1

Lecture 2. Synapses and their functions.

1. General features of synapses. Classification of synapses.

At first, I would like to define this concept.

A synapse is a junction between two neurons or between a neuron and an effector
cell (usually this is a muscle cell or a secretory cell). The main function of a
synapse is transmission of information from a neuron to another contacted cell.
Synaptic transmission can not only excite the contacted cell but also inhibit it.
Depending on the localization all synapses are divided into:
1. Axo­axonic synapses, in which an axon of one neuron terminates on an axon of
another neuron.
2. Axo­dendritic synapses, in which an axon of one neuron terminates on a
dendrite of another neuron.
3. Axo­somatic synapses, in which an axon of one neuron ends on a soma (cell
body) of another neuron or effector cell.

Depending on the method of the signal transmission, synapses are divided into:
1. Electrical synapses.
2. Chemical synapses.

Electrical synapse is a synapse, in which two neurons contact through the gap
junction. Gap junction provides a direct exchange of ions between two neurons.
As a result, an action potential reaching the terminal portion of a presynaptic
neuron directly enters the postsynaptic neuron. An important feature of electrical
synapse is a little synaptic delay because of the direct flow of current. Moreover,
the impulse is transmitted in either direction through the electrical synapse. This
type of impulse transmission occurs in some tissues like the cardiac muscle fibers,
smooth muscle fibers of intestine and the epithelial cells of lens in the eye.
But the vast majority of the synapses in the human body are chemical synapses.
In this type of synapses the signals are transmitted by the release of a chemical
transmitter. This chemical transmitter is called the mediator.
2. Anatomy of the chemical synapse and the mechanism of the synaptic
transmission.
Let’s consider the anatomy of a typical chemical synapse in detail.
A neuron, from which the axon arises is called a presynaptic neuron and a neuron,
on which the axon ends is called a postsynaptic neuron. An axon of the
presynaptic neuron divides into many small branches before forming the synapse.
These branches are known as presynaptic axon terminals. Each presynaptic
terminal contains a big amount of small vesicles filled with a mediator. Moreover,
it contains the neurofibrils, which can move the vesicles toward a synaptic cleft.
The synaptic cleft is a narrow space (of about 20­30 Angstrems) between the
presynaptic and postsynaptic neurons. The ionic composition of the synaptic cleft
is identical to the ionic composition in the extracellular space. This means that
there is a high concentration of sodium and chloride ions in the synaptic cleft
compared to the cellular content. The membrane of the postsynaptic neuron,
 2
which surrounds the synaptic cleft, is called the postsynaptic membrane. This
membrane has the receptors, to which the mediator can bind. If this binding
occurs, the permeability to the different ions is changing and a postsynaptic
graded potential is formed.
Let’s look on the mechanism of the synaptic transmission in detail. Action
potential reaches the presynaptic terminal and opens its calcium channels. The
calcium ions move into the cell according to the concentration gradient and
activate the exocytosis of mediator into the synaptic cleft. The molecules of the
mediator bind to the receptor of the postsynaptic membrane and change its
permeability to the ions. Depending on the receptor type, this binding produces a
depolarizing or hyperpolarizing graded potential in the postsynaptic membrane.
For example, the binding of acetylcholine to ligand­gated Sodium channels causes
them to open, allowing the diffusion of Sodium ions into the postsynaptic cell. If
the resulting depolarizing graded potential reaches the threshold, an action
potential is produced. On the other hand, the opening of Potassium or Chlorine
channels results in a hyperpolarizing graded potential.
Depending on the changes of the membrane potential in the postsynaptic cell all
synapses are divided into two types:
excitatory synapses, in which excitatory postsynaptic potential or EPSP occurs
and inhibitory synapses, in which inhibitory postsynaptic potential or IPSP
occurs.
EPSP is a local graded depolarization of the postsynaptic membrane. If this
depolarization reaches the threshold, the cell produces action potential and
conducts it along the membrane.
IPSP is a local graded hyperpolarization. It moves the membrane potential further
from threshold and decreases the likelihood of producing action potentials.
If the presynaptic neuron produces EPSP in the contacted cell, it is called
excitatory neuron. If it produces IPSP, it is called an inhibitory neuron.

