An-Najah National University

Faculty of Medicine
Department of Physiology, pharmacology
and toxicology
Medical physiology one
7102201

Dr. Azza Isleem, MD, PhD

Dr. Heba Salah, PhD
Dr. Abdalrahman Al Aqra’a, MD, Msc.

The Nervous System: A General Principles

The Nervous System
 The Nervous System
• The Nervous System has two major divisions:
1. The Central Nervous System (CNS), which is composed of the brain and
spinal cord.
2. The Peripheral Nervous System (PNS) is composed of the nerves that
connect the brain or spinal cord with the body’s muscles, glands, and sense
organs.

• The neuron is the basic cell type of both systems

• Neurons are amitotic, so they do not divide. They also have a very high
metabolic rate.

• Clusters of cell bodies in the CNS are called nuclei.

• The other major cell types of the nervous system are nonneuronal cells called glial
cells. These cells generally do not participate directly in electrical communication
from cell to cell as do neurons, but they are very important in various supportive 3

functions for neurons.

 Structure of the neurons
• Neurons occur in a wide variety of sizes
and shapes, but all share features that
allow cell-to-cell communication

• A neuron’s cell body (or soma) contains

the nucleus and ribosomes and thus has the
genetic information and machinery
necessary for protein synthesis.

• The dendrites are a series of highly

branched outgrowths of the cell that
receive incoming information from other
neurons.

• Dendritic spines increase the surface area

of dendrites still further. Thus, the
structure of dendrites in the CNS increases
a cell’s capacity to receive signals from
many other neurons. 4
 Structure of the neurons
• The axon is a long process that extends from the cell body
and carries outgoing signals to its target cells. In humans,
axons range in length from a few microns to over a meter.

• The region of the axon that arises from the cell body is
known as the axon hillock (or initial segment). The axon
hillock is the location where, in most neurons, propagated
electrical signals are generated.

• The axon may have branches, called collaterals. Near their

ends, both the axon and its collaterals undergo further
branching

• Each branch ends in an axon terminal, which is

responsible for releasing neurotransmitters from the axon.

• Varicosities??
BASIC NEURONES TPYES
 Structure of the neurons
• The axons of many neurons are covered by sheaths of
myelin, which usually consists of 20 to 200 layers of highly
modified plasma membrane wrapped around the axon by a
nearby supporting cell.

• In the brain and spinal cord, these myelin forming cells are a
type of glial cell called oligodendrocytes.

• Each oligodendrocyte may branch to form myelin on as

many as 40 axons.

• In the PNS, glial cells called Schwann cells form individual

myelin sheaths surrounding 1- to 1.5-mm-long segments at
regular intervals along some axons.

• The spaces between adjacent sections of myelin where the

axon’s plasma membrane is exposed to extracellular fluid are
called the nodes of Ranvier.
 Axonal Transport
• Axonal transport is the movement of various organelles and other materials between the cell body and
the axon terminals.

• This movement depends on a scaffolding of microtubule “rails” running the length of the axon and
specialized types of motor proteins known as kinesins and dyneins.

• At one end, these double-headed motor proteins bind to their cellular cargo, and the other end uses
energy derived from the hydrolysis of ATP to “walk” along the microtubules.
 Axonal Transport
• Kinesin transport mainly occurs from the cell body toward the axon terminals (anterograde) and
is important in moving nutrient molecules, enzymes, mitochondria, neurotransmitter-filled
vesicles, and other organelles.

• Dynein movement is in the other direction (retrograde), carrying recycled membrane vesicles,
growth factors, and other chemical signals that can affect the neuron’s morphology,
biochemistry, and connectivity.

• Retrograde transport is also the route by which some harmful agents invade the CNS, including
tetanus toxin and the herpes simplex, rabies, and polio viruses.
 Functional Classes of Neurons
• Neurons can be divided into three functional classes:
1. Afferent neurons convey information from the tissues and organs of the body toward the CNS.
2. Efferent neurons convey information away from the CNS to effector cells like muscle, gland, or
other cell types.
3. Interneurons connect neurons within the CNS.

