SECTION C: SYNAPSES

A synapse is an anatomically specialized junction between two neurons, at which the electrical activity in a presynaptic neuron
influences the electrical activity of a postsynaptic neuron.
● Presynaptic cell - neurotransmitter release through vesicles
○ Neurotransmitters will bind to specific receptors in the postsynaptic cell
● Postsynaptic cell - receptor molecules
○ Different from receptor cells because they are protein in nature and are specific for
neurotransmitters or hormones
● Extracellular space between these two cells

Synaptic transmission and definitions

● Paracrine communication
○ The level of excitability of a postsynaptic cell at any moment depends on the number of synapses active at
any one time and the number that are excitatory or inhibitory.
● Excitatory synapse - depolarized and is brought closer to the threshold
● Inhibitory synapse - stabilized at its resting potential at an inhibitory synapse
● Hyperpolarized - driven farther from threshold
● Convergence - hundreds or thousands of synapses from many different presynaptic cells can affect a single
postsynaptic cell → allowing information from many sources to influence a cell’s activity
● Divergence - a single presynaptic cell can send branches to affect many other postsynaptic cells →
allowing one cell to affect multiple pathways
● Electrical synapses - the plasma membrane of the presynaptic and postsynaptic cells are joined by gap
junctions.
○ These allow the local currents resulting from arriving action potentials to flow directly across the
junction through the connecting channels from one neuron to the other.
■ This depolarizes the membrane of the second neuron to threshold, continuing in
propagation of the action potential
○ Advantage: communication between cells is extremely rapid
○ Gap junctions - type of cell junction in which adjacent cells are connected through protein
channels

In the synapse, a local potential called the synaptic potential will be generated.
● Activity at synapses increases or decreases the likelihood that the postsynaptic neuron will fire action
potentials by producing a brief, graded potential in the postsynaptic membrane.
● Excitatory Postsynaptic Potential (EPSP)
○ Produced when Na+ enters
○ Upon binding of the neurotransmitter here, if it is an excitatory neurotransmitter, it will allow
EPSP to be generated. To generate the EPSP, you allow entry of Na+.
● Inhibitory Postsynaptic Potential (IPSP)
○ Produced when K+ exits the cell or if Cl- enters

Producing an action potential in the synaptic cleft

● Action potentials do not summate (difference between local and action potential)
● EPSPs must be able to undergo summation
 ○ Spatial summation - several presynaptic neurons will receive action potentials and will fire
simultaneously and they will also be producing EPSPs, one after the other, and will be producing
the action potential.
○ Temporal summation - repetitive firing of the action potential so that you have repetitive release
of neurotransmitters to produce a series of EPSPs that may undergo summation so they add up one
after the other, until the threshold is reached. That is when the action potential is produced.
● IPSPs are hyperpolarizing change in the membrane
○ They can summate but they are hyperpolarizing changes in the membrane. So, if the IPSPs
summate, then an action potential will not be produced -- a form of inhibition
○ Important because you need to inhibit the generation of your action potentials.

When the neurotransmitter binds in the receptor molecule in the postsynaptic membrane
● Presynaptic cell - neurotransmitter release through vesicles
○ Neurotransmitters will bind to specific receptors in the postsynaptic cell
● Postsynaptic cell - receptor molecules
○ Different from receptor cells because they are protein in nature and are specific for
neurotransmitters or hormones

Chemical Synapses
● The axon ends in slight swellings
● Synaptic vesicles contain neurotransmitter molecules
● Postsynaptic density
● Synaptic cleft - separates the presynaptic and postsynaptic neurons and prevents direct propagation of the
current from the presynaptic neuron to the postsynaptic cell.
● Signals are transmitted across the synaptic cleft by means of a chemical messenger - a neurotransmitter -
released from the presynaptic axon terminal
● Cotransmitter - additional neurotransmitter
● Advantage: they permit integration of multiple signals arriving at a given cell

Steps in chemical synaptic transmission

As the action potential reaches the axon terminal, voltage-gated Ca2+ channels open and calcium ions enter the
cell. In the vesicular membrane, you have proteins called the v-snares (synaptobrevin; vesicle snares), t-snares
(SNAP 25 & syntaxin; target snares), and synaptotagmin, where the Ca2+ will bind and will promote fusion of
vesicular membrane to your presynaptic membrane. The fusion happens as a result of the synaptobrevin forming a
complex with the syntaxin and SNAP 25. The content of the vesicles will then be released into the synaptic cleft.
Upon the release of the neurotransmitters, they will bind to their specific receptors present in the postsynaptic
membrane. The receptor molecules are proteins in nature, and are different from the receptor cells mentioned (i.e.,
sensory cells / organs). The receptor molecules may be located in the nucleus or in the plasma membrane.