3. The physiological properties of synapses.

Let’s consider the main properties of synapses. These are:

1) One way conduction law. According to this law, the impulses are
transmitted only in one direction, that is, from a presynaptic neuron to a
postsynaptic neuron.
2) Synaptic delay. Synaptic delay is a short delay that occurs during the
transmission of impulses through the synapse. This time is needed for release
of neurotransmitter, its passage from axon terminal to postsynaptic membrane
and an action of the neurotransmitter to open the ionic channels in postsynaptic
membrane. Normal duration of synaptic delay is from 0.3 (zero point
three) to 0.5 milliseconds.
3) Fatigue. Fatigue occurs if a synapse is stimulated for a long time. It is due to
the depletion of neurotransmitter. A presynaptic cell needs some time to
resynthesize a new portion of the mediator.
4) Summation is the fusion of effects or a progressive increase in the excitatory
postsynaptic potential in postsynaptic neuron when many presynaptic
 3
excitatory terminals are stimulated simultaneously or when a single
presynaptic terminal is stimulated repeatedly. Increased EPSP triggers the axon
potential in the initial segment of axon of postsynaptic neuron.

4. Physiological characteristics of mediators.

There are about 50 biologically active substances, which currently may be

considered mediators. They are divided into 6 groups according to their chemical
structure. These groups are:
Choline derivatives. Acetylcholin belongs to this group. It is secreted in the
cerebral cortex, cerebellum, basal ganglia, retina, spinal cord and has not only
an excitatory but also an inhibitory effect.
Amines. This group includes adrenalin, noradrenalin, dopamine, serotonin and
histamine. These mediators are secreted in different parts of the central and
peripheral nervous system. Adrenalin and noradrenalin have excitatory or
inhibitory effects depending on the receptors in the postsynaptic cells,
histamine has mainly an excitatory effect, dopamine and serotonin have
mainly an inhibitory effect.
Aminoacids. Neurotransmitters of this group are involved in fast synaptic
transmission and are inhibitory or excitatory. GABA, glycine, glutamate
(glutamic acid) and aspartate (aspartic acid) belong to this group. GABA and
glycine are mainly inhibitory mediators, while glutamate and aspartate are
mainly excitatory mediators.
Peptides. This group includes substance P, enkephalins, endorphins and some
other substances, like somatostatin, bombesin and vasoactive intestinal peptide.
Neurotransmitters from this group are often considered as neuromodulators,
which can modify synaptic activity of another mediator.
Nucleotides derivatives. ATP and adenosine belong to this group.
Soluble gases. These are nitric oxide (NO) and carbon monoxide (CO)

The action of neurotransmitters can be achieved by two mechanisms:

