Human Physiology
Lec-6 & 7
Synaptic Transmission and Neural Integration
Synapse: The term synapse means “coming together.” Where two structures or entities
come together, they form a synapse. Although one can use the word synapse to mean
any cellular junction, in physiology we traditionally limit its usage to: the junction of
two neurons, the junction between a neuron and a target cell (ex. the neuromuscular
junction), or the interface between adjacent cardiac muscle cells or adjacent smooth
muscle cells. In the nervous system, a synapse is the structure that allows a neuron to
pass an electrical or chemical signal to another cell.
Types of Synapses:
1. Electrical - Electrical synapses are due to gap junctions between cells that allow ions
or secondary messengers to flow from one cell to another. Gap junctions are important in the
transmission of signals among smooth and cardiac muscle cells. Recent studies indicate that gap
junctions transmit some signals between neurons in the adult brain and are important in the
development of the nervous system.
2. Chemical - Most neurons communicate by means of neurotransmitters at chemical synapses.
One neuron secretes a neurotransmitter into extracellular space upon the arrival of an action
potential. The neurotransmitter binds to receptors in the plasma membrane receiving the signal.
The cell membrane responds with a graded potential which may or may not initiate an action
potential.
In this chapter we will examine synapses between neurons. A synapse between a neuron and
an effector organ such as a muscle or a gland is called a neuroeffector junction.
Functional Anatomy of Chemical Synapse
The neuron that transmits a signal to another neuron is the presynaptic neuron and the neuron that
receives the signal is the postsynaptic neuron. The presynaptic axon terminal may synapse with the
postsynaptic cell's:
dendrite cell body (soma) axon terminal -
axodendritic synapse
axosomatic synapse
axoaxonic synapse
The presynaptic neuron releases neurotransmitter into a narrow space (30 - 50 nm) between the cells
called a synaptic cleft. The neurotransmitter is contained in synaptic vesicles and is released by
exocytosis. The neurotransmitter effects a change in the postsynaptic cell by a mechanism
called signal transduction.
Concentrated at the axon terminal are voltage-gated calcium channels. The depolarization of the
membrane associated with an action potential causes the calcium channels to open and Ca++ rushes
down its electrochemical gradient. Ca++ causes the membranes of the synaptic vesicles to fuse with the
cell membrane and releases its contents by exocytosis.
The Ca++ influx stops within a few msecs when the Ca++ channel close. However, when a series of
action potentials arrives at the axon terminal there is a greater inflow of Ca++ and more
neurotransmitter is released. Hence, the higher the frequency of action potentials the greater the
amount of neurotransmitter released.
The neurotransmitter is a ligand that binds to a receptor protein. The neurotransmitter needs to be
removed to end the signal and clear the way for the next signal.
Processes for Neurotransmitter Removal
1. Diffusion - Neurotransmitter may simply diffuse away.
2. Re-uptake - The presynaptic neuron may actively transport the neurotransmitter back into
itself.
3. Enzymatic Destruction - Enzymes located in cell membranes of pre- and postsynaptic cells or
glial cells may breakdown the neurotransmitter.
It takes about 0.5-5 msec from the time of arrival of the action potential to a response in the
postsynaptic cell this is called a synaptic delay and is due primarily to the time it takes for
calcium to trigger exocytosis.
Signal Transduction Mechanisms
Neurotransmitters can produce either a fast or a slow response. Fast response involves ionotropic
receptors where the neurotransmitter binds to a channel-linked receptor. All channel-linked receptors are
ligand-gated channels. The channel opens, the ions flow down their electrochemical gradients, and produce a
brief change in membrane potential called a postsynaptic potential (PSP). Slow responses act by triggering
biochemical changes through G protein-linked receptors. These are called metabotropic receptors.
Activation of the G protein may either open or close an ion channel. The final effect depends upon the type
of ion channel. If the result is a depolarization the response is excitation; if the result
is hyperpolarization the effect is inhibition.
