Central Nervous System

Synapses
 INTENDED LEARNING OBJECTIVES

To the end of the lecture students must be able to:

1. Understand the components of terminal boutons and the synapse.

2. Describe various types of synapses.
3. Explain the function of synapses and the various effects.
4. Be able to describe various aspects of neurotransmission.
5. Define the unique components of cholinergic synapses.
6. Define the unique components of adrenergic synapses.
7. Understand the mechanism of neurotransmitter release.
8. Name various neurotransmitter and their effects.
9. Describe various neurotransmitter receptors.
10. Explain the difference between neurotransmitters and
neuromodulators.
 PROPAGATION OF THE ACTION POTENTIAL

Propagation of the action

potential along the
membrane
(unmyelinated nerve
fibers!!!)

Velocity of Conduction - 0.25

m/sec in small unmyelinated fibers.
 Saltatory conduction in Myelinated
Nerve Fibers

Action potentials “jump” long distances from one node to the next!!
Information is transmitted in the central nervous system
mainly in the form of nerve action potentials, called
simply “nerve impulses,” through a succession of
neurons, one after another. However, in addition, each
impulse (1) may be blocked in its transmission from one
neuron to the next, (2) may be changed from a single
impulse into repetitive impulses, or (3) may be
integrated with impulses from other neurons to cause
highly intricate patterns of impulses in successive
neurons. All these functions can be classified as
synaptic functions of neurons.
 Types of Synapses—Chemical
and Electrical
A synapse is a site where information is transmitted
from one cell to another. The information can be
transmitted either electrically (electrical synapse) or via
a chemical transmitter (chemical synapse).
There are two major types of synapses:
(1) the chemical synapse and
(2) the electrical synapse.
Almost all the synapses used for signal transmission in
the central nervous system of the human being are
chemical synapses.
Electrical Synapses

Electrical synapses allow current

to flow from one excitable cell to
the next via low resistance
pathways between the cells called
gap junctions. Gap junctions are
found in cardiac muscle and in
some types of smooth muscle
and account for the very fast
conduction in these tissues. For
example, rapid cell-to-cell
conduction occurs in cardiac
ventricular muscle, in the uterus,
and in the bladder, allowing cells
in these tissues to be activated
simultaneously and ensuring that
contraction occurs in a
coordinated manner.
 Chemical Synapses
In chemical synapses, the
first neuron secretes at its
nerve ending synapse a
chemical substance called
a neurotransmitter (or
often called simply
transmitter substance),
and this transmitter in
turn acts on receptor
proteins in the membrane
of the next neuron to
excite the neuron,
inhibit it, or modify its
sensitivity in some other
way.
More than 40 important transmitter substances have
been discovered thus far. Some of the best known are
acetylcholine, norepinephrine, epinephrine,
histamine, gamma-aminobutyric acid (GABA),
glycine, serotonin, and glutamate.
 “One-Way” Conduction at
Chemical Synapses.
Chemical synapses have one exceedingly important
characteristic that makes them highly desirable for
transmitting most nervous system signals: they always
transmit the signals in one direction: that is, from
the neuron that secretes the transmitter substance,
called the presynaptic neuron, to the neuron on
which the transmitter acts, called the postsynaptic
neuron.
This is the principle of one-way conduction at chemical
synapses, and it is quite different from conduction through
electrical synapses, which often transmit signals in either
direction.
It allows signals to be directed toward specific goals. Indeed, it is this
specific transmission of signals to discrete and highly focused areas both
within the nervous system and at the terminals of the peripheral nerves
that allows the nervous system to perform its myriad functions of
sensation, motor control, memory, and many others.
Physiologic Anatomy of the
Synapse
Anterior motor neuron –
is composed of three major parts: the soma, which is the
main body of the neuron; a single axon, which extends
from the soma into a peripheral nerve that leaves the
spinal cord; and the dendrites, which are great numbers
of branching projections of the soma that extend as much
as 1 millimeter into the surrounding areas of the cord.
As many as 10,000 to 200,000 minute synaptic knobs
called presynaptic terminals lie on the surfaces of the
dendrites and soma of the motor neuron, about 80 to 95
per cent of them on the dendrites and only 5 to 20 per
cent on the soma.
These presynaptic terminals are the ends of nerve fibrils
that originate from many neurons. Many of these
presynaptic terminals are excitatory—that is, they
secrete a transmitter substance that excites the
postsynaptic neuron. But other presynaptic terminals
are inhibitory—they secrete a transmitter substance that
inhibits the postsynaptic neurons.
Later, it will become evident that many neurons in other
parts of the cord and brain differ from the anterior
motor neuron in
(1) the size of the cell body;
(2) the length, size, and number of dendrites,
ranging in length from almost zero to many centimeters;
(3) the length and size of the axon; and
(4) the number of presynaptic terminals, which may
range from only a few to as many as 200,000.
 Presynaptic Terminals
Electron microscopic studies of the presynaptic
terminals show that they have varied anatomical forms,
but most resemble small round or oval knobs and,
therefore, are sometimes called terminal knobs,
boutons, end-feet, or synaptic knobs.
The presynaptic terminal is separated from the
postsynaptic neuronal soma by a synaptic cleft having
a width usually of 200 to 300 angstroms. The terminal
has two internal structures important to the
excitatory or inhibitory function of the synapse: the
transmitter vesicles and the mitochondria.
The transmitter vesicles contain the transmitter
substance that, when released into the synaptic cleft,
either excites or inhibits the postsynaptic neuron—
excites if the neuronal membrane contains excitatory
receptors, inhibits if the membrane contains inhibitory
receptors. The mitochondria provide adenosine
triphosphate (ATP), which in turn supplies the energy
for synthesizing new transmitter substance.
When an action potential spreads over a presynaptic
terminal, depolarization of its membrane causes a
small number of vesicles to empty into the cleft.
The released transmitter in turn causes an immediate
change in permeability characteristics of the
postsynaptic neuronal membrane, and this leads to
excitation or inhibition of the postsynaptic neuron,
depending on the neuronal receptor characteristics.
 Mechanism by Which an Action Potential
Causes Transmitter Release from the
Presynaptic Terminals—Role of Calcium Ions
The membrane of the presynaptic terminal is called the
presynaptic membrane. It contains large numbers of
voltage-gated calcium channels. When an action
potential depolarizes the presynaptic membrane,
these calcium channels open and allow large
numbers of calcium ions to flow into the terminal.
The quantity of transmitter substance that is then
released from the terminal into the synaptic cleft is
directly related to the number of calcium ions that enter.
When the calcium ions enter the presynaptic terminal, it
is believed that they bind with special protein molecules
on the inside surface of the presynaptic membrane,
called release sites.

