Transcript Lecture 3: Synaptic Transmission

3. Synaptic transmission
Lecture 3. Synaptic
transmission
• Review:
• What decision is made by
a neuron?
• At what location the
decision is made?
• How the decision is
made?
• Simple decision rule:
if Em > threshold (-40mV)
 fire an action potential
Inject
current
Measure
Em
-
Let us simulate excitatory input by injecting
positive ions (electrical current) into neuron
• After action potential is initiated, it propagates to
the axon terminal in all-or-none manner
Peak = +30mV
Threshold = -40mV
Em
Inject
current
Resting Em= -80mV
2. Presynaptic
neuron
1. Synapse
(Greek “syn”=
together +
Greek “hapto”=
to clasp)
3. Postsynaptic
neuron
What happens
at the contact
between two
neurons?
Let’s start with something simple: The
only monosynaptic reflex in our body
• Stretch reflex - stretch a
muscle and the reflex circuit
leads to the contraction of
the same muscle.
• Why doctors check for this
reflex?
• Decreased stretch reflex is a
clinical sign of demyelination
of peripheral nerves (as
occurs in untreated syphilis
infection).
• Increased stretch reflex can
occur in patients with
cerebellar disease, the leg
can oscillate up to 8 times.
• Dorsal root
• From Latin
Dorsalis = Back
• Ventral horn
• from Latin
ventralis= belly,
abdomen
• SAME DAVE
Sensory – Dorsal
Afferent – Afferent
Motor – Ventral
Efferent - Efferent
Dorsal
Ventral
• In both the spine
and the brain: the
back (posterior) is
sensory
• the front (ventral)
is motor
• Sensor: Muscle spindle is a stretch
receptor = the length sensor
ΔL
Frequency (rate) of
action potentials
Em
Fmax
Stimulus = ΔL
• Conclusion: Information is coded in
frequency of action potentials (firing
frequency): the higher the frequency  the
stronger quadriceps muscle would contract
Reflexes
• Definition: we talk of a reflex when consciousness is not involved.
• A patient could be unconscious, but the reflex will still work.
• Other examples of a reflex?
• Crossed extensor reflex (a withdrawal reflex) after stepping on a
nail flexors in this leg contract and the extensors relax, while in the
other leg, the opposite occurs.
• Withdrawal from a hot object
• Pupillary light reflex
• Note that the firing of the motor neuron can be inhibited by the
brain
• The problem: we need to transmit signal from one cell
to another
• In the stretch reflex, the signal needs to be transmitted:
– from the stretch receptor axon terminal  the motor neuron
– from the motor neuron axon terminal  the muscle
Electrical synapse
Types of synapses
Chemical synapse
• Until 1920 scientists did not know how neurons communicated.
• Scientists formed two camps: they called themselves soups and
sparks. Soups were in favor of chemical transmission and sparks were
in favor of electrical communication. They were arguing for 50 years
and before 1920 sparks seemed to be winning.
• The solution to the question came to Otto Loewi in a dream in 1920…
Loewi’s Experiment Demonstrating Chemical Transmission
• Stimulated vagus nerve 
slowed heart A
• Injected solution from
heart A into heart B 
Heart B rate slowed
• Stimulated sympathetic
nerve  sped up heart A.
• Injected solution from
heart A into heart B 
Heart B rate sped up
• Loewi’s conclusion
– Heart uses chemical
messengers, not electrical
signal to control heart rate.
– Loewi got a Nobel prize in
1936
A
B
Which synapse is electrical? chemical?
Electrical synapse
Chemical synapse – note vesicles
in the presynaptic neuron’s axon
terminal
• Electron microscopy of synapses
Electrical synapses
• The first type of connection
that evolution tried was an
electrical contact: gap
junction
• Ions and small molecules (up
to 2nm) can diffuse without
leaking to extracellular space
• A kind of local plumbing
system
• A gap junction can be regulated:
• 1. by a number of small molecules
• 2. by insertion or removing gap junctions from the
membrane
Electrical
synapse
A
Differences
between chemical
and electrical
synapse
B
Em cell A
A
B
Em cell A
start of AP in cell A
Em cell B
Chemical synapse
start of AP in cell A
start of postsynaptic
potential in cell B
Em cell B
start of postsynaptic
potential in cell B
delay
No delay
Electrical
synapse
A
Differences
between chemical
and electrical
synapse
Chemical synapse
A
B
Action
potential
in cell A
Action
potential
in cell B
B
Em cell A
Em cell A
Em cell B
Em cell B
Em cell A
Em cell A
Em cell B
Em cell B
Electrical synapse
•
Why wasn’t evolution satisfied with electrical
synapses?
