Axon terminals

An action potential originates at the axon hillock, the junction

of the axon and cell body, and is actively conducted down
the axon into the axon terminals, small branches of the axon
that form the synapses, or connections with other cells. At
synapses signals are passed to other neurons or to a
muscle cell at a neuromuscular junction. A single axon in the
central nervous system can synapse with thousands of
neurons and induce responses in all of them simultaneously.

Synapses
The synapse is the elementary structural and functional unit for
the construction of neural circuits. In the traditional view, a synapse
is a simple connection that can impose either excitation or
inhibition on a receptive neuron. Much experimental evidence
indicates that this assumption needs to be replaced by an
appreciation of the complexity of this functional unit.
Most synapses involve the apposition of the plasma membranes
of two neurons to form a punctate junction, also termed an active
zone. The junction has an orientation, thus defining the presynaptic
process and the postsynaptic process. At a chemical synapse the
presynaptic process liberates a transmitter substance that acts on
the postsynaptic process. From an operational point of view, a
synapse converts a presynaptic electrical signal into a chemical
signal and back into a postsynaptic electrical signal.
 Synapses
An important property of the synapse is its small size. The area
of contact has a diameter of 0.5-2.0 m , and the presynaptic
terminal (a varicosity or bouton) has a diameter that
characteristically is only slightly larger. These small sizes mean
that large numbers of synapses can be packed into the limited
space available within the brain. For example, in the cat visual
cortex, 1 mm3 of gray matter contains approximately 50,000
neurons, each of which gives rise on average to some 6,000
synapses, making a total of 300 million synapses. If the cortical
area of one hemisphere in the human is approximately 100,000
mm2, there must be on the order of 10 billion cells in the human
cortex and 60 trillion (60 X 1012) synapses. In the cerebellum, it
has been estimated that the small granule cells number up to 100
billion, each making up to 100 synapses onto cerebellar nuclear
and cortical cells.

Excitatory and inhibitory synapses

Gray 1 Gray 2
Steps of synaptic transmission depolarization of the presynaptic
membrane;
influx of Ca2+ ions into the
presynaptic terminal;
a series of steps leading to fusion
of a synaptic vesicle with the
plasma membrane;
release of a packet (quantum) of
transmitter molecules;
diffusion of the transmitter
molecules across the narrow
synaptic cleft separating the
presynaptic and postsynaptic
processes;
action of the transmitter molecules
on receptor molecules in the
postsynaptic membrane, leading
in some cases to direct gating of
the conductance at an
ionotropic receptor.

Opening of ion channels changes the membrane potential and

hence the excitability of the postsynaptic process.
A depolarizing change increases the excitability; this is called an
excitatory postsynaptic potential (EPSP)
A hyperpolarizing change decreases the excitability, therefore it
is called an inhibitory postsynaptic potential (IPSP)
The mechanisms mediated by ionotropic receptors are
concerned with rapid (1-20 ms) transmission of information
 Measurement of synaptic effects

20 mV
2 mV

5 ms
afferent fiber pre
threshold

ME1 ME2 post

20 mV
400 V
25 ms
interneuron pre
principal
cell
post
efferent fiber

Steps of synaptic transmission

The transmitter molecule may

also activate a metabotropic
receptor linked to a second-
messenger pathway that
modulates a membrane
conductance or has other
metabolic effects
Steps of synaptic transmission

After their release into

synapses, catecholamines
and amino acid
neurotransmitters are
removed by transport into
the axon terminals that
released them. Re-uptake is
the most widely used
mechanism of transmitter
removal; enzymatic
degradation is used only for
acetylcholine and
neuropeptides.

Neurotransmitter re-uptake

Transporters for GABA, norepinephrine, dopamine, and

serotonin were the first to be cloned and studied. These four
transporters are encoded by a gene family, and are 60-70 percent
identical in amino acid sequences. Each transporter is thought to
have 12 membrane-spanning helices. All four are
Na+_neurotransmitter symporters and frequently Cl- is transported
along with the neurotransmitter. As with other Na+ symports, the
movement of Na+ into the cell down its electrochemical gradient
provides the energy for uptake of the neurotransmitter.
The norepinephrine, serotonin, and dopamine transporters are
all inhibited by cocaine. Cocaine inhibits dopamine uptake and thus
prolongs signaling at key brain synapses; the dopamine transporter
is the principle brain "cocaine receptor." Therapeutic agents such
as the antidepressant drugs fluoxetine, imipramine, and Prozac,
block the serotonin transporter, and the tricyclic antidepressant
desipramine blocks noradrenaline uptake
Steps of synaptic transmission

Presynaptic receptors
generally inhibit transmitter
release. By this negative
feed-back they prevent the
excessive elevation of
transmitter concentration in
the synaptic cleft.
Usually the presynaptic and
postsynaptic receptors are
of different subtype (e.g.
1-adrenergic receptors
are dominantly
postsynaptic, 2-adrenergic
receptors are presynaptic).

