SYNAPSE

Nerve signals are transmitted from one nerve cell to the next through interneuronal junctions called
synapses. This word comes from the Greek syn (together) and haptein (join). The synaptic
transmission is not a simply nerve impulse conduction, but a very complex process.
Classification of synapses
According to the way in which the nerve impulse is transmitted from one nerve cell to another, the
synapses can be divided in:
electrical synapse, which is characterized by a narrow space between the two nerve cells and
by the presence of the so called gap junctions. These are small proteic tubular structures, which
allow the free movement of ions from one cell to the other, and let the nerve impulse pass directly
from one neuron to the other. It is believed that in humans this type of synapse is present only in
the vestibular nuclei.
chemical synapse. In this type of synapse, the first neuron secretes a chemical substance
called a neurotransmitter which is released in the synaptic space and which will act on the second
neuron. The vast majority of the synapses in the human brain are chemical synapses. Chemical
synapses are slower than electrical ones but are also far more flexible.
According to the parts of the 2 neurons that establish the synaptic contact, the synapses can be:
Axo-dendritic
Axo-somatic
Axo-axonic
Dendro-dendritic
According to the effects produced on the postsynaptic neuron, the synapses can be:
Excitatory, if they tend to depolarize and activate the postsynaptic neuron
Inhibitory, if they tend to hyperpolarize and inhibit the postsynaptic neuron
Physiologic anatomy of the synapse
Synapses usually occur between the axon of a pre-synaptic neuron and a dendrite or cell body of a
post-synaptic neuron. Electron microscopic studies of the synapse have shown that the synapse is
composed by:
1. the presynaptic terminals
2. the synaptic cleft
3. the postsynaptic membrane


1. The presynaptic terminals (of the presynaptic neuron): At a synapse, the end of the axon is
'swollen' and referred to as an end bulb or synaptic knob or terminal buttons. Within the end bulb
are found lots of synaptic vesicles, which contain neurotransmitters. These neurotransmitters will
be released into the synaptic cleft. Because the release of neurotransmitters expends large amount
of energy, mitochondria are usually plentiful in this region of the neuron. Mitochondria provide
adenosine triphosphate (ATP), which is required to synthesize new neurotransmitter molecules.
Neurons in the brain and the cord differ in the number of presynaptic terminals, which may range
from only a few to several hundred thousands. These differences make neurons in different parts of
the nervous system react differently to incoming signals and therefore perform different functions.
2. The synaptic cleft: Between the end bulb and the dendrite (or cell body) of the post-synaptic
neuron, there is a gap commonly referred to as the synaptic cleft. The synaptic cleft has usually a
width of 20-30 nm. This means that pre- and post-synaptic membranes do not actually come in
contact and that the impulse cannot be transmitted directly. Rather, the impulse is transmitted by
the release of chemicals called chemical transmitters (or neurotransmitters), which act on the
postsynaptic membrane
3. The postsynaptic membrane belongs to the second neuron and it contains specific receptors
for neurotransmitters. Each type of neurotransmitter has a molecular form that lets it bind to the
right receptor on the second neuron to produce its particular effect.