–
–
•
PROBLEM: Gap junctions are straight forward
transducers of electricity:
–
–
•
Gap junctions synaptic transmission is fast
Gap junctions can be regulated
Presynaptic cell depolarized  Post is depolarized;
Postsynaptic cell depolarized Pre depolarized
It is impossible to build a highly compartmentalized
system with just electrical synapses
Chemical synapse
•
Evolution favored more complex systems. It is easier
to build complex systems with chemical synapses:
–
–
–
–
neurons are electrically isolated;
chemicals (called neurotransmitters) are used to
transmit signal between neurons.
Some neurotransmitters depolarize the postsynaptic
neuron; some hyperpolarize
Some neurotransmitters have only transient effect
(1ms); others long-lasting effect (100ms)
Electrical synapses connect
some neurons in some
animals:
• Example: crayfish giant motor
synapse, that mediates
emergency tail flip – the escape
reaction of crayfish.
• 4 giant axons of the ventral
nerve cord make contact with
axons of giant motor neurons
in each segment  all
abdominal flexor muscles
become activated
simultaneously and without
delay
•
•
(b) Photomicrograph of cross section of ventral nerve cord in abdomen of crayfish made near the level of the
third root (arrow in a); the largest axons near the top are giant fibers used in escape responses
(c) Relationship between lateral giant and motor giant axons as they make electrical synaptic contact near the
third root of an abdominal ganglion in the crayfish
• Gap junctions connect
neighboring cells in the
heart, smooth muscles, in
glands, liver, epithelia;
• At some stages of early
development of an embryo,
they couple all cells.
• In fact, most cell in the
body are connected by
electrical synapses;
• Except red blood cells,
neurons and skeletal
muscles.
From now on we’ll be talking about chemical synapses
only. Rules of the game at a chemical synapse
1. Excitatory synapse  always
depolarization
(Em gets closer to the threshold
for Na+ channels)
-50mV
Em=-60mV
Excitatory postsynaptic potential (EPSP)
15ms
2. Inhibitory synapse  always
hyperpolarization (Em gets
farther away from the
threshold for Na+ channels)
Em=-60mV
-70mV
Inhibitory postsynaptic potential (IPSP)
Excitatory
synapse
Action potentials in the
presynaptic cell 1 are
100ms apart  no
temporal summation
Action potentials in the
presynaptic cell 1 are
5ms apart  temporal
summation of excitatory
postsynaptic potentials
(EPSP) results in action
potential in the
postsynaptic cell
Simultaneous action
potentials in presynaptic
cell 1 and 2  spatial
summation of EPSP
results in action
potential in the
postsynaptic cell
Inhibitory postsynaptic
potential (IPSP) reduces
the probability of action
potential in the
postsynaptic cell
action potential
Summary
1. Postsynaptic potentials last
longer than action potentials
2. Postsynaptic potentials are local potentials
– they are not usually amplified
3. Postsynaptic potentials are graded
potentials: the more APs arrived  the
greater EPSP
(as opposed to all-or-none APs)
4. Since they are not amplified, postsynaptic
potentials are decreasing in amplitude as
one measures postsynaptic potentials
away from a synapse:
Em
10mV
5mV
3mV
Postsynaptic
potential
1mV
synapse
dendrite
AP in
presynaptic cell
axon
• Usually one finds a number of inhibitory synapses
right at the axon hillock
• So that even if there are a lot of excitatory inputs,
the inhibitor can decide whether to fire AP or not
The mechanism of neurotransmitter release
• Let’s look at the neuromuscular junction
• The goal of the neuron: to depolarize muscle so
that muscle fires an action potential
• Transmission is chemical  neurotransmitter has
to be delivered to the surface of the muscle
• Neurotransmitter is stored
inside synaptic vesicles
• What triggers the release of
vesicles?
The process of exocytosis
• Increase of Ca++
concentration
from 0.0001mM to
1mM in close
vicinity to vesicles
triggers exocytosis
• Neurotransmitter
packed inside
vesicles at high
concentration is
spilled on the
postsynaptic cell
• The number of
postsynaptic
receptors is
very large
• These
receptors can
be ion
channels
themselves or
they can be
coupled to
other proteins
that transmit
the signal
inside a
postsynaptic
cell
localization of ACh receptors
•
•
Electron microscope autoradiograph of the vertebrate neuro-muscular junction (nmj), showing localization of
ACh receptors (black developed grains) at the top one-third of the postsynaptic junctional folds.