Important to know these steps because drugs and viruses can act on these steps and will affect synaptic
transmission.
Presynaptic
1. Synthesize and store the neurotransmitter in the
small vesicles with lipid bilayer membranes
a. Initiated for release when an action
potential reaches the presynaptic
terminal membrane
i. Triggers the opening of Ca2+
channels, resulting in Ca2+
influx, further resulting in the
fusion of docked vesicles with
the synaptic terminal membrane
b. Many vesicles are docked on the
presynaptic membrane at the active
zones
i. Anchored in the vesicle
membrane
2. Release of neurotransmitters
a. Calcium ions bind to synaptotagmins,
triggering a conformational change in
the SNARE complex that leads to
membrane fusion and neurotransmitter
release (see figure b)
b. Once neurotransmitters are released from
a presynaptic axon terminal, they diffuse
across the cleft.
3. Vesicles can then either completely fuse with the
membrane or they can fuse only briefly while
they release their contents and then reseal the pore
and withdraw back into the axon terminal (a mechanism called “kiss-and-run fusion”)

Postsynaptic
4. Binding of neurotransmitters to specific postsynaptic receptors
a. Specific ligand-gated ion channels opens or closes which leads to changes in the membrane
potential of the postsynaptic cell
5. Deactivation of neurotransmitters
a. Happens in different ways
i. Enzymatically
1. Acetylcholinesterase
ii. Reuptake of neurotransmitters back into the presynaptic cell
iii. Diffusion of neurotransmitters away from the synapse
b. Reuptake is essential to ensure that there are enough neurotransmitters that can be used for the
next signal transmission

Note: if the concentration of unbound neurotransmitters in the synaptic cleft decreases, the number of occupied
receptors will decrease. The ion channels in the postsynaptic membrane return to their resting state

Electrical Synapses
● Closer gap between presynaptic and postsynaptic terminal
○ Directly connected through the gap junction membrane proteins.
● Advantage: communication between cells is extremely rapid
Steps in Electrical Synaptic Transmission
1. Local currents from arriving action potentials flow directly across the junction through the connecting
channels from one neuron to the other.
2. This depolarizes the membrane of the second neuron to threshold, continuing the propagation of the action
potential

Postsynaptic Mechanisms of Excitatory Chemical Synapses

Postsynaptic response to the neurotransmitter is a depolarization, bringing the membrane potential closer to
threshold

1. Nonselective channels that are permeable to Na+ and

K+ open
2. Both electrical and concentration gradients drive Na+
into the cell, thus larger number of Na+ moves in
3. Electrical gradient opposes concentration gradient, thus
relatively small number of K+ move out of the cell
4. The net movement of positive ions is into the
postsynaptic cell, causing a slight depolarizing graded
potential that decreases in magnitude as it spreads away
from the synapse by local current
Postsynaptic Mechanisms of Inhibitory Chemical Synapses
Postsynaptic response to the neurotransmitter is a hyperpolarization, bringing the membrane potential closer to the
K+ or Cl- equilibrium potential

1. Cl- or K+ channels open

2. Hyperpolarization
a. For cells that actively transport Cl-, the Cl-
equilibrium potential is more negative than the
resting membrane potential. Therefore, as Cl-
channels open, Cl- enters the cell until its
equilibrium potential, producing a
hyperpolarization
b. Similarly, K+ equilibrium potential is more
negative than the resting membrane potential
c. For cells that do not actively transport Cl-, the
equilibrium potential for Cl- is equal to the
resting membrane potential. If any positive
charges enter a cell, Cl- ions will also enter and neutralize their effect. Thus, membrane potential
is stabilized near the resting value, and it is more difficult for excitatory inputs from other
synapses to change the potential when these chloride channels are simultaneously open

How Synapses allow Neurons to act as Integrators

Integration involves processing of information through communicating the stimuli received by sensory structures to
the nervous system. This involves the propagation of information from one neuron to another. In most neurons, one
excitatory synaptic event by itself is not enough to reach the threshold in the postsynaptic neuron. This being the
case, an action potential can be initiated only by the combined effects of many excitatory synapses. The following
mechanisms combined, help increase the chances of reaching the threshold for the information to propagate and be
processed by the Central Nervous System.