• As a rough estimate, for each afferent neuron entering the CNS, there are 10 efferent neurons and
200,000 interneurons. Thus, the great majority of neurons are interneurons.
 Functional Classes of Neurons
Afferent neurons
• Afferent neurons are unusual because they have only a single process, usually considered
an axon

• The axon has two branches:

1. The peripheral process, begins at the receptors
2. The central process, enters the central nervous system to form junctions with other
neurons

• At their peripheral ends (the ends farthest from the central nervous system), afferent
neurons have sensory receptors, which respond to various physical or chemical changes
in their environment by generating electrical signals in the neuron

• The receptor region may be a specialized portion of the

plasma membrane or a separate cell closely associated with
the neuron ending

• Afferent neurons propagate electrical signals from their

receptors into the brain or spinal cord
 Functional Classes of Neurons
Afferent neurons
• The cell body and the long axon of the afferent neurons are outside the central
nervous system, and only a part of the central process enters the brain or spinal cord

• The cell bodies and dendrites of efferent neurons are within the central nervous
system, and the axons extend out to the periphery

• A nerve fiber is a single axon, and a nerve is a bundle of axons (fibers) bound
together by connective tissue

• Nerves : Groups of afferent and efferent neurons

• Interneurons :
 lie entirely within the central nervous system.
 They account for over 99 percent of all neurons and
have a wide range of physiological properties, shapes,
and functions.
 The number of interneurons interposed between specific
afferent and efferent neurons varies according to the
complexity of the action they control
Characteristic of the functional classes of neurons
 The synapse
• The synapse is the anatomically specialized junction
between two neurons where one neuron alters the electrical
and chemical activity of another .

• At most synapses, the signal is transmitted from one neuron

to another by neurotransmitters, a term that also includes the
chemicals efferent neurons use to communicate with effector
cells (e.g., a muscle cell).

• The neurotransmitters released from one neuron alter the

receiving neuron by binding with specific protein receptors
on the membrane of the receiving neuron.

• Most synapses occur between an axon terminal of one

neuron and a dendrite or the cell body of a second neuron.

• A neuron that conducts a signal toward a synapse is called a

presynaptic neuron, whereas a neuron conducting signals
away from a synapse is a postsynaptic neuron.
 Glial Cells
• Glial cells surround the axon and dendrites of neurons, and provide them with physical and metabolic
support.

• Glial cells retain the capacity to divide throughout life. Consequently, many CNS tumors actually
originate from glial cells rather than from neurons

• Types of glial cells:

1. Oligodendrocyte, which forms the
myelin sheath of CNS axons.
 Glial Cells
Types of glial cells
2. Astrocyte:
 Helps regulate the composition of the extracellular fluid in the CNS by removing potassium ions
and neurotransmitters around synapses.

 Another important function of astrocytes is to stimulate the formation of tight junctions between
the cells that make up the walls of capillaries found in the CNS. This forms the blood–brain
barrier which is a much more selective filter for exchanged substances than is present between
the blood and most other tissues.

 Astrocytes also sustain the neurons metabolically— for example, by providing glucose and
removing the secreted metabolic waste product ammonia.

 In embryos, astrocytes guide CNS neurons as they migrate to their ultimate destination, and they
stimulate neuronal growth by secreting growth factors.

 In addition, astrocytes have many neuronlike characteristics. For example, they have ion
channels, receptors for certain neurotransmitters and the enzymes for processing them, and the
capability of generating weak electrical responses.
 Glial Cells
Types of glial cells

3. The microglia
 Specialized, macrophage-like
cells that perform immune
functions in the CNS
 May also contribute to synapse
remodeling and plasticity.

4. Ependymal cells
 Line the fluid-filled cavities
within the brain and spinal cord
and regulate the production and
flow of cerebrospinal fluid
 PNS Glial Cells
 The PNS glial cells are the satellite cells and the Schwann cells

 Satellite cells surround neuron bodies located in the PNS

 Schwann cells surround and form myelin sheaths around the larger nerve fibers
 Structure of the Nervous System
Terminology
• Nerve refers to a group of many axons that are traveling together to and from the
same general location in the PNS.

• There are no nerves in the CNS.

• A group of axons traveling together in the CNS is called a pathway, a tract, or,
when it links the right and left halves of the brain, a commissure.

• Pathways can be either long neuronal or multisynaptic pathways:

• long neural pathways: information is carried directly between the brain and
spinal cord or between large regions of the brain by neurons with long axons

• multisynaptic pathways made up of many neurons and many synaptic

connections where many neural processing can occur

• Groups of neuron cell bodies in the PNS are called ganglia (singular, ganglion).

