THE SYNAPSE - Sherrington studied reflexes, automatic muscular cord to muscle and calculated the speed at which the

responses to stimuli. In a leg flexion reflex, a
The Concept of the Synapse
Chemicals are, however, the main way your neurons
communicate. They communicate by transmitting
chemicals at specialized junctions called synapses.
- If one neuron is separate from another, a reflex must
THE GREAT PIONEERS OF MODERN
NEUROSCIENCE
Ramón y Cajal (late 1800)
- Anatomically demonstrated a narrow gap separating
one neuron from another.
impulse traveled to produce the response.
sensory neuron excites a second neuron, which in
turn excites a motor neuron, which excites a muscle.
The circuit from sensory neuron to muscle response
is called a reflex arc.
require communication between neurons, and
therefore, measurements of reflexes might reveal
some of the special properties of that
communication.

Charles Scott Sherrington (1906)

- Physiologically demonstrated that communication

between one neuron and the next differs from
communication along a single axon.
- He inferred a specialized gap between neurons and
introduced the term synapse to describe it.
- Discovery was an amazing feat of scientific
reasoning, as he used behavioral observations to
infer the major properties of synapses half a century
before researchers had the technology to measure
those properties directly.
PROPERTIES OF SYNAPSES
Speed of a Reflex and Delayed Transmission at
the Synapse
Sherrington observed several properties of reflexes
that suggest special processes at the junctions between
neurons:
1. Reflexes are slower than conduction along an
axon.
2. Several weak stimuli presented at nearby places
or times produce a stronger reflex than one
stimulus alone does.
3. When one set of muscles becomes excited, a
different set becomes relaxed

Speed of a Reflex and Delayed Transmission at

the Synapse

- When Sherrington pinched a dog’s foot, the dog

flexed that leg after a short delay. During that delay,
an impulse had to travel up an axon from the skin
receptor to the spinal cord, and then an impulse had
to travel from the spinal cord back down the leg to a
muscle. Sherrington measured the total distance that
the impulse traveled from skin receptor to spinal
- He found that the speed of conduction through the -
reflex arc varied but was never more than about 15
meters per second (m/s). In contrast, previous
research had measured action potential velocities
along sensory or motor nerves at about 40 m/s.
Sherrington concluded that some process must be
slowing conduction through the reflex, and he
 inferred that the delay occurs where one neuron
communicates with another. This idea is critical, as
it established the existence of synapses.
Sherrington, in fact, introduced the term synapse
Temporal Summation
- Temporal summation phenomenon or meaning
summation over time is the cumulative effect that
Sherrington found that repeated stimuli within a
brief time.
Spatial Summation
- Spatial summation or summation over space is what
Sherrington found when synaptic inputs from
separate locations combine their effects on a neuron.
A graded depolarization is known as an excitatory
postsynaptic potential (EPSP). It results from a flow of
sodium ions into the neuron. If an EPSP does not cause
the cell to reach its threshold, the depolarization
decays quickly.
Inhibitory Synapses
- A pinch on the foot sends a message along a sensory
neuron to an interneuron (an intermediate neuron)
that excites the motor neurons connected to the
flexor muscles of that leg and the extensor muscles
of the other legs. Also, the interneuron sends
messages to inhibit the extensor muscles in that leg
and the flexor muscles of the three other legs.
- At these synapses, input from an axon
hyperpolarizes the postsynaptic cell. That is, it
increases the negative charge within the cell, Relationship of EPSP & IPSP and Action
moving it farther from the threshold and decreasing Potential
the probability of an action potential. This
temporary hyperpolarization of a membrane—
called an inhibitory postsynaptic potential
(IPSP)—resembles an EPSP. An IPSP occurs when
synaptic input selectively opens the gates for
potassium ions to leave the cell (carrying a positive
charge with them) or for chloride ions to enter the
cell (carrying a negative charge).
- Most neurons have a spontaneous firing rate, a
periodic production of action potentials even
 without synaptic input. In such cases, the EPSPs
increase the frequency of action potentials above
the spontaneous rate, whereas IPSPs decrease it.
- Some synapses produce fast, brief effects, and
others produce slow, long-lasting effects. In many
cases, the effect of two synapses at the same time
can be more than double the effect of either one, or
less than double (Silver, 2010). Certain
combinations of synapses summate with one
another more strongly than others do (Lavzin,
Rapoport, Polsky, Garion, & Schiller, 2012). Also,
the strength of a synapse can vary from one time to
another. The nervous system is indeed complex.
CHEMICAL EVENTS AT THE SYNAPSE
The Discovery of Chemical Transmission at
Synapses
released something that increased heart rate. He knew
he was collecting and transferring chemicals, not loose
electricity. Therefore, Loewi concluded, nerves send
messages by releasing chemicals.
Despite Loewi’s work, most researchers over the next
three decades continued to believe that most synapses
were electrical and that chemical synapses were the
exception. Finally, in the 1950s, researchers
established that chemical transmission predominates
throughout the nervous system. That discovery
revolutionized our understanding and encouraged.
The Sequence of Chemical Events at a Synapse
Understanding the chemical events at a synapse is
fundamental to understanding the nervous system.
Here are the major events:

T. R. Elliott, a young British scientist, reported in 1. The neuron synthesizes chemicals that serve as Some major events in transmission at a synapse.
1905 that applying the hormone adrenaline directly to neurotransmitters. It synthesizes the smaller The structure shown in green is an astrocyte that
the surface of the heart, the stomach, or the pupils neurotransmitters in the axon terminals and shields the synapse from outside chemicals. The
produces the same effects as those of the sympathetic synthesizes neuropeptides in the cell body. astrocyte also exchanges chemicals with the two
nervous system. Elliott therefore suggested that the 2. Action potentials travel down the axon. At the neurons.
sympathetic nerves stimulate muscles by releasing presynaptic terminal, an action potential enables
calcium to enter the cell. Calcium releases At a synapse, a neuron releases chemicals that affect
adrenaline or a similar chemical.
neurotransmitters from the terminals and into the another neuron. Those chemicals are known as
He initially posited that there is a set of nerves called synaptic cleft, the space between the presynaptic neurotransmitters.
the sympathetic nervous system accelerates the and postsynaptic neurons.
Types of Neurotransmitters
heartbeat, relaxes the stomach muscles, dilates the 3. The released molecules diffuse across the narrow
Amino Acids glutamate, GABA,
pupils of the eyes, and regulates other organs. cleft, attach to receptors, and alter the activity of glycine, aspartate, maybe
the postsynaptic neuron. Mechanisms vary for others
Otto Loewi, a German physiologist, liked the idea of altering that activity. A Modified Amino acetylcholine
chemical synapses repeatedly stimulated the vagus 4. The neurotransmitter molecules separate from Acid
nerve, thereby decreasing a frog’s heart rate. He then their receptors. Monoamines (also indoleamines: serotonin
collected fluid from around that heart, transferred it to 5. The neurotransmitter molecules may be taken modified from catecholamines: dopamine,
a second frog’s heart, and found that the second heart back into the presynaptic neuron for recycling, or amino acids) norepinephrine,
also decreased its rate of beating. they may diffuse away. epinephrine
6. Some postsynaptic cells send reverse messages to Neuropeptides endorphins, substance P,
Then Loewi stimulated the accelerator nerve to the
control the further release of neurotransmitter by (chains of amino neuropeptide Y, many
first frog’s heart, increasing the heart rate. When he
presynaptic cells. acids) others
collected fluid from that heart and transferred it to the Purines ATP, adenosine, maybe
second frog’s heart, its heart rate increased. That is, others
stimulating one nerve released something that Gases NO (nitric oxide), maybe
inhibited heart rate, and stimulating a different nerve others
The oddest transmitter is nitric oxide (chemical
formula NO), a gas released by many small local
neurons. (Do not confuse nitric oxide, NO, with
nitrous oxide, N2 O, sometimes known as “laughing
gas.”) Nitric oxide is poisonous in large quantities and
difficult to make in a laboratory.