THE SYNAPTIC TRANSMISSION
The process by which the information is communicated from one neuron to the next is called
synaptic transmission and can be broken into 6 steps:
1. Neurotransmitter synthesis: first of all, the neurotransmitter has to be synthesized either in the
nerve terminal or in the soma of the neuron. From the soma, the neurotransmitter will be
transported into the nerve terminal.
2. The storage of the neurotransmitter. Once the neurotransmitter is synthesized, it will be stored in
vesicles so that when an action potential arrives at the nerve ending, the cell is ready to pass it
along to the next neuron. The storage is necessary for the case in which the neuron discharges
action potentials more rapidly than the neurotransmitter can be synthesized.
3. The release of the neurotransmitter into the synaptic cleft: when an action potential arrives at the
terminal, it will depolarize it. The depolarization of the end bulb cause some voltage-dependent
calcium (Ca2+) channels embedded in the pre-synaptic membrane to open and Ca2+ rushes in.
The calcium ions cause the transmitter vesicle to bind to and fuse with the prresynaptic membrane.
Finally, the vesicles open to the exterior and the neurotransmitter is released into the synaptic cleft.
This process is called exocytosis. Following exocytosis, the vesicular membrane, presently a
continuous extension of the pre-synaptic membrane, forms a pit and pinches off into the terminal to
form a new, vacant vesicle. This vesicle is then either recycled and refilled with more of the
neurotransmitter, or sent to the cell body, where it is broken down, processed into a new vesicle,
and transported to the terminal where it can then be filled with the neurotransmitter. The quantity of
the neurotransmitter released into the synaptic cleft depends on the number of calcium ions that
have entered the neuron.
4. The crossing of the synaptic cleft:The neurotransmitter crosses the synaptic cleft by Brownian
movement. Once it recheaes the postsynaptic membrane, it will bind to specific neurotransmitter
receptors.The neurotransmitter thus acts somewhat like a key. If it is the right shape for the next
neuron (shown here as a lock), it will produce an effect on that neuron.
5. The activation of postsynaptic neuron: The neurotransmitter will be recognized and bound by the
specific neurotransmitter receptors found on the postsynaptic membrane. The receptors are
membrane proteins consisted of two parts: a binding component that protrudes outward from the
membrane into the synaptic cleft and an ionophore component, that passes through membrane and
that is either a ion channel or an enzyme. So, the binding of the neurotransmitter to the specific
receptor either opens an ion chanell, or activates an internal metabolic change inside the cell. The
ion channels act quickly (in 1-2 milliseconds) to depolarize or hyperpolarize the postsynaptic
neuron. The enzyme receptors act slower and their effects last more 9hundreds of milliseconds,
minutes. These receptors are important in some forms of memory.
6. After its recognition by the receptor, the neurotransmitter must be inactivated so that it does not
continually occupy the receptor sites of the postsynaptic cell. Inactivation of the neurotransmitter
avoids constant stimulation of the postsynaptic cell, while at the same time freeing up the receptor
sites so that they can receive additional neurotransmitter molecules, should another action potential
arrive. Some neurotransmitters are removed from the synaptic cleft by special transporter proteins
on the pre-synaptic membrane. These transporter proteins carry the neurotransmitter back into the
pre-synaptic cell, where it is either re-packaged into a vesicle and stored until it is once again
needed to transmit a chemical message, or broken down by enzymes. Not all neurotransmitters are
recycled by the presynaptic cell. Some neurotransmitters quickly diffuse away from the receptors
into the surrounding medium. Other neurotransmitters, such as acetylcholine, has a specialized
enzyme for inactivation right in the synaptic cleft called acetylcholinesterase (AChE).
Types of postsynaptic responses
Binding of the neurotransmitter to their specific receptors on the postsynaptic membrane sometimes
activate the postsynaptic neuron, sometimes inhibit it.




Excitatory postsynaptic potential (EPSP)
When the neurotransmitter depolarizes the postsynaptic membrane, it is said to produce an
excitatory postsynaptic potential. The depolarization is explained by opening Na channels, which
enters the cell and shifts the membrane potential closer to the threshold for action potential
generation and so renders the postsynaptic membrane more excitable. EPSP lasts for 15-20 msec
and rarely exceeds a few millivolts. EPSP is not an all-or-none event, but are graded with the
intensity of activation. The EPSP that occurs as a result of activation of individual synapses has
alow amplitude. This means that a single EPSP usually cannot generate an action potential in the
second neuron. An action potential is given by summation. The temporal summation refers to the
repeated activation of the same synapse. The amplitude of the EPSP will increase until it reaches
the threshold for generating the action potential. The spatial summation refers to activation of
different synapses on different part of the cell at the same time, leading to a high enough EPSP to
generate the action potential.

Inhibitory postsynaptic potential (IPSP)
When the neurotransmitter hyperpolarizes the postsynaptic membrane, it is said to produce an
inhibitory postsynaptic potential. IPSP is explained either by opening the K channels, allowing K to
leave the cell and render the membrane more negatively charged on the inside or by opening the Cl
channels, allowing Cl to enter the cell, with the same result. AS the EPSP, IPSP lasts for 20 msec
and has an amplitude of a few millivolts. During the IPSP the postsynaptic neuron is less excitable
than normal. IPSP is allows graded with the intensity of activation and can summate with EPSP or
others IPSP, temporally or spatially. If an IPSP tends to decrease the membrane potential to a more
negative value and an EPSP tends to increase it at the same time, their effects can nullify each
other. Or, if a neuron is being excited by an EPSP, then an inhibitory signal from another neuron
can reduce the postsynaptic potential to less than the threshold value for excitation.