• In the CNS, they are called nuclei (singular, nucleus)

 Nerves

Nerve: a group of many axons that are traveling together to

and from the same general location in the peripheral nervous
system

Structure of a nerve:
• Endoneurium surrounds each fiber

• Groups of fibers are bound into fascicles by perineurium

• Fascicles are bound together by epineurium

 Central Nervous System: Brain
• Forebrain, midbrain, and hindbrain

• The forebrain develops into two major

subdivisions, the cerebrum and the
diencephalon.

• The midbrain remains as a single major division.

• The hindbrain develops into three parts: the pons,

medulla oblongata, and the cerebellum
• The brain also contains four interconnected
cavities, the cerebral ventricles, which are filled
with fluid and which provide support for the brain.
 Forebrain

• The cerebrum consists of the right and left

cerebral hemispheres

• The cerebral hemispheres are connected by a

massive bundle of nerve fibers known as the
corpus callosum

• The cerebral hemispheres consist of

1. The cerebral cortex, an outer shell of gray
matter composed primarily of cell bodies that
give the area a gray appearance
2. An inner layer of white matter, composed
primarily of myelinated fiber tracts.

• The cortex of each cerebral hemisphere is

divided into four lobes:
 Frontal
 Parietal
 Occipital
 Temporal
.
 Forebrain: Diencephalon
• The diencephalon, which is divided in two by the narrow third cerebral ventricle,
contains the thalamus, hypothalamus, and epithalamus.

• The thalamus is the relay stations and important integrating centers for most
inputs to the cortex, and plays a key role general arousal.

• Hypothalamus is the master command center for neural and endocrine

coordination since it has many important centers and it regulates the function of
pituitary gland

• Vasopressin and oxytocin are synthesized in the hypothalamus and stored in the
posterior lobe of the pituitary gland

• The epithalamus is a small mass of tissue that includes the pineal gland, which
has a role in regulating biological rhythms
 Cerebellum

• Although the cerebellum does not

initiate voluntary movements, it is an
important center for coordinating
movements and for controlling
posture and balance.

• .

The cerebellum consists of an outer layer of cells, the

cerebellar cortex, and several deeper cell clusters
 Brainstem
• All the nerve fibers that relay signals between the
forebrain, cerebellum, and spinal cord pass through
the brainstem.

• Running through the core of the brainstem and

consisting of loosely arranged neuron cell bodies
intermingled with bundles of axons, is the reticular
formation, the one part of the brain absolutely
essential for life.

• The reticular formation is involved in motor

functions, cardiovascular and respiratory control,
and the mechanisms that regulate sleep and
wakefulness and focus of attention.

• The brainstem contains nuclei involved in

processing information for 10 of the 12 pairs of
cranial nerves. These are the peripheral nerves that
connect directly with the brain and innervate the
muscles, glands, and sensory receptors of the head,
as well as many organs in the thoracic and
abdominal cavities.
 Spinal Cord

• The spinal cord lies within the bony vertebral

column and is a slender cylinder of soft tissue
about as big around as the little finger.

• The central butterfly-shaped area of gray matter

is composed of interneurons, the cell bodies and
dendrites of efferent neurons, the entering axons
of afferent neurons, and glial cells.

• The regions of gray matter projecting toward the

back of the body are called the dorsal horns,
whereas those oriented toward the front are the
ventral horns.

• The gray matter is surrounded by white matter,

which consists of groups of myelinated axons.
 Peripheral Nervous System
• Neurons in the peripheral nervous system
transmit signals between the central
nervous system and receptors and
effectors in all other parts of the body.

• The peripheral nervous system has 43

pairs of nerves: 12 pairs of cranial nerves
and 31 pairs that connect with the spinal
cord as the spinal nerves.