Release of neurotransmitters

Synaptic vesicles import

neurotransmitters from the
cytosol using a proton-
neurotransmitter antiport.
The vesicles then move to the
"active zone" near the
plasma membrane where
they dock at defined sites
Exocytosis of the docked
vesicles is triggered by the
rise in cytosolic Ca2+, with
release of neurotransmitters
into the synaptic cleft.
 Botulinum toxin inhibits acetylcholine release

Botulinum toxin is a protein produced by the anaerobic bacillus

Clostridium botulinum, an organism that can multiply in preserved
food and can cause botulism, an extremely serious type of food
poisoning. The potency of botulinum toxin is extraordinary, the
minimum lethal dose in a mouse being less than 10-12g, only a few
million molecules.
Botulinum toxin contains several components (A-G). They are
peptidases that cleave specific proteins involved in exocytosis
(synaptobrevins, syntaxins, etc.), thereby producing a long-lasting
block of synaptic function.
Botulinum poisoning causes progressive parasympathetic and
motor paralysis, with dry mouth, blurred vision and difficulty in
swallowing, followed by progressive respiratory paralysis.
Botulinum toxin, injected locally into muscles, is fashionable as a
wrinkle remover, removing frown lines by paralysing the superficial
muscles that pucker the skin.

Tetanus toxin prevents glycine release

Tetanus toxin is a bacterial toxin resembling botulinum toxin. It

acts selectively to prevent glycine release from inhibitory
interneurons in the spinal chord, causing excessive reflex
hyperexcitability and violent muscle spasms (lockjaw,
opisthotonus).
Synaptic vesicle recycling

The synaptic vesicle

membrane proteins are then
specifically recovered by
endocytosis in clathrin-
coated vesicles and move
away from the active zone
The clathrin coat is
depolymerized, and the
vesicles fuse with larger,
low pH, endosomes
New synaptic vesicles then
form by budding from these
endosomes and then are
filled with neurotransmitters
completing the cycle.

Clathrin
 Dendrites
Most neurons have multiple dendrites, which are specialized
to receive chemical signals from the axon termini of other
neurons.
Particularly in the central nervous system, neurons have
extremely long dendrites with complex branches. This
allows them to form synapses with and receive signals
from a large number or other neurons (up to thousands).
Dendrites convert synaptic chemical signals into small
electric impulses and transmit them to the cell body
(cellulipetal conduction).
Electric disturbances generated in the dendrites or cell body
spread to the axon hillock. If the depolarization there is
great enough (threshold), an action potential will be
generated and will be actively conducted down the axon.

Simplified representation of a neuron

 Electrotonic conduction

Electrotonic conduction
Most dendrites do not possess fast sodium channels,
therefore can not generate action potentials.
They conduct waves of membrane potential passively
(electrotonically) a short distance along their length as the
result of currents that flow intracellularly along the
cytoplasm and simultaneously across the plasmalemmal
membrane.
When the change of membrane potential spreads along a
stretch of membrane, it becomes exponentially smaller
(decrement).
Due to this attenuation, distant synapses have smaller effect
on somatic membrane potential than proximal ones.
Localization of synapses on different dendritic domains
(e.g. apical vs. distal, proximal vs. distal) affects their
efficacy.
 Dendritic attenuation of synaptic currents

Postsynaptic potentials

presynaptic 20 mV
2 mV
action potential
5 ms

threshold
postsynaptic
EPSP, Excitatory Postsynaptic Potential
response

20 mV
400 V
presynaptic 25 ms

postsynatic

IPSP, Inhibitory Postsynaptic Potential

 Synaptic integration
Inhibitory synapses are more abundant on the cell body
while excitatory synapses are distributed throughout the
dendritic tree. Most excitatory synapses terminate on
dendritic spines.
Resting membrane potential is 10-20 mV more negative
than the threshold (Vrest=-70 to -80mV, Vt=-55 to -60mV).
Postsynaptic potentials are not larger than 1-2mV, therefore
activation of a single excitatory synapse can not drive the
target neuron to fire action potentials.
The dynamic interaction of excitatory and inhibitory inputs to
both the somatic and dendritic membranes determines
whether the neuron will be sufficiently depolarized to
generate one or more action potentials.
This processing of multiple synaptic inputs to blend into a
functioning or unified whole is termed synaptic (dendritic)
integration.

