similarly, in response to
repeated sessions of sensitization, the number of synapses connecting the sensory
and the motor neurons increases. Presumably, these changes in synapse number
are related to long-term learning. The results of experiments using the mammalian hippocampus show that the number of synapses can change rapidly in
cultured preparations. Within about 30 minutes of inducing LTE, new dendritic
spines appear, suggesting that new synapses are formed during LTE. Possibly the
formation of new synapses can similarly be responsible for new learning.
HOW DO NEURONS COMMUNICATE?
KEY TERMS
adrenergic neuron, p. 172
ascending activating
system, p. 173
associative learning, p. 183
cholinergic neuron, p. 171
dopamine, p. 166
doubly gated channel, p. 182
gamma-aminobutyric acid
(GABA), p. 166
glutamate, p. 166
habituation, p. 177
Hebb synapse, p. 177
ionotropic receptor, p. 167
long-term enhancement
(LTE), p. 181
metabotropic receptor,
p. 169
neuropeptides, p. 166
nitric oxide (NO), p. 167
second messenger, p. 170
sensitization, p. 179
small-molecule
transmitters, p. 165
transmitter-activated
receptor, p. 160
transporter, p. 160
REVIEW QUESTIONS
1. Explain the way in which neurotransmitters are synthesized, stored, released, and
broken down.
2. How many kinds of neurotransmitters are there? Describe some problems in
proving that a chemical found in a neuron is a neurotransmitter.
3. Describe the differences in function between the two main kinds of transmitteractivated receptors.
4. Describe an example of the organization of a neurotransmitter system.
5. What mechanisms are the same and what mechanisms are different in the various
kinds of learning discussed in this chapter?
FOR FURTHER THOUGHT
Can you speculate about how synaptic systems in the brain have origins that parallel
the evolution of species? Why could such a relation be important?
RECOMMENDED READING
Cooper, J. R., Bloom, F. E., & Roth, R. H. (1991). The biochemical basis of neuropharmacology.
New York: Oxford University Press. If you would like a readable and up-to-date account
of the chemical systems in the brain, this is a good reference. The book describes the
various kinds of brain neurotransmitters and the kinds of synapses and chemical systems in which they are found.
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