• The 31 pairs of spinal nerves are

designated by the vertebral levels from
which they exit: cervical (8), thoracic (12),
lumbar (5), sacral (5), and coccygeal (1).
Cranial nerves

Cranial Nerves
 Peripheral Nervous System

• These peripheral nerves can contain nerve fibers that are the axons
of efferent neurons, afferent neurons, or both.
• All the spinal nerves contain both afferent and efferent fibers, whereas
some of the cranial nerves contain only afferent fibers or only efferent
fibers.
• Efferent neurons carry signals out from the central nervous system to
muscles or glands. The efferent division of the peripheral nervous
system is more complicated than the afferent, being subdivided into a
somatic nervous system and an autonomic nervous system.
Somatic Nervous System
All the nerve fibers going from the central nervous system to skeletal
muscle cells

The cell bodies of these neurons are located in groups in the brainstem
(cranial nerve) or the ventral horn of the spinal cord (spinal nerve)

These neurons have large-diameter, myelinated axons that leave the

CNS and pass without any synapses to skeletal muscle cells

The neurotransmitter: acetylcholine

Effect: excitation (nicotinic receptor), leading to contraction of the

innervated skeletal muscle

These neurons are called motor neurons (alpha motor neuron Aα, large
neuron)

There are no somatic neurons that inhibit skeletal muscles.

Inhibition of motor neurons leads to muscle relaxation

Autonomic Nervous System
• the sympathetic system leave the central nervous system
from the thoracic (chest) and lumbar regions of the
spinal cord
• The neurons of the parasympathetic fibers from the
brainstem and the sacral portion of the spinal cord.
• Sympathetic division is also called the thoracolumbar
division, has short pre-ganglionic and long post-
ganglionic synapses. The major neurotransmitters are
ACh at the pre-ganglionic synapse and usually NE and
Epi at the post-ganglionic synapse. This is the “Flight or
Fight” response system.
• Parasympathetic is called the craniosacral division, it has
long pre-ganglionic and short post-ganglionic synapses.
The major neurotransmitter is ACh at both pre- and post-
ganglionic synapses. This is the “Rest and Digest” system
 D1

Cholinergic and adrenergic

neurons
Adrenergic receptors
 Recycling of norepinephrine

1. 50 to 80 % of the secreted norepinephrine is transported back into the

adrenergic nerve endings by an active transport process

2. The rest of secreted norepinephrine diffuses away from the nerve endings
into the surrounding body fluids and then into the blood

3. Small amounts of secreted norepinephrine is destructed by tissue enzymes

(monoamine oxidase, which is found in the nerve endings, and another is
catechol-O-methyl transferase, which is present diffusely in the tissues).
Peripheral Nervous
System
 Physical Support of the CNS
• Bone serves to support and to protect the structures of the CNS and PNS.
• Cranium
• Vertebrae

• Meninges are the membranes that line the structures and add additional support and protection.
• Dura mater
• Arachnoid mater
• Pia mater

• Cerebrospinal fluid (CSF) protects and cushions the structures.

Membrane potential and
Action potential
 The Resting Membrane Potential

• When talking about action potentials

and graded potentials we use these
terms: depolarization, repolarization,
hyperpolarization.
• These terms are all relative to the
resting membrane potential (RMP).
• Depolarization is the potential moving
from RMP to less negative values.
• Repolarization is the potential moving
back to the RMP.
• Hyperpolarization is the potential
moving away from the RMP in a more
negative direction.

Note: In large nerve fiber raising the membrane potential from -90 to −65 millivolts is
enough to initiate the action potential
 Graded Potentials

• Graded potential are changes in membrane potential that are confined to a

relatively small region of the plasma membrane.

• They are usually produced when some specific change in the cell’s
environment acts on a specialized region of the membrane.

• They are called graded potentials simply because the magnitude of the
potential change can vary (is “graded”).
Graded Potentials
Whenever a graded potential
occurs, charge flows between the
place of origin of this potential and
adjacent regions of the plasma
membrane, which are still at the
resting potential
 Graded Potentials

If additional stimuli occur

before the graded potential has
died away, these can add to the
graded potential from the first
stimulus. This process, termed
summation

42
Mechanism of an Action
Potential
 Other contributors to action potential

Calcium ions:

• Low calcium concentration enhances sodium channel activation, so, the nerve
fiber becomes highly excitable, sometimes discharging repetitively without
provocation rather than remaining in the resting state.

• The calcium ion concentration needs to fall only 50 percent below normal before
spontaneous discharge occurs in some peripheral nerves, often causing muscle
―tetany.‖ This is sometimes lethal because of tetanic contraction of the
respiratory muscles
 Refractory Period
• Refractory Periods During the action
potential, a second stimulus, no matter how
strong, will not produce a second action
potential. That region of the membrane is then
said to be in its absolute refractory period.