Major neurotransmitters in the central nervous system

Amino acid transmitters
Glutamate
Aspartate excitatory
-Aminobutyric acid (GABA)
inhibitory
Glycine
Amine transmitters
Noradrenaline
Dopamine
5-Hydroxytryptamine (Serotonin)
Histamine
Acetylcholine
Purines
Other CNS mediators
Melatonin
Nitric oxide
Lipid mediators
 Glutamate

Glutamate receptor subtypes:

(distinguished on pharmacological basis - selective agonists and antagonists)
- metabotropic
- ionotropic: - NMDA (N-methyl-D-aspartic acid)
- AMPA (-amino-3-hydroxy-5-methylisoxazole-4-propionic acid)
- kainate
Glutamate receptors are most abundant in the cortex, basal
ganglia and sensory pathways. NMDA and AMPA
receptors are generally colocalised, but kainate receptors
have a much more restricted distribution.
AMPA and kainate receptors mediate fast synaptic effects.
The membrane potential of the postsynaptic neuron
changes very rapidly (in 0.1 to 2 ms). They are mixed
cation channels, permeable mainly to Na+ and to a lesser
extent to K+.

Special features of NMDA receptors

NMDA receptors are highly permeable to Ca2+, as well as to

other cations, so activation of NMDA receptors is
particularly effective in promoting Ca2+ entry.
They are readily blocked by Mg2+, and this block shows
marked voltage dependence. It occurs at physiological
Mg2+ concentrations when the cell is at resting potential,
but disappears, if the cell is depolarised.
Activation of NMDA receptors requires glycine as well as
glutamate. The binding site for glycine is distinct from the
glutamate-binding site, and both have to be occupied for
the channel to open.
 Long-term potentiation (LTP)
LTP is a long-lasting enhancement in signal transmission
between two neurons that results from stimulating them
synchronously.
It is widely considered one of the major cellular mechanisms
that underlies learning and memory.
NMDA receptor is a key molecule in LTP induction
Two conditions must be fulfilled for the ion channel to open:
- glutamate must be bound and
- the membrane must be partly depolarized.
In this way, the NMDA receptor functions as a coincidence
detector: it integrates activity of the postsynaptic cell
(reflected in its depolarized plasma membrane) with
release of neurotransmitter from the presynaptic cell,
generating a cellular response greater than that caused by
glutamate release alone.

Long-term potentiation (LTP)

Activation of a single synapse generally causes only a small

depolarization of the membrane of the postsynaptic cell.
Therefore long-term potentiation is induced only when many
synapses on a single postsynaptic neuron are activated
simultaneously and/or the postsynaptic cell is firing an
action potential synchronously with the presynaptic cell.
Opening of the NMDA glutamate receptors causes an influx
of Ca2+ ions and an activation of many Ca2+-dependent
enzymes in the postsynaptic cell (via Ca2+ - calmodulin-
dependent protein kinase II)
Postsynaptically, phosphorilation of AMPA receptors
facilitates synaptic transmission.
 Long-term potentiation (LTP)

presynaptic mechanisms

postsynaptic mechanisms

Long-term potentiation (LTP)

NO synthase produces NO from the amino acid arginine.
NO, unlike classical neurotransmitters, simply diffuses out
of the postsynaptic cell and into neighboring cells. There it
activates several enzymes, among them guanylyl cyclase,
an enzyme that synthesizes cyclic GMP, and the cGMP is
thought to change the presynaptic cell such that more
glutamate is released during the arrival of each action
potential.
Mice genetically engineered to have a deletion in the gene
encoding calmodulin-dependent protein kinase II (knock
out), in most respects grow and behave normally (their
abilities to eat and mate are normal, and they have the
coordinated motor skills to swim normally in water), but are
impaired in a particular type of learning process.
 Long-term potentiation (LTP)
In a psychological test, the mice are placed in a round pool
of opaque water; to escape the water the mice must swim
to a submerged platform. The mice can find easily the
platform if it is made visible by a flag. When the platform is
hidden, the mice must learn to find it from integrating
multiple spatial relationships between objects in the room
surrounding the pool (e.g., pictures on the wall) and the
position of the platform. The mice with defective Ca2+-
calmodulin-dependent protein kinase take longer to learn
to find the platform than do their normal littermates. This
demonstrates that the Ca2+-calmodulin-dependent protein
kinase II plays an important role in spatial learning.