Special characteristics of the synaptic transmission
1. One way conduction: because only the terminal buttons contain neurotransmitters and only the
postsynaptic membrane contains receptors for neurotransmitters, synapses transmit the signal in
one single direction: from the presynaptic neuron to the postsynaptic neuron. This is different from
the conduction in one nervous fiber, in which the action potential can be transmitted both ways.
2. Synaptic delay: in synaptic transmission there is a delay of 0.5 msec. This time is needed for
release, diffusion and action of the neurotransmitter on the postsynaptic membrane. The higher the
number of synapses in a neuronal circuit, the longer the time of information to reach the target.
3. Fatigue of synaptic transmission: when excitatory synapses are repetitively stimulated, The
number of discharges by the postsynaptic neuron is at first very great, but it becomes less in a few
milliseconds. This is called synaptic fatigue and is mainly due to exhaustion of the stores of
neurotransmitter in the terminal buttons. The development of fatigue is a protective mechanism
against excessive neuronal activity, as when areas of nervous system become overexcited, fatigue
causes them to lose this excess excitability after a while.
4. Effects of hypoxia and drugs on synaptic transmission
Because synaptic transmission is energy consuming, it depends on an adequate supply of oxygen.
Lack of oxygen can cause cessation of synaptic transmission. This is seen when the cerebral
circulation is interrupted and when the person becomes unconscious within 3-5 seconds.
As for drugs, most anesthetics exert their effects on synapses, either by increasing the release of
inhibitory neurotransmitter, or by decreasing the excitatory neurotrasmitters.
Caffeine in coffee, theophyline in tea, theobromin in cocoa increase neuronal excitability by
reducing the threshold for excitation.
5. Temporal and spatial summation (see above)


Neurotransmitters
Neurotransmitters are chemical molecules that ferry nerve impulses across the synapse from one
neuron to the next. Each type of neurotransmitter has a molecular form that lets it bind to the right
site on the second neuron to produce its particular effect.
The neurotransmitters can be divided into 6 classes:
1. Esters: acetylcholine (Ach)
2. Monoamines: norepinephrine (noradrenaline), dopamine, serotonin
3. Aminoacids: glutamate, gamma-amino butyric acid (GABA)
4. Purines: ATP
5. Peptides: enkephalins, substance P
6. Inorganic gases: NO
Usually, only a single type of transmitter is released by each type of neuron. A certain
neurotransmitter may be more highly concentrated in one area of the brain than it is in another. In
addition, the same neurotransmitter may elicit a variety of different responses based on the type of
tissue being targeted. Some nerve terminals are known to contain 2 different kinds of
neurotransmitter, which are released at the same time whne the nerve terminal is activated. For
example, the parasympathetic nerves of the salivary glands release both Ach, whih increases
salivary secretion and vasoactive intestinal peptide (VIP), which increases the local blood flow.
Neurotransmitters are divided into two categories according to the effect that they have on the
second neuron once they are released into the synaptic gap. Neurotransmitters that help this
neuron to propagate the nerve impulse are classified as excitatory neurotransmitters. Such
excitatory neurotransmitters are Ach in most cases, noradrenaline in most cases, glutamate.
Neurotransmitters that reduce the likelihood of this neurons propagating the impulse are called
inhibitory neurotransmitters. Such neurotransmitters are GABA and glycine.

The neuromuscular junction
The neuromuscular junction is a specific type of synapse; in this case the nerve endings make the
junction with a muscle fiber. The skeletal muscle fibres are innervated by large, myelinate nerve
fibres that originate in the large alpha motomeurons of the anterior horns of the spinal cord. Each
nerve branches many times and innervates 3 to several hundred muscle cells. One neuron and the
muscle fibres innervated by it form a motor unit.
The neuromuscular junction is usually placed in the middle of the muscle fiber. The nerve terminal
invaginate into the muscle fiber. This means that nerves are fairly firmly attached to the muscles
they innervate. The invagination of the muscle fibre is called the synaptic gutter. At the bottom of it
there are many small folds of the membrane, which increase the surface area of the postsynaptic
membrane.

The neurotransmitter of the neuromuscular junction is always Ach, that has an excitatory effect on
muscle fibre. A single action potential that reaches the nerve terminal is able to produce the
depolarization of muscle cell membrane; for neuromuscular junction there is no need of summation.
From the synaptic gutter, the depolarization travels very rapidly in both directions to the muscle fiber
ends. Muscle fiber depolarization will be followed by the muscle fiber contraction.
Ach will be rapidly removed from the neuromuscular junction, being degraded by the enzyme
acetylcholinesterase and thus preventing muscle re-excitation after the fiber has recovered from the
first action potential.
Drugs that affect neurotransmission
Drugs with Ach-like effects: metacholine, nicotine, carbachol have the same effects as ACh on
muscle fibers. Because they are not decomposed by acetylcholinesterase, thaie effect lasts
for minutes and hours, causing spasms.
Drugs that stimulate neuromuscular transmission by inactivating acetylcholinesterase:
neostigmine, diisopropylfluorophosphate. They cause Ach to accumulate and repetitively
stimulate the muscle fiber, producing spasms.
Drugs that block neuromuscular transmission: curariform drugs 9d-tubocurarine) prevent
transmission of impulses from nerve terminals to muscle fibers.