Transcript The Synapse - University of Toronto

The Synapse
Neurons generate action potentials which consist of brief reversals in the polarity
(electrical state) of the axon (transmitting region) of the cell. These action potentials
cause the release of a chemical messenger from a storage vesicle in the axon
terminal. The chemical messenger (called a neurotransmitter) travels across a
synapse to bind to a postsynaptic receptor protein. The act of binding to the receptor
protein sets in motion a series of events which eventually brings about a change in
the electrical state of the postsynaptic cell. Some neurotransmitter-receptor bindings
excite the cell and others inhibit it. At any given moment a neuron receives
thousands of these messages and integrates this input to bring about
only one of two possible outcomes - the neuron stays in a resting state
or it generates an action potential to communicate with another neuron.
The Synapse
1.....Postsynaptic Neuron
2.....Presynaptic Neuron
3.....Vesicle with Neurotransmitter (NT)
Molecules
4.....Mitochondrion (for energy production
from glucose)
5.....Synaptic Cleft
6.....Neurotransmitter (NT) Molecules
7.....Postsynaptic Membrane (with NT
receptors)
Neurotransmitters are released from storage vesicles
and diffuse across the synaptic cleft to bind to a
specific receptor site on the postsynaptic neuron.
The neurotransmitter then activates (excites or
inhibits) the next neuron and is then reuptaken into
the sending neuron or destroyed either in the cleft or
in the presynaptic neuron. It is at the synapse that
most drugs or chemicals work to alter the brain and
thus the mental state of the person.
The Synapse
Coated
Vesicle
Punctum
Adhaerens
Double-Walled
Vesicle
Mitochondrion
Synaptic
Vesicles
Endoplasmic
Reticulum
Active
Zone
Postsynaptic
Density
Dense Core
Vesicle
Presynaptic Axon
Postsynaptic
Spine
Astrocyte
Synaptic Cleft
The Synapse
Dendritic
Spine
Active Zones and the
Postsynaptic Density (PSD)
Active Zone
Synaptic
Cleft
Astrocytes
Vesicles
Coated Vesicles
Synaptic Vesicles
Coated vesicles are pieces of
membrane retrieved from the
plasmalemma through
endocytosis.
Neurotransmitter Release:
A nerve impulse that reaches a presynaptic ending produces
a transient depolarization of the presynaptic membrane,
which activates voltage-sensitive calcium channels. Calcium
ions flow across the membrane. Increased calcium levels
cause vesicles that store the chemical transmitters to move
toward the synaptic cleft (the space between pre- and
postsynaptic cells). The vesicles fuse with the inner surface
of this region, and the transmitters are transported across
the membrane and released into the cleft region. The
transmitter molecules diffuse across the cleft. Some bind to
receptor molecules on the postsynaptic membrane, changing
the permeability of the membrane.
Presynaptic Receptors & the
control of NT release.
Presynaptic Receptors & the
control of NT release.
Vesicle release
Vesicle release
The EPSP
Squid
Mouse
Calcium Channel Blockers &
the CNS: L-type
Dihydropyridines: Blockers of L-type VSCCs
L-type VSCCs found on Neurons, but also on vascular smooth muscle &
other muscle cells throughout the body.
Calcium Channel Blockers &
the CNS: N-type
Omega-conotoxin MVIIa (SNX111): A selective blocker for Ntype calcium channels from the
cone snail Conus magus
Conus Geographicus
Conus Geographicus
Na Channel Blocker: TTX
Blocks voltage-gated sodium channels
Commonly used in labs around the world
Fugu Poisoning: Estimates as high as 200 cases per year have
been reported with mortality approaching 50%
Neurotransmitters
A neurotransmitter is a chemical
compound, secreted by a neuron, that
either stimulates or inhibits the flow of
an impulse between neurons. Shortly
after a neurotransmitter completes its
action, it is taken up or broken
down by an enzyme. Acetylcholine , norepinephrine are examples of
stimulatory neurotransmitters; gamma aminobutyric acid is an example
of an inhibitor. Two other neurotransmitters, sertonin and dopamine,
are stimulatory in some parts of the brain but inhibitory in others.
Acetylcholine also stimulates muscle contraction wherevera neuron
connects with a muscle.
