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Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Chemical Neurotransmission
(page 5 in syllabus)
Stephen M. Stahl, MD, PhD
Adjunct Professor, Department of Psychiatry
University of California, San Diego School of Medicine
Honorary Visiting Senior Fellow, Cambridge University, UK
Sponsored by the Neuroscience Education Institute
Additionally sponsored by the American Society for the Advancement of Pharmacotherapy
This activity is supported solely by the sponsor, Neuroscience Education Institute.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Faculty Editor / Presenter
Stephen M. Stahl, MD, PhD, is an adjunct professor in the department of psychiatry at
the University of California, San Diego School of Medicine, and an honorary visiting
senior fellow at the University of Cambridge in the UK.
Grant/Research: AstraZeneca, BioMarin, Dainippon Sumitomo, Dey, Forest, Genomind,
Lilly, Merck, Pamlab, Pfizer, PGxHealth/Trovis, Schering-Plough, Sepracor/Sunovion,
Servier, Shire, Torrent
Consultant/Advisor: Advent, Alkermes, Arena, AstraZeneca, AVANIR, BioMarin, Biovail,
Boehringer Ingelheim, Bristol-Myers Squibb, CeNeRx, Cypress, Dainippon Sumitomo,
Dey, Forest, Genomind, Janssen, Jazz, Labopharm, Lilly, Lundbeck, Merck,
Neuronetics, Novartis, Ono, Orexigen, Otsuka, Pamlab, Pfizer, PGxHealth/Trovis,
Rexahn, Roche, Royalty, Schering-Plough, Servier, Shire, Solvay/Abbott,
Sunovion/Sepracor, Valeant, VIVUS,
Speakers Bureau: Dainippon Sumitomo, Forest, Lilly, Merck, Pamlab, Pfizer,
Sepracor/Sunovion, Servier, Wyeth
Individual Disclosure Statement
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Learning Objectives
• Describe the structure and function of neurons
• Explain the anatomical basis of synaptic
neurotransmission
• Explain the chemical basis of synaptic
neurotransmission
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Structure and Function
of Neurons
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
dendrites
dendritic spines cell body (soma)
axon en passant
presynaptic
axon terminals
presynaptic
axon terminals
General Structure of the Neuron
1-1A
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Another General Structure of the Neuron
dendritic spines
dendrites
cell body (soma)
axon
dendritic
tree
1-1B
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dendritic
tree
pyramidal
cell body
recurrent
collateral
(axon)
presynaptic
axon terminal
axon
motor cortex
Realistic Pyramidal Cell
pyramidal
cell body
apical dendrite
basal dendrites
axon
presynaptic
axon terminal
Icon of Pyramidal Cell
1-2
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Synaptic Neurotransmission and
the Anatomically Addressed
Nervous System
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Pretest Question 1
Which of the following neurodevelopmental
processes are mostly complete by birth?
1. Neuronal selection
2. Synaptogenesis
3. Competitive elimination
4. 1 and 2
5. 1, 2, and 3
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
2-1
Time Course of Neurodevelopment
development
conception
4 wks
8 wks
12 wks
16 wks
20 wks
24 wks
28 wks
32 wks
4 mos
2 yrs
5 yrs
18 yrs
60+
time
birth
competitive elimination
synaptogenesis
differentiation and myelination
migration from ventricular zone
neuronal selection
neurogenesis
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
2-2
Overview of Neurodevelopment
stem
cell
immature
neurons
neurogenesis
eliminated
eliminated
selection migration differentiation
synaptogenesis
(presynaptic;
axonal
growth &
connections)
synaptogenesis
(postsynaptic;
dendritic
arborization)
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Pretest Question 2
Neurogenesis has recently been discovered to
occur in adults:
1. Only in the dentate gyrus of the hippocampus
2. In the dentate gyrus of the hippocampus and in the
olfactory bulb
3. In the dentate gyrus of the hippocampus, the olfactory
bulb, and the lateral nucleus of the amygdala
4. Throughout the brain
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
2-3
Adult Neurogenesis in the Dentate Region of
the Hippocampus
pyramidal neuron
in CA1 and CA3
dentate neuron
(granule cell neuron)
stem cell
dentate region
CA3
CA1
proliferation migration
differentiation
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cell loss/atrophy
2-4
Adult Neurogenesis in the Hippocampus: Effects of Stress, Depression, and Aging
pyramidal neuron
in CA1 and CA3
dentate neuron
(granule cell neuron)
stem cell
stress
depression
aging
dentate region
CA3
CA1
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2-4
Adult Neurogenesis in the Hippocampus: Effects of Learning, Exercise, Growth Factors, Antidepressants
pyramidal neuron
in CA1 and CA3
dentate neuron
(granule cell neuron)
stem cell learning
exercise
growth factors
antidepressants
dentate region
CA3
CA1
cell growth
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2-9
= defective neuron
= healthy neuron
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good neuronal selection
2-9
= defective neuron
= healthy neuron
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bad neuronal selection
2-9
= defective neuron
= healthy neuron
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2-12
good migration bad migration
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necrosis
neuronal assassination
apoptosis
neuronal suicide
2-10
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2-13
normal
growth
cone
attractive
growth factor
repulsive
growth factor
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2-13
normal
growth
cone
attractive
growth factor
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2-14
guidepost
glial cell
target neuron
attractive
growth factor
repulsive
growth factor
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undeveloped neuron
growth factor
(protein)
2-17
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2-18
undeveloped neuron
developmental
disease or
no stimulation
normal
development
adult degenerative
disease
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Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Pretest Question 3
Synapses form only at axodendritic
locations.