AChE is at the bottom of postsynaptic junctional folds is not marked
• POSTSYNAPTIC RECEPTOR: In the case of a neuromuscular
junction, ACh receptor itself is a channel
• Following binding of two ACh molecules, the channel opens
• Sodium enters the muscle and ….what happens?
• Positive sodium depolarizes the muscle, making it more likely
to fire an action potential.
+30mV
?
– –
– – –
+
–
-
-40mV
-
+
+
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+ +
+ + +
+
•
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•
Na+
+
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+
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- +
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++
+
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- +
+
+
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+
- +
++
+
+ - +
++ - +- + -+
+
-+
+
- + - +
+
- +
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+ +
+- +
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[K ]=150mM
[Na ]=15mM
Na+
-
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+ -
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[K+]=4mM
[Na+]=145mM
Positive sodium depolarizes the muscle 
membrane potential becomes more positive
more sodium channels open 
Even more sodium ions enter the cells 
membrane potential even more positive  and so on ==
Positive feedback loop == explosion == gun powder
• The release of one vesicle usually is not enough to
trigger AP in a muscle.
• Many vesicles at many release zones have to exocytose
to result in muscle AP and a corresponding twitch.
• Each neuronal AP releases many vesicles,
• Each neuronal AP normally results in a muscle AP
• If ACh is
allowed to
hang around
ACh receptor
for too long
new signal will
not get
through.
• Therefore ACh
has to be
quickly
removed from
synaptic cleft
• Name several
possible
mechanisms?
Inside axon terminals:
choline + AcetylCoA  ACh + CoA
ACh is then packaged into vesicles
Choline
transporter
AChR AChR AChR AChR
AChE AChE
•
•
•
•
AChE AChE
AChE
ACh is broken down by ACh esterase (AChE)
AChE is located in postjunctional folds (AChR are on the surface)
ACh is broken into choline and acetate
Choline is transported back into the neuron by choline transporter
•
•
Electron microscope autoradiograph of the vertebrate nmj, showing localization of ACh receptors (black
developed grains) at the top one-third of the postsynaptic junctional folds.
AChE is at the bottom of postsynaptic junctional folds
Find two errors
Find two errors
Disease: Myasthenia gravis
• G. myo=muscle +
asthenia=weakness
• Severe dropping of
eyelids
• Patient cannot move his
eyes to look to either
side
• Severity varies within a
single day, day to day…
Disease: Myasthenia gravis
• Autoimmune disease in which antibodies are produced
against the nicotinic AChR
• Viral or bacterial antigens may share epitopes with the AChR
• This reduces the number of ACh receptors, increases receptor
turnover and degradation
Disease: Myasthenia gravis
• Normally an AP in a motor axon releases enough vesicles to induce
a muscle AP.
• In fact the number of vesicles can be reduced by 25% before it fails
to initiate AP
• In MG the number of ACh receptors goes down and infoldings are
reduced  more ACh is broken down by AChE that is closer to
synaptic cleft
Disease: Myasthenia gravis
• The weakness is reversed by drugs that inhibit AChE
• E.g. neostigmine block the breakdown of ACh by AChE
and temporarily increases the levels of ACh at the
neuromuscular junction
Types of neurotransmitters (You are not responsible for learning
different types of neurotransmitters, their function, and location)
Neurotransmitter
Function
Amino Acids
Glutamate (Glu)
The major excitatory neurotransmitter in the brain and spinal cord.
Gamma-aminobutyric acid
(GABA)
The major inhibitory neurotransmitter. Its receptors respond to alcohol and the class of
tranquilizers called benzodiazepines. Deficiency in GABA or receptors is one cause of
epilepsy. Inhibitory neurons are 20% of all neurons in brain.
Glycine (Gly)
Inhibitory neurotransmitter in the spinal cord and lower brain. Works by opening Chloride
channels that hyperpolarizes the cell. The poison strychnine causes convulsions and death by
blocking Gly binding site on the Chloride channels.
Biogenic amines (contain NH2 amino group)
Acetylcholine (Ach)
Neurotransmitter at the neuromuscular junction; in brain, involved in memory, etc.
Dopamine (DA)
Involved in reward circuits in the PFC. Abnormalities in DA system are implicated in
schizophrenia and Parkinson’s disease. Cocaine blocks DA reuptake. Attention deficit disorder
drug Ritalin also blocks DA reuptake. Amphetamine (Adderall) modulates DA as well as 5-HT
and NE).