The G protein may either be directly coupled to an ion channel or may trigger the activation or inhibition
through a secondary messenger system. The duration of the response may range from msec to hours.
Excitatory Synapses
An excitatory synapse causes a graded potential that depolarizes the membrane and brings it
closer to threshold. The depolarization is an excitatory postsynaptic potential (EPSP) and may be
either fast or slow.
Fast EPSP's involve the opening of small cation channels (for K+ and Na+). Because there is a
larger influx of Na+ compared to K+ a net depolarization results.
Slow EPSP typically involve the closing of K+ channels through the mediation of a G protein and
cAMP as a second messenger. The decrease in K+ permeability causes the net influx of positive
charge (associated with Na+) to increase which depolarizes the membrane. These EPSP take longer to
develop and last longer.
Inhibitory Synapses
An inhibitory synapse decreases the likelihood that an action potential will occur by
either hyperpolarizing the membrane or keeping it at the resting level.
At inhibitory synapses the neurotransmitter opens channels for either K+ or Cl- . Opening
K+ channels causes K+ to leave the cell hyperpolarizing the membrane and creating aninhibitory
post-synaptic potential (IPSP). The effect of a neurotransmitter that opens Cl- channels depends
upon the electrochemical force acting upon Cl-.
In some neurons Cl- are actively transported out of the cell. This creates an equilibrium potential
for Cl- that is more negative than the resting potential. In these cells there is an electrochemical force
driving Cl- into the cell. When the Cl- channels are opened, Cl- goes into the cell down its gradient
and hyperpolarizes it (make it more negative).
In other neurons there is no active transport of Cl- and Cl- is at equilibrium. The way the opening
the Cl- channels in these cells is inhibitory is more complicated.
The opening of the Cl- channels interferes with the ability of excitatory synapses to induce EPSP's.
This is because if the Cl- channels open at the same time as the cation channel that produces an EPSP,
Cl- moves into the cell as the membrane potential becomes more positive. The movement of
negatively charged Cl- then cancels out the change that would have resulted from the influx of
positive charges. As a result, the membrane potential does not change and threshold is not reached.
Neural Integration
The axon hillock of the postsynaptic neuron is influenced by the electrotonic conduction of all the
membrane potential changes produced by the various excitatory and inhibitory synapses. The net
change in membrane potential at the axon hillock that results from this process is called neural
integration. Whether or not the potential at the axon hillock reaches threshold depends upon the
additive effects of all the graded potentials. The graded potential can either add in time or space.
Temporal Summation
In temporal summation postsynaptic potentials at the same synapse occur in rapid succession.
Because the effect of the first potential does not have time to dissipate the succeeding potentials add
to the previous ones and increase the change in potential. Summation can occur with IPSP's as well
as with EPSP's.
Temporal summation can occur because postsynaptic potentials last longer than action potentials.
Neurotransmitter released into the synaptic cleft by a previous action potential may still be present
when a succeeding action potential causes the release of more neurotransmitter.
Spatial Summation
In spatial summation multiple postsynaptic potentials from different synapses occur about the same
time and sum. The EPSP's of different synapses are not strong enough to generate an action potential
but by reinforcing one another may trigger an action potential. It is important to keep in mind that
EPSP's and IPSP's will also add up to cancel each other's effects.
Frequency Coding
Neural integration of postsynaptic potentials not only triggers action potentials but also affects
the frequency of action potentials when summation results in a suprathreshold potential. The
relationship between the strength of suprathreshold stimuli and the frequency of action potentials is
called frequency coding.
Presynaptic Modulation
With axoaxonic synapses the neurotransmitter from the presynaptic neuron modulates the axon
terminal by affecting the amount of calcium that enters in response to an action potential.
Presynaptic Facilitation
Presynaptic facilitation results when an axoaxonic synapse causes an action potential arriving
at the postsynaptic axon terminal to release more neurotransmitter and thereby cause a larger
EPSP. Note that this type of synapse only influences the effect of another neuron at its synapse
with a postsynaptic neuron. In other words, presynaptic modulation will only affect transmission
to the postsynaptic neuron at one specific synapse.