• Following the absolute refractory period,

there is an interval during which a second
action potential can be produced— but only if
the stimulus strength is considerably greater
than usual. This is the relative refractory
period
 Refractory Period
• The refractory periods limit the number of action potentials an excitable membrane can
produce in a given period of time.

• Most neurons respond at frequencies of up to 100 action potentials per second, and some
may produce much higher frequencies for brief periods.

• Refractory periods contribute to the separation of these action potentials so that individual
electrical signals pass down the axon.

• The refractory periods also are the key in determining the direction of action potential
propagation.
 Action Potential Propagation

• Action potentials in neurons are unidirectional (can only go forward down the axon,
since the space behind is in its refractory period).

• In skeletal muscle cells the action potentials are initiated near the middle of the cells
and propagate toward the two ends.

• The velocity with which an action potential propagates along a membrane depends
upon fiber diameter and whether or not the fiber is myelinated.

• The larger the fiber diameter, the faster the action potential propagates, because a
large fiber offers less resistance to local current; more ions will flow in a given time.
 Action Potential Propagation

• Myelin is an insulator that makes it more difficult for charge to flow between
intracellular and extracellular fluid compartments.

• Action potentials occur only at the nodes of Ranvier, where the myelin coating is
interrupted and the concentration of voltage-gated Na + channels is high.

• Thus, action potentials jump from one node to the next as they propagate along a
myelinated fiber, and for this reason such propagation is called saltatory conduction.
 Saltatory Conduction
• Propagation via saltatory conduction is faster than propagation in nonmyelinated
fibers of the same axon diameter.
• Moreover, because ions cross the membrane only at the nodes of Ranvier, the
membrane pumps need to restore fewer ions.
• Myelinated axons are metabolically more efficient than unmyelinated ones.
• Myelin adds speed, reduces metabolic cost, and saves room in the nervous system
because the axons can be thinner.
The differences between graded potentials and action potential

50
 Multiple sclerosis (MS)
MS is an autoimmune condition in which the myelin sheaths surrounding axons in the
central nervous system are attacked and destroyed by antibodies and cells of the
immune system

The loss of insulating myelin sheaths results in increased leak of potassium. This
results in hyperpolarization and failure of action potential conduction of neurons in
the brain and spinal cord

Depending upon the location of the affected neurons, symptoms can include muscle
weakness, fatigue, decreased motor coordination, slurred speech, blurred or hazy
vision, bladder dysfunction, pain or other sensory disturbances, and cognitive
dysfunction

The severity and rate of progression of MS varies isolated, episodic attacks with
complete recovery in between steadily progressing neurological disability

(MRI) : multiple, scarred (sclerotic) areas within the brain and spinal cord
 Excitation
Any factor that causes sodium ions to begin to diffuse inward through the
membrane in sufficient amount

Examples of factors causing excitation:

1. Mechanical disturbance of the membrane: mechanical pressure to excite
sensory nerve endings in the skin
2. Chemical effects on the membrane: chemical neurotransmitters to
transmit signals from one neuron to the next in the brain
3. Passage of electricity through the membrane: electrical current to
transmit signals between successive muscle cells in the heart and
intestine
 Action Potential Inhibition

• The generation of action potentials is prevented by local anesthetics such as

procaine and lidocaine because these drugs block voltage-gated Na+ channels,
preventing them from opening in response to depolarization.

• Some animals produce toxins (poisons) that work by interfering with nerve
conduction in the same way that local anesthetics do. For example, some organs of
the pufferfish produce an extremely potent toxin, tetrodotoxin, that binds to
voltage gated Na+ channels and prevents the Na+ component of the action
potential.

• Membrane stabilizers decrease excitability Calcium ions as a stabilizer : a high

extracellular fluid calcium ion concentration decreases membrane permeability to
sodium ions and simultaneously reduces excitability
Synapses and neurotransmitters
 Synapses
• Excitatory synapses vss. Inhibitory synapses
 Functional Anatomy of Synapses
There are two types of synapses: electrical and chemical
electrical synapse
• the electrical activity of the presynaptic neuron affects the
electrical activity of the postsynaptic neuron.

• the plasma membranes of the presynaptic and postsynaptic

cells are joined by gap junction

• Advantages: communication between cells via these

synapses is extremely rapid.

• They have important functions in synchronization of

electrical activity of neurons clustered in local CNS
networks and communication between glial cells and
neurons.