NEUROTRANSMITTERS
Name Location Function
Acetylcholine Brain, Muscle
Spinal Movement, Each pathway in the Figure above begins with
Cord, Cognitive substances found in the diet. Acetylcholine, for
PNS Functioning
example, is synthesized from choline, which is
(excitatory,
inhibitory) abundant in milk, eggs, and peanuts. The amino acids
Glutamate Brain, Memory phenylalanine and tyrosine, present in proteins, are
Spinal (excitatory) precursors of dopamine, norepinephrine, and
Cord epinephrine. People with phenylketonuria lack the
enzyme that converts phenylalanine to tyrosine. They STORAGE OF TRANSMITTERS
Gamma- Brain, Eating,
Amino Butyric Spinal Aggression, can get tyrosine from their diet, but they need to Most neurotransmitters are synthesized in the
Acid Cord Sleeping minimize intake of phenylalanine, because excessive presynaptic terminal, near the point of release. The
(inhibitory) phenylalanine would accumulate and damage the presynaptic terminal stores high concentrations of
Serotonin Brain, Sleeping, Mood, brain. neurotransmitter molecules in vesicles, tiny nearly
Spinal Pain, Depression
The amino acid tryptophan, the precursor to serotonin, spherical packets (see Figure 2.14). (Nitric oxide is
Cord (inhibitory)
crosses the blood–brain barrier by a special transport an exception to this rule. Neurons release nitric oxide
Dopamine Brain Muscles Disorder,
Mental Disorder, system that it shares with other large amino acids. as soon as they form it instead of storing it.) The
Parkinson’s Your serotonin levels rise after you eat foods richer in presynaptic terminal also maintains much
Disease tryptophan, such as soy, and fall after something low neurotransmitter outside the vesicles.
(inhibitory / in tryptophan, such as maize (American corn).
excitatory) Neurons that release serotonin, dopamine, or
Endorphins Brain, Pain Suppression, One way to increase tryptophan entry to the brain is to norepinephrine contain an enzyme, MAO
Spinal Pleasure Feelings, decrease consumption of phenylalanine. Another is to (monoamine oxidase), that breaks down these
Cord Appetites eat carbohydrates. Carbohydrates increase the release transmitters into inactive chemicals, thereby
(inhibitory) of the hormone insulin, which takes several competing preventing the transmitters to accumulate to harmful
amino acids out of the bloodstream and into body cells, levels. The first antidepressant drugs that
SYNTHESIS OF TRANSMITTERS thus decreasing the competition against tryptophan psychiatrists discovered were MAO inhibitors. By
(Wurtman, 1985). blocking MAO, they increase the brain’s supply of
The relationship among epinephrine, norepinephrine, serotonin, dopamine, and norepinephrine. However,
and dopamine—compounds known as MAO inhibitors also have other effects, and exactly
catecholamines, because they contain a catechol group how they help relieve depression is still not certain.
and an amine group.
 RELEASE AND DIFFUSION OF
TRANSMITTERS
At the end of an axon, an action potential itself does
not release the neurotransmitter. Rather,
depolarization opens voltage dependent calcium gates
in the presynaptic terminal. Within 1 or 2 milliseconds
(ms) after calcium enters the terminal, it causes
exocytosis—bursts of release of neurotransmitter from
the presynaptic neuron. An action potential often fails
to release any transmitter, and even when it does, the
amount varies (Craig & Boudin, 2001). After its
release from the presynaptic cell, the neurotransmitter
diffuses across the synaptic cleft to the postsynaptic
membrane, where it attaches to a receptor. The
neurotransmitter takes no more than 0.01 ms to diffuse
across the cleft, which is only 20 to 30 nanometers
(nm) wide.
(a) An electronic micrograph showing a synapse from
the cerebellum of the mouse. The small round
structures are vesicles (b) An electronic micrograph
showing axon terminals onto the soma of neuron.
ACTIVATING RECEPTORS OF THE
POSTSYNAPTIC CELL
Researchers discovered more and more
neurotransmitters and wondered, “Why does the
nervous system use so many chemicals, if they all
produce the same type of message?” Eventually they
found that the messages are more complicated and
more varied.
The effect of a neurotransmitter depends on its
receptor on the postsynaptic cell. When the
neurotransmitter attaches to its receptor, the receptor
may open a channel —exerting an ionotropic effect—
or it may produce a slower but longer effect—a
metabotropic effect.
VARIATION IN RECEPTORS
The brain has a variety of receptor types for each
neurotransmitter. Receptors for a given transmitter
differ in their chemical structure, responses to drugs,
and roles in behavior.
Because of this variation in properties, it is possible to
devise drugs with specialized effects on behavior. For
example, the serotonin receptor type 3 mediates
nausea, and the drug ondansetron that blocks this
receptor helps cancer patients undergo treatment
without nausea.
DRUGS THAT ACT BY BINDING TO
RECEPTORS
A drug that chemically resembles a neurotransmitter
can bind to its receptor. Many hallucinogenic drugs—
that is, drugs that distort perception, such as lysergic
acid diethylamide (LSD)— chemically resemble
serotonin (see Figure 2.17). They attach to serotonin
type 2A (5-HT2A) receptors and provide stimulation
at inappropriate times or for longer-than-usual
durations. LSD increases the connections among brain
areas that ordinarily do not communicate much with
one another.
A possible explanation for the hallucinogenic effect is
that the increased spontaneous communication within