This binding in turn causes the release sites to open

through the membrane, allowing a few transmitter
vesicles to release their transmitter into the cleft after
each single action potential.
For those vesicles that store the neurotransmitter
acetylcholine, between 2000 and 10,000 molecules
of acetylcholine are present in each vesicle, and
there are enough vesicles in the presynaptic terminal to
transmit from a few hundred to more than 10,000 action
potentials.
 Action of the Transmitter Substance
on the Postsynaptic Neuron—Function of
“Receptor Proteins”
The membrane of the postsynaptic neuron contains
large numbers of receptor proteins, also shown in Figure
45–6. The molecules of these receptors have two
important components: (1) a binding component that
protrudes outward from the membrane into the synaptic
cleft—here it binds the neurotransmitter coming from
the presynaptic terminal—and (2) an ionophore
component that passes all the way through the
postsynaptic membrane to the interior of the
postsynaptic neuron.
The ionophore in turn is one of two types:
(1) an ion channel that allows passage of specified
types of ions through the membrane or
(2) a “second messenger” activator that is not an
ion channel but instead is a molecule that protrudes
into the cell cytoplasm and activates one or more
substances inside the postsynaptic neuron. These
substances in turn serve as “second messengers” to
increase or decrease specific cellular functions.
 Ion Channels
The ion channels in the postsynaptic neuronal
membrane are usually of two types:
(1) cation channels that most often allow sodium
ions to pass when opened, but sometimes allow
potassium and/or calcium ions as well, and
(2) anion channels that allow mainly chloride ions
to pass but also minute quantities of other anions.
The cation channels that conduct sodium ions are
lined with negative charges.
These charges attract the positively charged sodium ions
into the channel when the channel diameter increases
to a size larger than that of the hydrated sodium ion.
But those same negative charges repel chloride ions
and other anions and prevent their passage.
For the anion channels, when the channel diameters
become large enough, chloride ions pass into the
channels and on through to the opposite side, whereas
sodium, potassium, and calcium cations are blocked,
mainly because their hydrated ions are too large to pass.
When cation channels open and allow positively charged
sodium ions to enter, the positive electrical charges of
the sodium ions will in turn excite this neuron.

Therefore, a transmitter substance that opens cation

channels is called an excitatory transmitter.
Conversely, opening anion channels allows negative
electrical charges to enter, which inhibits the neuron.
Therefore, transmitter substances that open these
channels are called inhibitory transmitters.
When a transmitter substance activates an ion
channel, the channel usually opens within a fraction
of a millisecond; when the transmitter substance is
no longer present, the channel closes equally rapidly.

The opening and closing of ion channels provide a

means for very rapid control of postsynaptic
neurons.
“Second Messenger” System in
the Postsynaptic Neuron.
Many functions of the nervous system—for instance,
the process of memory—require prolonged changes
in neurons for seconds to months after the initial
transmitter substance is gone.