• Multiple isoforms of gap-junction proteins have been

described, and the conductance of some of these is
modulated by factors such as membrane voltage,
intracellular pH, and Ca2+ concentration.
 Functional Anatomy of Synapses
There are two types of synapses: electrical and chemical

Chemical Synapses
• signals are transmitted across the synaptic cleft by
neurotransmitter

• Neurotransmitter binds to receptors on post-synaptic

neurons

• Sometimes more than one neurotransmitter may be

simultaneously released from an axon, in which case
the additional neurotransmitter is called a
cotransmitter.
 Anatomy of the synapse

Presynaptic Terminals of the presynaptic neuron:

• They have varied anatomical forms
• Most resemble small round or oval knobs and are sometimes called terminal
knobs, end-feet, or synaptic knobs
• The presynaptic terminals have the transmitter vesicles containing the
transmitter substance, and the mitochondria for ATP supplement for the
synthesis of the new transmitter
• They contain large numbers of voltage-gated calcium channels

Postsynaptic membrane of a postsynaptic neuron

Synaptic cleft:
• The space between the presynaptic terminal and the postsynaptic membrane.
• This space has a width usually of 200 to 300 angstroms
 Mechanisms of Neurotransmitter Release
Depolarization of the presynaptic membrane by the
action potential leads to opening of the voltage-
gated calcium allowing large numbers of calcium
ions to flow into the presynaptic terminal

The precise mechanism by which the calcium ions

cause this release is not known, but it is believed
that calcium ions entering the presynaptic terminal
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

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.
 Activation of the Postsynaptic Cell
• Neurotransmitters rapidly and reversibly bind to receptors on the plasma membrane of
the postsynaptic cell.

• The activated receptors themselves may be ion channels, which designates them as
ionotropic receptors

• Alternatively, the receptors may indirectly influence ion channels through a G protein
and/or a second messenger, a type referred to as metabotropic receptors.

• In all cases, the result of the binding of neurotransmitter to receptor is the opening or
closing of specific ligand-gated ion channels in the postsynaptic plasma membrane,
which eventually leads to changes in the membrane potential in that neuron.

• there is a very brief synaptic delay—about 0.2 msec—between the arrival of an action
potential at a presynaptic terminal and the membrane potential changes in the
postsynaptic cell.
 Removal of Neurotransmitter from the Synapse

• To terminate the signal in a chemical synapse the

neurotransmitter must be removed. This is accomplished by:

1. Diffusion of the transmitter from the cleft

2. Degradation of the transmitter by enzymes
3. Reuptake into the pre-synaptic cells for reuse

• Receptors in the post-synaptic cell are removed from the

membrane.

61
 Types of Chemical Synapses

1. Excitatory chemical synapses:

• generate an excitatory postsynaptic potential (EPSP).
• EPSPs serve to bring the membrane potential closer to threshold for generating an
action potential.

2. Inhibitor chemical synapses

• generate an inhibitory postsynaptic potential (IPSP).
• IPSPs make the cell’s membrane potential more negative, making it harder to generate
an action potential.

62
 Excitatory Postsynaptic Potential

• The EPSP is a depolarizing graded potential that

decreases in magnitude as it spreads away from the
synapse by local current.

• Its only function is to bring the membrane potential

of the postsynaptic neuron closer to threshold.
 Inhibitory Postsynaptic Potential

• At inhibitory chemical synapses, the potential change in the

postsynaptic neuron is generally a hyperpolarizing graded
potential called an inhibitory postsynaptic potential

• The activation of an inhibitory synapse lessens the likelihood

that the postsynaptic cell will depolarize to threshold and
generate an action potential.

• At an inhibitory synapse, the activated receptors on the

postsynaptic membrane open Cl− or K+ channels; Na+
permeability is not affected
 Synaptic Strength
• The effectiveness or strength of a given synapse is influenced by both
presynaptic and postsynaptic mechanisms.