1. True
2. False
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2-20
dendritic
tree
axodendritic synapse
axosomatic synapse
axoaxonic (initial segment) synapse
axon
axoaxonic (terminal) synapse
postsynaptic dendrite
postsynaptic
density
dendrite
spine
dendritic spines
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
2-22
Overview of Formation of a Synapse
hemisynapse
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2-22
Overview of Formation of a Synapse
trial contact
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2-22
Overview of Formation of a Synapse
ordering
supplies
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2-22
Overview of Formation of a Synapse
erecting
synaptic
scaffolding
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2-22
Overview of Formation of a Synapse
erecting intra-
neuronal
scaffolding
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2-22
Overview of Formation of a Synapse
decorating
the
structure
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Strengthening the Synapse With Neuronal Activity:
The Neurons That Fire Together Wire Together
2-28
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Strengthening the Synapse With Neuronal Activity:
The Neurons That Fire Together Wire Together
2-28
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Strengthening the Synapse With Neuronal Activity:
The Neurons That Fire Together Wire Together
2-28
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Pretest Question 4
Excitotoxicity is hypothesized to be:
1. A natural process through which unneeded synapses
are eliminated
2. A process through which dendrites are inappropriately
destroyed
3. A process through which entire neurons are
inappropriately destroyed
4. 2 and 3
5. 1, 2, and 3
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2-32
dendrites in need
of "pruning"
normal "pruning"
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2-33
A disease may let the normal process of pruning get out of control. The disease can
cause the neuron to be "pruned to death."
"pruning" out of
control
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birth age 6 age 14–16
2-38
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Signal Transduction and the
Chemically Addressed Nervous
System
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Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Pretest Question 5
Communication between human CNS
neurons at synapses is:
1. Chemical
2. Electrical
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Classical Synaptic Neurotransmission: Fast Communication
reception
integration chemical encoding
electrical encoding
signal propagation
signal transduction
neurotransmitter
light
hormone
drug
nerve impulse
A
B
3-1
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Classical Synaptic Neurotransmission: Fast Communication
reception
integration chemical encoding
electrical encoding
signal propagation
signal transduction
neurotransmitter
light
hormone
drug
nerve impulse
neurotransmitter
A
B
3-1
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Pretest Question 6
Examples of neurotransmitters produced
specifically as retrograde neurotransmitters (i.e.,
those that communicate from postsynaptic neuron
to presynaptic neuron) include
1. Histamine
2. Galanin
3. Nitric oxide
4. 1 and 2
5. 1, 2, and 3
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
3-3
Classical Neurotransmission Versus Retrograde Neurotransmission
(Short Feedback Loop)
classical
A
A retrograde
CB1 receptor
cGMP targets
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3-3
Classical Neurotransmission Versus Retrograde Neurotransmission
(Short Feedback Loop)
classical
A
A retrograde
CB1 receptor
cGMP targets
EC
EC
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
3-3
Classical Neurotransmission Versus Retrograde Neurotransmission
(Short Feedback Loop)
classical
A
A retrograde
CB1 receptor
cGMP targets
EC
EC
NO (nitric oxide)
NGF (nerve growth factor)
NGF
NGF
NG
F
NG
F
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Pretest Question 7
All chemical neurotransmission requires a
synapse.