An ionotropic mechanism and a metabotropic mechanism.
When a mediator acts through the ionotropic mechanism, it opens ionic
channels immediately after binding with the receptor of postsynaptic membrane. This
mechanism is direct, is accomplished very quickly and lasts a few milliseconds.
When a mediator acts through the metabotropic mechanism, it triggers a chain
of biochemical reactions at the membrane and cytoplasm of the cell, which leads to
the formation of secondary messengers. These are the biologically active substances,
which change the permeability of the cell membrane to the ions. This mechanism is
longer then the ionotropic mechanism. In most cells it requires the G­protein of the
cell membrane.
The G­protein consists of three subunits: alfa, beta and gamma. If a mediator
binds to the receptors of the cell membrane, the alfa subunit of this protein
disconnects from it and triggers the formation of such second messengers as cyclic
AMP, cyclic GMP, activates the intracellular enzymes, gene transcription or opens
the ions channel. All these processes lead to the excitation or the inhibition of the
 4
cell. But this mechanism requires much more time, and such synapses are
considered as slow synapses.
The effect of a neurotransmitter depends on a type of the receptor, to which it
binds. Previously it has been believed that all mediators can be divided into
excitatory and inhibitory or ionotropic and metabotropic. But these days it is clear,
that each neurotransmitter can act simultaneously as excitatory and inhibitory
mediator through ionotropic or metabotropic mechanism. Thus, the action of a
neurotransmitter depends on the type of its receptor in the postsynaptic cell.
After the execution of the action, neurotransmitter is inactivated by three
different mechanisms:
1. It is removed by reuptake into the axon terminal.
2. It is destroyed or disintegrated by specific enzymes.
3. It diffuses out of the synaptic cleft to the area where it has no action and is
engulfed by astrocytes.
Let’s consider several examples. Such widespread disease as depression is
associated with a lack of the neurotransmitter serotonin in the synapses of the limbic
system. The inhibition of the protein, which promotes the reuptake of serotonin into
the presynaptic terminal, leads to its accumulation in the synaptic cleft. Such an effect
is characteristic of Prozac and Zoloft – the two most common antidepressive drugs.
As a second example, the enzyme cholinesterase destroys the mediator
acetylcholine at the neuromuscular junction. The drugs like Prozerinum inhibit the
cholinesterase and promote the accumulation of acetylcholine at the neuromuscular
synapse and enhance muscle contraction.
Let’s consider some important neurotransmitters in detail.
Acetylcholine is a cholinergic neurotransmitter. It has mainly an excitatory
function. It produces the excitatory function by opening the ligand­gated sodium
channels.
Acetylcholine is the mediator at the neuromuscular synapses. It is also released in the
autonomic nervous system, retina and many regions of brain.
Action of Ach is short lived. Within one millisecond after the release from the
vesicles, it is hydrolyzed into acetate and choline by the enzyme acetylcholin­
esterase. This enzyme is present in the basal lamina of the synaptic cleft.
There are two types of receptors through which Ach acts on the tissues,
namely, muscarinic receptors and nicotinic receptors. The reason for the terminology
of these receptors is following: a poisonous substance from a mushroom called
muscarine, acts on a specific group of receptors known as muscarinic receptors;
similarly, another substance called nicotine acts on a specific group of receptors
known as nicotinic receptors but Ach acts on both these receptors.
Muscarinic receptors are present in all the organs innervated by the postganglionic
fibers of the parasympathetic system and by the sympathetic cholinergic nerves.
Nicotinic receptors are present in the synapses between preganglionic and
postganglionic neurons of both sympathetic and parasympathetic systems. Nicotinic
receptors are also present in the neuromuscular junction on the membrane of skeletal
muscle.
Noradrenaline is the neurotransmitter in adrenergic nerve fibers. It is released
from the postganglionic sympathetic nerve endings, cerebral cortex, hypothalamus,
 5
basal ganglia, brainstem, spinal cord. In many places, noradrenaline is the
excitatory mediator and in very few places, it causes inhibition. It is believed to be
involved in dreams, arousal and elevation of moods. There are two types of
adrenergic receptores: alfa and beta and their different subtypes. Noradrenalin acts as
a metabotropic mediator through the G­protein of the postsynaptic membrane.
Dopamine is secreted by nerve endings in the basal ganglia, hypothalamus,
and limbic system. Dopamine has an inhibitory action on the postsynaptic cells. It is
believed that the Parkinson’s disease is caused by the lack of Dopamine. This disease
is manifested by constant trembling of the limbs.
Serotonin is synthesized from an amino acid tryptophan. Large amount of
serotonin is found in enterochromatin cells of GI tract. A small amount is found in
platelets and the nervous system. Serotonin is an inhibitory substance. It inhibits