1. Presynaptic Mechanisms:
• A presynaptic terminal does not release a constant amount of neurotransmitter
every time it is activated. One reason for this variation involves Ca2+
concentration

• If Ca2+ removal does not keep up with entry, as can occur during high
frequency stimulation, Ca2+ concentration in the terminal, and consequently
the amount of neurotransmitter released upon subsequent stimulation, will be
greater than usual

• If The greater the amount of neurotransmitter released, the greater the number
of ion channels opened in the postsynaptic membrane and the larger the
amplitude of the EPSP or IPSP in the postsynaptic cell
 Synaptic Strength

1. Presynaptic Mechanisms:
• axo–axonic synapse

• presynaptic inhibition Vss. presynaptic

facilitation

• Autoreceptors are a built-in brake for the system.

Once the neurotransmitter is released it will
diffuse and activate the post-synaptic cell, but
also bind to the autoreceptors and turn off further
release from the pre-synaptic cell.
 Synaptic Strength

2. Postsynaptic Mechanisms
• Many types and subtypes of receptors exist for each kind of neurotransmitter.

• The different receptor types operate by different signal transduction mechanisms and
can have different—sometimes even opposite—effects on the postsynaptic
mechanisms they influence.

• A given signal transduction mechanism may be regulated by multiple

neurotransmitters, and the various second-messenger systems affecting a channel
may interact with each other.

• Receptors up- and down-regulation

• Receptors desensetization
Factors that determine
synaptic strength.
Modification of Synaptic Transmission by Drugs and Disease
 Modification of Synaptic Transmission by Drugs and Disease

• Drugs act by interfering with or stimulating normal processes in the neuron involved in
neurotransmitter synthesis, storage, and release, and in receptor activation.

• Diseases can also affect synaptic mechanisms.

Examples: Clostridium tetani (tetanus toxin) prevents vesicle fusion with the membrane, inhibiting
neurotransmitter release and causes increased muscle contraction.
Clostridium botulinum bacilli toxin (botulism), interferes with actions of SNARE proteins at
excitatory synapses that activate muscles; botulism is characterized by muscle paralysis.
Low doses of botulinum toxin (Botox) are injected therapeutically to treat a number of
conditions, including facial wrinkles, severe sweating, hypercontracted neck muscles,
uncontrollable blinking, misalignment of the eyes, and others.

70
 Acetylcholine
• Acetylcholine (ACh) is found in PNS and CNS. Neurons that use ACh as
the primary neurotransmitter are known as cholinergic neurons.

• ACh acts at muscarinic (G protein coupled) or nicotinic (ion channels)

receptors. Nicotininic receptors are found at the neuromuscular junctions
of skeletal muscles.
 Acetylcholine
• ACh is produced in the presynaptic axon by the enzyme choline acetyl
transferase (CAT) as follows:
• Acetyl CoA + choline  acetylcholine + CoA
• Degradation of ACh occurs in synaptic cleft and is done by the enzyme
acetylcholinesterase (AChE) as follows:
• Acetylcholine  acetate + choline
 Cholinergic System Issues
• Some chemical weapons, such as the nerve gas Sarin, inhibit
acetylcholinesterase, causing a buildup of ACh in the synaptic cleft.

• Overstimulation of postsynaptic ACh receptors causes uncontrolled

muscle contractions, ultimately leading to receptor desensitization
and paralysis.

• Nicotinic receptors in the brain are important in cognitive functions

and behavior.

• The presence of nicotinic receptors on presynaptic terminals in

reward pathways of the brain explains why tobacco products are
among the most highly addictive substances known.
 Alzheimer’s Disease

• Neurons associated with the ACh system degenerate in people with

Alzheimer’s disease. Alzheimer’s disease affects 10 to 15 percent of people
over age 65, and 50 percent of people over age 85.

• Because of the degeneration of cholinergic neurons, this disease is associated

with a decreased amount of ACh in certain areas of the brain and even the loss
of the postsynaptic neurons that would have responded to it.

• These defects and those in other neurotransmitter systems that are affected in
this disease are related to the declining language and perceptual abilities,
confusion, and memory loss that characterize Alzheimer’s victims.
 Biogenic Amines
• Biogenic amine neurotransmitters are made from amino acids as follows:
• Catecholamines
• Made from tyrosine:
• Dopamine
• Norepinephrine
• Epinephrine

• Made from tryptophan:

• Serotonin

• Made from histidine:

• Histamine

• The enzymes which degrade the biogenic amine

neurotransmitters are:
• Monoamine oxidase (MAO)
• Catechol-o-methyltransferase
 Parkinson’s Disease
• This disease involves the loss of dopamine-releasing neurons in the substantia
nigra.