● Convergence occurs when hundreds or thousands of synapses from many different presynaptic cells affect
a single postsynaptic cell, increasing the potential combined effects of many excitatory synapses.
● Summation is the process of adding up graded potential
○ Temporal Summation occurs when a second synaptic potential adds to the previous one and
creates a greater depolarization than from one input alone. The input signals arrive from the same
presynaptic cell at different times. The potentials summate because an additional influx of positive
ions occurs before ions leaking out through the membrane have returned it to the resting potential.
○ Spatial Summation occurs when input from the two separate neurons at different locations on the
cell also summate in the postsynaptic neuron, resulting in a greater degree of depolarization.
 ● Presynaptic Facilitation occurs when a separate neuron A
releases neurotransmitters that would bind with the
presynaptic receptor of neuron B (axo-axonic synapse)
which would then increase the amount of neurotransmitters
released by neuron B.
○ Note: Presynaptic Inhibition can also occur if the
neurotransmitters released by A caused a
decrease of the amount of neurotransmitters
released by B.

How Drugs Can Alter the Effectiveness of Synapses

The great majority of therapeutic, illicit, and so-called
“recreational” drugs that act on the nervous system do so by altering synaptic mechanisms and thus synaptic
strength. Drugs act by interfering with or stimulating normal processes in the neuron involved in neurotransmitter
synthesis, storage, and release, and in receptor activation.

A Drug might,
A. increase leakage of neurotransmitter from
vesicle to cytoplasm, exposing it to enzyme
breakdown
B. increase transmitter release into cleft
C. block transmitter release
D. inhibit transmitter synthesis
E. block transmitter reuptake
F. block cleft or intracellular enzymes that
metabolize transmitter
G. bind to receptor on postsynaptic membrane to
block (antagonist) or mimic (agonist) transmitter
action
H. inhibit or stimulate second-messenger activity
within postsynaptic cell

How Diseases Can Alter the Effectiveness of Synapses

● Tetanus is caused by the bacillus Clostridium
tetani, which produces a toxin (tetanus toxin).
○ This toxin is a protease that destroys SNARE proteins in the presynaptic terminal so that fusion of
vesicles with the membrane is prevented, inhibiting neurotransmitter release.
○ Specifically affects inhibitory neurons in the CNS that normally are important in suppressing the
neurons that lead to skeletal muscle activation.
■ results in an increase in muscle contraction and a rigid or spastic paralysis
● Botulism is caused by Clostridium botulinum bacilli which blocks neurotransmitter release from synaptic
vesicles by destroying SNARE proteins.
○ They target the excitatory synapses that activate skeletal muscles
■ Characterized by reduced muscle contraction, or a flaccid paralysis.
○ Note: Low doses of one type of botulinum toxin (Botox) are injected therapeutically to treat a
number of conditions, including facial wrinkles, severe sweating, uncontrollable blinking,
misalignment of the eyes, migraine headaches,

Factors that determine synaptic strength

I. Presynaptic factors
 A. Availability of neurotransmitter
1. Availability of precursor molecules
2. Amount (or activity) of the rate-limiting enzyme in the pathway for neurotransmitter
synthesis
B. Axon terminal membrane potential
C. Axon terminal Ca2+
D. Activation of membrane receptors on presynaptic terminal
1. Axo–axonic synapses
2. Autoreceptors
3. Other receptors
E. Certain drugs and diseases, which act via the above mechanisms A–D

II. Postsynaptic Factors

A. Immediate past history of electrical state of postsynaptic membrane (e.g., excitation or
inhibition from temporal or spatial summation)
B. Effects of other neurotransmitters or neuromodulators acting on postsynaptic neuron
C. Up- or down-regulation and desensitization of receptors
D. Certain drugs and diseases

III. General factors

A. Area of synaptic contact
B. Enzymatic destruction of neurotransmitter
C. Geometry of diffusion path
D. Neurotransmitter uptake

Neurotransmitters Neuromodulators

1. Elicit IPSPs and EPSPs 1. Messengers for complex responses that can’t be
2. Receptors for neurotransmitters described as simply IPSPs or EPSPs
influence ion channels that directly 2. Receptors for neuromodulators, more often bring
affect excitation or inhibition of the about changes in metabolic processes in neurons,
postsynaptic cell often via G proteins coupled to second-messenger
3. These mechanisms operate within systems.
milliseconds 3. Such changes, which can occur over minutes, hours,
4. Involved in rapid communication or even days, include alterations in enzyme activity
or, through influences on DNA transcription, in
protein synthesis.
4. Associated with slower events such as learning,
development, and motivational states.
5. Many hormones, paracrine factors, and messengers
used by the immune system serve as neuromodulators
6. Often modify the postsynaptic cell’s response to
specific neurotransmitters, amplifying or dampening
the effectiveness of ongoing synaptic activity
7. They may change the presynaptic cell’s synthesis,
release, reuptake, or metabolism of a transmitter

The distinctions between neuromodulators and neurotransmitters are not always clear. Certain
neuromodulators are often synthesized by the presynaptic cell and co-released with the neurotransmitters.