The ion channels are not suitable for causing

prolonged postsynaptic neuronal changes because
these channels close within milliseconds after the
transmitter substance is no longer present.
However, in many instances, prolonged postsynaptic
neuronal excitation or inhibition is achieved by
activating a “second messenger” chemical system
inside the postsynaptic neuronal cell itself, and then it is
the second messenger that causes the prolonged effect.
Common mechanisms by which chemical messengers in
the ECF bring about changes in cell function.
There are several types of second messenger systems. One of the most
common types uses a group of proteins called
G-proteins.
A G-protein is attached to the portion of the receptor that protrudes into
the interior of the cell.
The G-protein in turn consists of three components:
- An alpha (α) component that is the activator portion of the G-
protein, and
-beta (β) and
- gamma (g) components
that are attached to the alpha component and also to the inside of the cell
membrane adjacent to the receptor protein.
On activation by a nerve impulse, the alpha portion of the G-protein
separates from the beta and gamma portions and then is free to
move within the cytoplasm of the cell.
Inside the cytoplasm, the separated alpha
component performs one or more of multiple
functions, depending on the specific characteristic
of each type of neuron.

There are four changes that can occur.

They are as follows:
1. Opening specific ion channels through the postsynaptic cell
membrane. A potassium channel that is opened in response to the G-
protein; this channel often stays open for a prolonged time, in contrast to
rapid closure of directly activated ion channels that do not use the second
messenger system.
2. Activation of cyclic adenosine monophosphate (cAMP) or cyclic guanosine
monophosphate (cGMP) in the neuronal cell.
Either cyclic AMP or cyclic GMP can activate highly specific metabolic machinery in the
neuron and, therefore, can initiate any one of many chemical results, including long-term
changes in cell structure itself, which in turn alters long-term excitability of the neuron.
3. Activation of one or more intracellular enzymes.
The G-protein can directly activate one or more intracellular enzymes. In turn
the enzymes can cause any one of many specific chemical functions in the cell.
 4. Activation of gene transcription.
This is one of the most important effects of activation of the second messenger
systems because gene transcription can cause formation of new proteins
within the neuron, thereby changing its metabolic machinery or its structure.
Indeed, it is well known that structural changes of appropriately activated
neurons do occur, especially in long-term memory processes.
G-protein type or of other types, is extremely important
for changing the long-term response characteristics of
different neuronal pathways!
 Toxin Production
Effects of toxins produced by bacteria are also by second-
messenger system.

Exotoxins are produced by several gram-positive and

some gram-negative bacteria, in contrast to endotoxins,
which are present only in gram-negative bacteria.
How do bacteria damage the host?
 ENDOTOXIN vs EXOTOXIN
Composition
LPS (lipidA) vs protein(immunogenic)
Toxic response -fever and shock vs specific affect
Typically produced by gram negatives vs gram positives
and negatives
 Exotoxin
 Many exotoxins have an A-B subunit structure;
 The A (or active) subunit possesses the toxic activity,
and
 The B (or binding) subunit is responsible for binding
the exotoxin to specific receptors on the membrane of
the human cell.
 Important exotoxins that have an A-B subunit structure
include;
 diphtheria toxin, tetanus toxin, botulinum
toxin, cholera toxin, and the enterotoxin of E. coli
Mode of action of E.coli &
V. cholerae enterotoxins
Mechanism of action-Exotoxin
The A subunit of several important exotoxins acts by
ADP-ribosylation; ie, the A subunit is an enzyme
that catalyzes the addition of adenosine
diphosphateribose (ADP-ribose) to the target
protein in the human cell.

The addition of ADP-ribose to the target protein

often inactivates it but can also hyperactivate it,
either of which can cause the symptoms of disease
 Excitatory or Inhibitory Receptors in the
Postsynaptic Membrane
Some postsynaptic receptors, when activated, cause
excitation of the postsynaptic neuron, and others cause
inhibition.
The importance of having inhibitory as well as excitatory
types of receptors is that this gives an additional
dimension to nervous function, allowing restraint of
nervous action as well as excitation.
The different molecular and membrane mechanisms
used by the different receptors to cause excitation or
inhibition include the following.
 Excitation
1. Opening of sodium channels to allow large numbers
of positive electrical charges to flow to the interior of the
postsynaptic cell.

This raises the intracellular membrane potential in the

positive direction up toward the threshold level for
excitation. It is by far the most widely used means for
causing excitation.
2. Depressed conduction through chloride or
potassium channels, or both!!!

This decreases the diffusion of negatively charged

chloride ions to the inside of the postsynaptic neuron or
decreases the diffusion of positively charged potassium
ions to the outside. In either instance, the effect is to
make the internal membrane potential more positive
than normal, which is excitatory.
3. Various changes in the internal metabolism of the
postsynaptic neuron to excite cell activity or, in some
instances, to increase the number of excitatory
membrane receptors or decrease the number of
inhibitory membrane receptors.
 Inhibition
1. Opening of chloride ion channels through the
postsynaptic neuronal membrane.

This allows rapid diffusion of negatively charged

chloride ions from outside the postsynaptic neuron to
the inside, thereby carrying negative charges inward and
increasing the negativity inside, which is inhibitory.
2. Increase in conductance of potassium ions out of
the neuron.
This allows positive ions to diffuse to the exterior, which
causes increased negativity inside the neuron; this is
inhibitory.

3. Activation of receptor enzymes that inhibit

cellular metabolic functions that increase the number
of inhibitory synaptic receptors or decrease the number
of excitatory receptors.