• Symptoms include persistent tremors, head nodding and pill rolling

behaviors, a forward bent walking posture, shuffling gait, stiff facial
expressions and they are slow in initiating and executing movement.

• The cause is not clearly understood, but loss of the dopamine neurons is
critical.

• It is currently treated with the drug L-Dopa in the initial stages to alleviate
symptoms. This is often given with the drug deprenyl (which prevents the
breakdown of L-Dopa). This is NOT curative. We can only treat the
symptoms.

• Experimental treatments currently include deep brain stimulation by

surgically implanting electrodes, gene therapy and fetal/stem cell transplants.
 Adrenergic Receptors
• Adrenergic receptors are utilized by the neurotransmitters Norepinphrine (NE) and
Epinephrine (Epi). NE is found in both the CNS and PNS but Epi is found mainly in
the PNS. Adrenergic comes from historical use as Noradrenaline (NA) and
adrenaline for NE and Epi, respectively.

• Adrenergic receptors are G protein coupled that are generally linked to second
messenger signal transduction pathways.

• Alpha adrenergic receptors

‒ Alpha1 (α1)
‒ Alpha2

• Beta adrenergic receptors

‒ Beta1 (β1)
‒ Beta2
‒ Beta3
 Serotonin
• Also known as 5-hydroxytryptamine or 5-HT

• CNS neurotransmitter and is also made by enterochromaffin cells in

the gut (90%) and is taken up and stored in nerve terminals and
platelets

• Functions
• Regulating sleep
• Emotions
• 5-HT3 receptors in the area postremia are involved in the vomiting
reflex
• Regulates cell growth
• Vascular smooth muscle cell contraction
 Histamine
• CNS neurotransmitter whose major location is the
hypothalamus

• Histamine is commonly known for paracrine

actions.

• Histamine is also found in the peripheral system. It

is involved in allergic reactions, nerve sensitization,
and acid production in the stomach.
 Amino Acid Neurotransmitters
• Amino acid neurotransmitters at excitatory
synapses are:
• Aspartate
• Glutamate is the most prevalent excitatory
neurotransmitter in the brain.

• Amino acid neurotransmitters at inhibitory synapses

are:
• Glycine … is the major inhibitory neurotransmitter in
spinal cord and brain stem
• GABA….. is the major inhibitory neurotransmitter in the
brain.
 Neuropeptides
• Neuropeptides are short chains of amino acids with peptide bonds.
Some 85 neuropeptides have been identified, but their
physiological roles are not all known.

• In the cell body, the precursor protein is packaged into vesicles,

which are then moved by axonal transport into the terminals where
the protein is cleaved by specific peptidases.

• Many of the precursor proteins contain multiple peptides, which

may be different or be copies of one peptide. Neurons that release
one or more of the peptide neurotransmitters are collectively called
peptidergic. In many cases, neuropeptides are cosecreted with
another type of neurotransmitter and act as neuromodulators.
 Neuropeptides
• Examples include:
• Endogenous opioids
• Enkephalins
• Endorphins
• Morphine and codeine are synthetic opioids that are used as
analgesics (pain reducers).

• Substance P
• Released by afferent neurons that relay sensory
information into the central nervous system.
• It is known to be involved in pain sensation.
 Gas Neurotransmitters
• Gases are not released by exocytosis of presynaptic vesicles,
nor do they bind to postsynaptic plasma membrane receptors.
They are produced by enzymes in axon terminals (in response
to Ca2+ entry), and simply diffuse from their sites of origin in
one cell into the intracellular fluid of other neurons or effector
cells, where they bind to and activate proteins.
• Examples:
• Nitric oxide (NO) is produced by nitric oxide synthetase and
undergoes very rapid degradation. Once in the target cell, it
activates cGMP signaling pathways.

• Carbon monoxide and hydrogen sulfide are also emitted by

neurons as signals.
 Purine Neurotransmitters
• Other nontraditional neurotransmitters include the purines, ATP
and adenosine, which act principally as neuromodulators.

• ATP is present in all pre-synaptic vesicles and is co-released with

one or more of the classical neurotransmitters in response to Ca 2+
influx into the terminal.

• Adenosine is derived from ATP via extracellular enzymatic

activity.

• Both presynaptic and postsynaptic receptors have been described

for adenosine, and the roles these substances play in the nervous
system and other tissues is an active area of research.