the brain dominates over the input coming from the
sense organs
Nicotine, a compound present in tobacco, stimulates a
family of acetylcholine receptors, conveniently known
as nicotinic receptors. Because nicotinic receptors are
abundant on neurons that release dopamine, nicotine
increases dopamine release (Levin & Rose, 1995;
Pontieri, Tanda, Orzi, & DiChiara, 1996). Because
dopamine release is associated with reward, nicotine
stimulation is rewarding also.
INACTIVATION AND REUPTAKE OF
NEUROTRANSMITTERS
A neurotransmitter does not linger at the postsynaptic
membrane, where it might continue exciting or
inhibiting the receptor. Various neurotransmitters are
inactivated in different ways. The neuropeptides,
however, are not inactivated. They simply diffuse
away. Because resynthesizing these large molecules
takes time, a neuron can temporarily exhaust its
supply.
Serotonin and the catecholamines (dopamine,
norepinephrine, and epinephrine) do not break down
into inactive fragments at the postsynaptic
membrane. They simply detach from the receptor. At
that point, the next step varies. The presynaptic
neuron takes up much or most of the released
neurotransmitter molecules intact and reuses them
This process, called reuptake, occurs through special
membrane proteins called transporters. The activity
of transporters varies among individuals and from
one brain area to another. Any transmitter molecules
that the transporters do not take will instead break
down by an enzyme called COMT (catechol-o-
methyltransferase). The breakdown products wash
away and eventually show up in the blood and urine.
Stimulant drugs, including amphetamine and cocaine,
inhibit the transporters for dopamine, serotonin, and
norepinephrine, thus decreasing reuptake and
prolonging the effects of the neurotransmitters
(Beuming et al., 2008; Schmitt & Reith, 2010; Zhao
et al., 2010). Most antidepressant drugs also block
reuptake of one or more neurotransmitters, but more
weakly than amphetamine and cocaine do.
When stimulant drugs increase the accumulation of
dopamine in the synaptic cleft, COMT breaks down
the excess dopamine faster than the presynaptic cell
can replace it. A few hours after taking a stimulant
drug, a user has a deficit of dopamine and enters a
withdrawal state, marked by reduced energy, reduced cells. A neurotransmitter is like a telephone signal: It The hypothalamus maintains fairly constant
motivation, and mild depression. conveys a message from the sender to the intended circulating levels of certain hormones through a
receiver. Hormone’s function more like a radio negative feedback system. For example, when the
Summary of Some Drugs and Their Effects station: They convey a message to any receiver tuned level of thyroid hormone is low, the hypothalamus
Drugs Main Synaptic Effects to the right station. Neuropeptides are intermediate. releases TSH-releasing hormone, which stimulates
Amphetamine Blocks reuptake of They diffuse within part of the brain, but not to other the anterior pituitary to release TSH, which in turn
dopamine and several parts of the body. causes the thyroid gland to secrete more thyroid
other transmitters hormones.
Hormones are particularly useful for coordinating
Cocaine Blocks reuptake of
dopamine and several long-lasting changes in multiple parts of the body. For
other transmitters example, birds that are preparing for migration secrete
Methylphenidate Blocks reuptake of hormones that change their eating and digestion to
(Ritalin) dopamine and others, store extra energy for a long journey. Two types of
but gradually hormones are protein hormones and peptide
MDMA (“Ecstasy”) Releases dopamine hormones, composed of chains of amino acids.
Releases serotonin (Proteins are longer chains and peptides are shorter.)
Nicotine Stimulates nicotinic- Protein and peptide hormones attach to membrane
type acetylcholine receptors, where they activate a second messenger
receptor, which (among within the cell— exactly like a metabotropic synapse.
other effects) increases
dopamine release in Just as circulating hormones modify brain activity,
nucleus accumbens hormones secreted by the brain control the secretion of
Opiates (e.g., heroin, Stimulates endorphin many other hormones. The pituitary gland, attached to
morphine) receptors the hypothalamus, has two parts, the anterior pituitary
Cannabinoids Excites negative- and the posterior pituitary, which release different sets
(marijuana) feedback receptors on of hormones. The posterior pituitary, composed of
presynaptic cells; those neural tissue, can be considered an extension of the
receptors ordinarily hypothalamus. Neurons in the hypothalamus
respond to anandamide
synthesize the hormones oxytocin and vasopressin
and 2AG
(also known as antidiuretic hormone), which migrate
Hallucinogens (e.g., Stimulates serotonin
LSD) type 2A receptors (5- down axons to the posterior pituitary. Later, the
HT2A) posterior pituitary releases these hormones into the
blood.
HORMONES The anterior pituitary, composed of glandular tissue,
Hormonal influences resemble synaptic transmission synthesizes six hormones, although the hypothalamus
in many ways, including the fact that many chemicals controls their release. The hypothalamus secretes
serve both as hormones and as neurotransmitters. A releasing hormones, which flow through the blood to
hormone is a chemical secreted by cells in one part of the anterior pituitary. There they stimulate or inhibit
the body and conveyed by the blood to influence other the release of other hormones.
NEUROTRANSMITTERS AND BEHAVIOR