Neurotransmitters
Detailed Notes
Provided
Catecholamines: Synthesis
Catecholamines: Metabolism
Catecholamines: Projections
Acetylcholine
Acetylcholine
Parkinson’s Disease
Described > 180 Yrs ago by James Parkinson
Affects > 1 million people in North America
Prevalence increases with increasing age
Shortens life & increases disability
Parkinson’s Disease
Characterized by the progressive
death of selected neurons
• Dopaminergic neurons of the
pars compacta of the substantia
nigra
• Selected aminergic brainstem nuclei (catecholaminergic
and serotoninergic)
• Cholinergic nucleus basalis of Meynert
Results in a loss of dopamine in the striatum
Parkinson’s Disease:
Characterized by
T
R
A
P
Which are due to an
imbalance in the
excitatory and
remor
inhibitory circuitry of
igidity
the basal ganglia –
Structures
kinesia
responsible for motor
ostural Instability
control.
Parkinson’s Disease:
Treated with L-dopa
(metabolized in the
CNS to dopamine)
Parkinson’s Disease:
Treated
surgically by
lesioning the
globus pallidus
(pallidotomy)
or subthalamic
nucleus
GABA Receptors
There are two basic subtypes, GABA-a and GABA-b. GABA-a is the
most prevalent in the mammalian brain. The GABA-a receptor is similar
to acetylcholine receptor in that it is related to an ion channel. In the
case of GABA-a it is the chloride ionophore. Binding of GABA to this
receptor increases the permeability to chloride ion which causes a
hyperpolarization of the neuron or inhibition.
The GABA-a receptor has four basic subunits, 2-alpha and 2 beta
peptides which surround a chloride channel.
There are three basic binding sites on this complex. The first is the
GABA site. The second is a benzodiazepine site. The third is in
the channel and is essentially a barbiturate site.
Glutamate receptors
Responsible for
mediating
Rapid Synaptic
Excitation in
the CNS
Back to the patient:
Enhance
GABAA
+
Block EAA
Receptors
=
Anesthesia
Evoked
Potentials
Monitoring
Evoked Potentials
Somatosensory Evoked Potentials
The SSEP assesses the pathways
from the nerves in the arms or
legs, through the spinal cord to
the brain. Electrodes are placed
on the scalp. A small electrical
current is applied to
the skin near nerves on your
arms or legs. The evoked
potential is measured from the
scapl. This test can also be used
to monitor coma patients, and
test hearing in infants and
others whose hearing
cannot be tested in standard
ways.
Succinylcholine
Succinylcholine chloride is an ultra short-acting, depolarizing-type,
skeletal muscle relaxant for intravenous administration
It is a depolarizing skeletal muscle relaxant. It competes with
acetylcholine for the cholinergic receptors of the motor endplate, and,
like acetylcholine, it combines with these receptors to produce
depolarization.
Succinylcholine, however, causes a more prolonged depolarization than
acetylcholine because it has a high affinity for thecholinergic receptor
and a strong resistance to acetylcholinesterase. Depolarization results in
fasciculation of the skeletal muscles followed by muscle paralysis.
Neuromuscular transmission is inhibited as long as an adequate
concentration of succinylcholine remains at the receptor site.
Pancuronium
Pancuronium bromide is a nondepolarizing neuromuscular blocking
agent. It is similar to, but five times as potent as, tubocurarine.
Pancuronium is used to induce relaxation of the skeletal muscles during
surgery and to facilitate pulmonary compliance during mechanical
ventilation
Nondepolarizing agents produce skeletal muscle paralysis by blockade at the
myoneural junction. Pancuronium competes with acetylcholine for cholinergic
receptor sites. Unlike depolarizing agents, pancuronium has little agonist
activity, having no depolarizing effect at the motor endplate. Skeletal muscle
relaxation proceeds in predictable order, starting with muscles associated with
fine movements, e.g., eyes, face, and neck. These are followed by muscles of
the limbs, chest, and abdomen and, finally, the diaphragm. Larger doses
increase the risk of respiratory depression due to relaxation of the intercostal
muscles and diaphragm. Muscle tone returns in the reverse order.
How to Gauge Depth of
Neuromuscular Relaxation:
One last look…