impulses of pain sensation in posterior gray horn of spinal cord. Its shortage is a
probable cause of mood and sleep disorders. Serotonin causes vasoconstriction,
platelet aggregation and smooth muscle contraction. It also controls food intake.
Histamine is secreted in nerve endings of hypothalamus, limbic cortex and
other parts of cerebral cortex. It is also secreted by gastric mucosa and mast cells.
Histamine is an excitatory neurotransmitter. It is believed to play an important role in
allergic reactions (airway constriction and edema).
Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter in
synapses, particularly in the CNS. It is responsible for presynaptic inhibition. GABA
causes synaptic inhibition by opening chloride channels. Thus, negatively charged
chlorine ions enter into the postsynaptic cell. This leads to hyperpolarization, which
is known as the inhibitory postsynaptic potential (IPSP).
Substance P is a neuropeptide that acts as a neurotransmitter and as a
neuromodulator. Substance P is secreted by the nerve endings (first order neurons) of
the pain pathway in spinal cord. It is also found in many peripheral nerves, different
parts of brain (particularly in hypothalamus), retina and intestine. It mediates pain
sensation. It is a potent vasodilator in the CNS. It is responsible for regulation of
anxiety, stress, mood, neurotoxicity, nausea and vomiting.
Nitric oxide (NO) is a neurotransmitter in the CNS. It is also the important
neurotransmitter in the neuromuscular junctions of the GI tract. Nitric oxide acts as a
mediator for the dilatory effect of Ach in small arteries. In the smooth muscle fibers
of arterioles, NO activates the enzyme guanylyl cyclase, which in turn causes
formation of cyclic guanosine monophosphate (cGMP) from GMP. The cGMP is a
smooth muscle relaxant and causes dilatation of arterioles. Thus, NO indirectly
causes dilatation of arterioles. A peculiar property of NO is that it is neither produced
by the neuronal cells nor stored in the vesicles. It is produced by non­neuronal cells
like the endothelial cells of blood vessels. It diffuses from the site of production into
the neuronal and non­neuronal cells where it exerts its action.
5. Interaction of synaptic processes.
A single stimulus can produce only a graded potential on the postsynaptic
membrane (EPSP or IPSP). But the graded potential is not sufficient to produce an
action potential. In order to do this, a summation of the EPSP is needed. There are
two types of summation in the synapses.
Temporal summation and Spatial summation.
 6
Spatial summation occurs when many presynaptic terminals are stimulated
simultaneously.
Temporal summation occurs when one presynaptic terminal is stimulated
repeatedly.
Both types of summation are important not only for the cell excitation but also
for cell inhibition.
Tetanic potentiation refers to the enhanced excitability of the postsynaptic
membrane if the synapse is stimulated for a long time (a few hours). It lasts even after
the stimulation is over. A possible mechanism of the titanic potentiation is an
accumulation of Calcium ions in the presynaptic terminal. This mechanism is
important for the fixation of information in memory during learning.
Presynaptic inhibition and facilitation. Through axoaxonic synapses, one
neuron can release a neuromodulator that influences the release of a neurotransmitter
from the presynaptic terminal of another neuron. In presynaptic inhibition, there is a
reduction in the amount of neurotransmitter released from the presynaptic terminal.
For example, sensory neurons responsible for pain can release neurotransmitters from
their presynaptic terminals and stimulate the postsynaptic membranes of neurons in
the brain or spinal cord. Perception of pain occurs only if action potentials are
produced in the postsynaptic membranes of the CNS neurons. Enkephalins and
endorphins released from inhibitory neurons of axoaxonic synapses can reduce or
eliminate pain sensations by inhibiting the release of neurotransmitter from the
presynaptic terminals of sensory neurons. Enkephalins and endorphins can block
voltage­gated Ca2+channels because of the depolarization of the axonal membrane.
Thus, when action potentials reach the presynaptic terminal, the influx of Ca2+ that
normally stimulates neurotransmitter release is blocked.
Another example of the presynaptic inhibition is the release of GABA in the
axoaxonic synapses in spinal cord. GABA is a typical inhibitory neurotransmitter,
which can hyperpolarize the postsynaptic axonal membrane and stop the conduction
of action potentials along an axon. Thus, there are two types of presynaptic
inhibition depending on the change of membrane potential – depolarized and
hyperpolarized.
In presynaptic facilitation, there is an increase in the amount of
neurotransmitter released from the presynaptic terminal. For example, serotonin,
released in certain axoaxonic synapses, functions as a neuromodulator that increases
the release of neurotransmitter from the presynaptic terminal by causing voltage­
gated Ca2+ channels to open.
Most neurotransmitters from the last three chemical groups are considered as
neuromodulators. For example, opioid and non­opioid peptides are substances that
inhibit pain sensation by modifying the synapses in thalamus and hypothalamus.