Acetylcholine (ACh) Norepinephrine (NE) Epinephrine (Epi

They are released by cholinergic neurons
Synthesized from choline and acetyl
coenzyme A in the cytoplasm of synaptic
terminals and stored in synaptic vesicles
Major neurotransmitter in the PNS at the
neuromuscular junction and in the brain
(For Parasympathetic)
ACh Receptors:
● Nicotinic Receptors respond not
only to ACh but also to Nicotine
(due to its chemical similarity to the
ligand ACh).
○ They are present in
neuromuscular junctions.
○ They contain ion channels
permeable to both K+ and Na+.
○ Since Na+ has the larger
electrochemical driving force,
the net effect of opening these
channels is depolarization (Na+
influx).
○ This will produce a local
potential, which is similar to the
EPSP but is called the endplate
potential.
○ The potential will undergo
summation and will produce
Biogenic amines, specifically Catecholamines along with
Dopamine (DA)
Synthesis
Begins with the uptake of tyrosine by the axon terminals and its
conversion to another precursor, L-dihydroxyphenylalanine (L-
dopa) by the rate-limiting enzyme (tyrosine hydroxylase) in the
pathway.
Depending on the enzymes expressed in a given neuron, any one
of the three catecholamines may be released. Autoreceptors on
the presynaptic terminals strongly modulate synthesis and release
of the catecholamines.
Location
Both are synthesized in the adrenal glands
Receptors
(For Sympathetic)
NE and Epi Receptors:
● Alpha-adrenergic receptor (alpha-adrenoceptors) .
○ α2: Can inhibit NE release in presynaptic neuron
○ α1: Can stimulate or inhibit activity of different K
channels in postsynaptic neuron
● Beta-adrenergic receptors (beta-adrenoceptors)
○ act via stimulatory G proteins to increase cAMP in the
postsynaptic cell.
○ There are three subclasses of beta-receptors, β1, β2,
and β3, which function in different ways in different
tissues
Note:
receptors are metabotropic, and thus use second messengers
to transfer a signal from the surface of the cell to the
cytoplasm.
 action potential and will be
conducted through the
sarcolemma (cell membrane in
the skeletal muscle cells) and
goes into the skeletal muscle
cell, which causes contraction to
take place.

● Muscarinic Receptors
○ Are metabotropic and couple
with G proteins, which then
alter the activity of different
enzymes and ion channels.
○ They are found at some
cholinergic synapses in the
brain and at junctions where the
PNS innervates glands, tissues
and organs.

Degradation

● After ACh activates receptors in the ● Diffusion

postsynaptic membranes.
Acetylcholinesterase (enzyme)
rapidly destroys ACh,
● releasing choline and acetate.
● The choline is then transported
back into the presynaptic axon
terminals where it is reused in the
synthesis of new ACh.
● Reuptake - Membrane transporter protein actively
transports the catecholamine back into the axon terminal.
● Broken down by enzymes such as monoamine oxidase
(MAO) in both the extracellular fluid and the axon terminal
Note:
Monoamine oxidase inhibitors are used in the treatment of
mood disorders such as depression through slowing the
degradation of NE and DA, increasing their amount in the
synapse

Function & Location

● In sympathetic nervous system ● Major neurotransmitter in ● Not a common

○ In peripheral ganglia of both CNS and PNS neurotransmitter in the
presynaptic neuron ● In sympathetic nervou CNS,
○ In Some neuro-effector system ● functions as a major
junctions ○ Found in in neuro- hormone
● In parasympathetic nervous effector junction
system
○ In both junction and synapse

Others

Alzheimer’s Disease:
Caused by degeneration of cholinergic
neurons, associated with the decrease of
the amount of ACh and postsynaptic
neurons that normally respond to ACh.

Note:
Some chemical weapons, (e.g. nerve
gas Sarin) inhibit
acetylcholinesterase, causing a
buildup of ACh in the synaptic cleft
and overstimulating postsynaptic
ACh receptors, initially causing
uncontrolled muscle contractions but
ultimately leading to receptor
desensitization and paralysis.

However, synthetic chemicals that act

like nerve gas (but nontoxic) are
currently used to help slow the
progression of Alzheimer’s through
inhibiting activity of
acetylcholinerase, which in turn help
maintain the concentration of
acetylcholine in synapses of
remaining cells