1. True
2. False
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3-4
Classical Neurotransmission Versus Retrograde Neurotransmission
(Short Feedback Loop)
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3-4
Classical Neurotransmission Versus Retrograde Neurotransmission
(Short Feedback Loop)
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3-5
Volume Neurotransmission
A B
DA neuron
D1
receptors
1
2
3
synaptic neurotransmission at 1 and diffusion to 2 and 3
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3-6 dendritic monoamine
synaptic vesicle
autoreceptor
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3-6 dendritic monoamine
synaptic vesicle
autoreceptor
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3-9
first messenger 1
first messenger 1
second messenger
second messenger
2
2
Ca++
third messenger kinase
third messenger
phosphatase
activation / inactivation
of fourth messengr phosphoprotein
diverse biological responses
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3-9
first messenger 1
first messenger 1
second messenger
second messenger
2
2
Ca++
third messenger kinase
third messenger
phosphatase
fourth
messenger
activation / inactivation
of fourth messenger phosphoprotein
diverse biological responses
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3-10
Time Course of Signal Transduction
response
time
1 hr 1 day 10 days
long-term effects of late gene products
activation of late genes
activation of early genes
activation of third and fourth messengers
enzymatic formation of second messengers
activation of ion channels
binding of first messenger
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Pretest Question 8
In a G protein-linked signal transduction cascade,
the second messenger can be synthesized:
1. In the postsynaptic neuron
2. In the synaptic cleft
3. 1 and 2
4. Neither 1 nor 2
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3-13
7
G
first messenger
receptor
G protein
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3-14
7
G
The first messenger causes the receptor to change.
G protein can now bind to the receptor.
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3-15
7
G
Once bound to the receptor, the G protein
changes shape so it can bind to an enzyme capable
of synthesizing a second messenger.
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3-16
7
G
Once this binding takes place, the second
messenger will be released.
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Activating a Third Messenger Kinase Through Cyclic AMP
first messenger – neurotransmitter
second messenger
3-17
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Activating a Third Messenger Kinase Through Cyclic AMP
first messenger – neurotransmitter
second messenger
inactive protein kinase
activation third messenger –
active
protein kinase
3-17
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3-19
Third Messenger Kinases Put Phosphates on Critical Proteins
third
messenger –
kinase
first
messenger
1
second
messenger
2
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regulatory
enzymes 4
3-19
Third Messenger Kinases Put Phosphates on Critical Proteins
third
messenger –
kinase
first
messenger
1
second
messenger
2
voltage-gated
ion channel 4
4
ligand-gated
ion channel 4
4
4
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
regulatory
enzymes
voltage-gated
ion channel
ligand-gated
ion channel 4
4
4
3-20
Third Messenger Phosphatases Undo What Kinases Create — Take Phosphates Off Critical Proteins
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
regulatory
enzymes
voltage-gated
ion channel
ligand-gated
ion channel 4
4
4
first messenger – neurotransmitter
1
second
messenger
Ca++
2
inactive
calcineurin
2
3 third messenger –
active calcineurin
(phosphatase)
3-20
Third Messenger Phosphatases Undo What Kinases Create — Take Phosphates Off Critical Proteins
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
regulatory
enzymes
voltage-gated
ion channel
ligand-gated
ion channel 4
4
4
first messenger – neurotransmitter
1
second
messenger
Ca++
2
inactive
calcineurin
2
3 third messenger –
active calcineurin
(phosphatase)
3-20
Third Messenger Phosphatases Undo What Kinases Create — Take Phosphates Off Critical Proteins
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Third Messenger Activating a Transcription
Factor for an Early Gene
inactive
transcription factor
TF
activated "early"
transcription factor
TF 4
3-25
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3-22
transcription factor –
(inactive)
RNA polymerase
(inactive)
cell nucleus
protein kinase
enhancer promoter coding
gene
Gene is off
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3-23
activated
transcription factor –
RNA polymerase
cell nucleus
enhancer promoter coding
gene
Transcription factor is activated; gene is turning on
TF 4
TF 4
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3-24
RNA polymerase
activated
cell nucleus
DNA Gene is activated
mRNA
protein
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VIDEO
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Pretest Question 9
Fos and Jun are examples of:
1. Proteins that act as enzymes to activate second
messengers
2. Proteins that act as G proteins to activate second
messengers
3. Proteins that act as transcription factors to activate
immediate-early genes
4. Proteins that act as transcription factors to activate late
genes
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3-26
nucleus
nucleus
cFOS
cJUN
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3-26
nucleus
nucleus
cFOS
cJUN
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3-26
nucleus
nucleus
cFOS
cJUN
FOS – fifth messenger
5
JUN – fifth messenger
5
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3-27,28
FOS – fifth messenger
JUN – fifth messenger
sixth messenger
6
ZIPPER
FOS JUN nucleus
nucleus
late gene
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3-27,28
FOS – fifth messenger
JUN – fifth messenger
sixth messenger
6
ZIPPER
FOS JUN nucleus
nucleus
late gene late gene
product
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3-29
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
3-29
mRNA
mRNA
mRNA
mRNA
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3-29
mRNA
mRNA
mRNA
mRNA
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Summary
• The anatomy and function of neurons determine their
role in chemical neurotransmission
• The anatomically addressed central nervous system
involves neurons, glia, and their components to form
the structural basis of synaptic neurotransmission
• The chemically addressed central nervous system
comprises neurotransmitters and their signal
transduction cascades that regulate neuronal function
via synaptic neurotransmission