Serotonin (5-HT)
Involved in regulation of mood, sleep and arousal, sexuality, aggression, body temperature.
Abnormalities in 5-HT system are implicated in depression, obsessive-compulsive disorder.
Psychedelic drugs like LSD activate 5-HT receptors as well as some DA receptors.
Norepinephrine (NE)
Released during stress. Neurotransmitter in the brain to increase arousal and attentiveness
to events in the environment. ADD drug Strattera affects only NE.
Epinephrine (Epi)
A stress hormone related
norepinephrine.
Garrett:to
Brain
& Behavior 4e Also called Adrenalin.
Histamine (His)
Modulates sleep: antihistamines induce sleepiness (Dramamine)
Neurotransmitter
Function
Neuropeptides
Endorphins (over 85
different
neuropeptides)
Endogenous opioids (5 amino acid polypeptide) reduce pain and enhance
reinforcement. Exogenous opioids: morphine, heroine also activate these
receptors.
Substance P
Neurotransmitter in neurons sensitive to pain.
Neuropeptide Y
Initiates eating and produces metabolic shifts.
Gases
Nitric Oxide
Viagra enhances male erections by increasing nitric oxide’s ability to relax
blood vessels and produce penile engorgement.
CO
carbon monoxide
• Every molecule of neurotransmitter has a number of
different target receptors, increasing the system
complexity
Regulation of the synaptic strength
• Presynaptically
• Short-term transmitter release facilitation.
e.g. increase in [Ca++ ], Ca++ -calmodulindependent protein kinase II phosphorylation
of synapsin, autophosphorylation of protein
kinase II that becomes persistently active
independent of Ca++ -calmodulin,…
• Short-term transmitter release depression,
e.g. reduction of available vesicles
• Calcium channel regulation
• Autoreceptors provide feedback mechanism
• AP duration (AP longer more Ca++ in
more release
• Long-term: regulate the number of
synapses between the cells
• regulate the number of active zones per
synapse
• Modify recycling of neurotransmitter
• Postsynaptically
• Modify postsynaptic
receptors via ligands
• Modify receptor
subunit composition
• Change number of
receptors
Regulate the number of synapses between
the cells: grow dendritic spines
Sleep and memory
newly formed dendritic
spines (filled arrowheads)
• Sleep is good for memory consolidation (conversion of memory into
permanent memory).
• Memory improvement is most dramatic for procedural memory (riding
a bike, skating, playing the piano).
• Even a short nap can really improve memory.
Example: growth
of neuronal
connections
Within the first day after plating one of the short processes of a
hippocampal neuron becomes defined as the single axon of the cell
that grows out very rapidly. Both rate and direction of outgrowth
are influenced by the nature of the substrate the axon encounters.
This movie follows the elongation of the axon on a uniform
substrate over a period of 16 hours. Note how the axon elongates
in spurts.
Time lapse: 16.5 hours (one loop of movie)
Poisons
• Botulinum toxin (from Latin “sausage”)  fusion proteins are
cut  vesicles are not released
• Most potent toxin on the planet. Medial lethal dose 1ng/1kg
(compare to strychnine 1,000,000ng/kg)
• You only need 300gram to kill every person on earth
Botulinum toxin cuts
Syntaxin, SNAP-25,
and Synaptobrevin
Clostridium botulinum
• Canned food creates ideal anaerobic environment
for the bacterium Clostridium botulinum 
allows the spores to germinate, after which the
bacteria can multiply and produce toxin 
• Do not eat food from
cans that are swollen!
• The spores Clostridium botulinum
survive boiling at 100°C
• To kill spores canning companies
use high pressure to raise
temperature to 121°C for 3 min
• Bottox
Poisons
Botulinum toxin
Choline
transporter
AChR AChR AChR AChR
AChE AChE
AChE AChE
AChE
Black widow spider toxin
Cobratoxin
Organophosphates
Why all victims die?
• Botulinum toxin (from Latin “sausage”)  fusion protein are cut 
vesicles are not released
• Black widow spider toxin  vesicles are released without Ca++
• Cobratoxin binds tightly to nAChR, preventing activation of nAChR
• Organophosphates (biological weapons): irreversible inhibitors of
AChE  ACh is not broken down  desensitization of AChR
Conclusions
• Most interesting
staff
– short-term
memory
– long-term
memory
– learning
happens at the
synapses.
• Stop
Electrical
synapse
A
Differences
between chemical
and electrical
synapse
Chemical synapse
A
B
B
Em cell A
Action
potential
in cell A
Em cell A
delay
Em cell B
Em cell B
No delay