Presynaptic Inhibition
In presynaptic inhibition the neurotransmitter from the presynaptic neuron at the axonic
synapse causes the postsynaptic axon terminal to release less neurotransmitter when an action
potential arrives.
It is important to keep in mind that presynaptic modulation can affect inhibitory synapses as well as
excitatory synapses.
Neurotransmitters
Neurotransmitters are the chemicals which allow the transmission of signals from one
neuron to the next across synapses. They are also found at the axon endings of motor
neurons, where they stimulate the muscle fibers.
1. Cholinergic
Acetylcholine (ACh)Found in both central and peripheral nervous systems. It is the most
abundant neurotransmitter in the peripheral nervous system. ACh is synthesized in the cytoplasm
of the axon terminal from two substrates, acetylCoA and choline, in a reaction catalyzed
by choline acetyl transferase.
ACh is stored in synaptic vesicles until an action potential causes its release by exocytosis.
ACh binds to receptors called cholinergic receptors and is degraded by
acetylcholinesterase (AChE), an enzyme that can be found in both the pre- and postsynaptic
membranes. The degradation products are acetate which enters the blood and choline which is
taken up by the presynaptic neuron and recycled.
There are two types of receptors for ACh:
1. Nicotinic cholinergic receptors are ionotropic and open channels for small
cations (Na+ + K+) causing EPSP. Nicotinic receptors are located in the peripheral nervous
system in certain autonomic neurons; on skeletal muscles; and in some regions of
the central nervous system.
2. Muscarinic cholinergic receptors are metabotropic receptors operating through G
proteins. The G protein may either open or close an ion channel or activate an enzyme
depending upon the postsynaptic neuron in question. These receptors are found on some
effector organs of the autonomic nervous system and are the dominant cholinergic receptor
in the central nervous system.
2. Biogenic Amines
Biogenic amines are derived from amino acids and contain an amine group -NH2.
The
amines
include catecholamines (dopamine,
norepinephrine
and
epinephrine), serotonin and histamine. All are synthesized in the cytosol of the
axon terminal.
The different catecholamines bind to specific receptors. The receptors
for dopamine are called dopaminergic.
The receptors for epinephrine and norepinephrine are adrenergic because
epinephrine and norepinephrine are also know as adrenalin and noradrenalin.
Among the adrenergic receptors there are two main classes, alpha adrenergic and
beta adrenergic receptors. Each has its own subclasses and
Catecholamines generally produce slow responses through G proteins. 
Following their release catecholamines are degraded by monoamine
oxidase (MAO) and catechol-o-methyl transferase (COMT).
Serotonin is found in the brain stem and some of its functions include regulating
sleep and emotions.
Histamine (also associated with allergic
neurotransmitter in the hypothalamus.
reactions)
functions
as
a
3. Amino Acid Neurotransmitters
Amino acid neurotransmitters are the most abundant class
of
neurotransmitters
in
the central
nervous
system. Aspartate and glutamate are excitatory neurotra
nsmitters
while glycine and
GABA
(gammaaminobutyric acid) are inhibitory.
4. Neuroactive Peptides
Neuroactive peptides are short chains of amino acids. Many neuropeptides are known as
hormones such as:
TRH (thyroid releasing hormone) which releases TSH
Vasopressin (ADH)
Oxytocin
Substance P
Endogenous opioids including enkephalins and endorphins
Most neuropeptides are secreted from the same axon terminals as other neurotransmitters
and act on metabotropic receptors to modulate the response of the postsynaptic neuron to the
other neurotransmitters.
5. Other Neurotransmitters
Nitric oxide cannot be stored as it easily crosses the cell membrane as soon as it is
synthesized. Its release is controlled by controlling its synthesis in a reaction catalyzed
by nitric oxide synthetase. NO acts by altering the activity of proteins.
6. ATP also serves as a neurotransmitter.