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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.

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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.

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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

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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

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Structure and Function

of Neurons

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dendrites

dendritic spines cell body (soma)

axon en passant

presynaptic

axon terminals

presynaptic

axon terminals

General Structure of the Neuron

1-1A

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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

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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

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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

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2-2

Overview of Neurodevelopment

stem

cell

immature

neurons

neurogenesis

eliminated

eliminated

selection migration differentiation

synaptogenesis

(presynaptic;

axonal

growth &

connections)

synaptogenesis

(postsynaptic;

dendritic

arborization)

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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

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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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Copyright © 2011 Neuroscience Education Institute. All rights reserved. 2-11

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Copyright © 2011 Neuroscience Education Institute. All rights reserved. 2-11

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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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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

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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

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Strengthening the Synapse With Neuronal Activity:

The Neurons That Fire Together Wire Together

2-28

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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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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

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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

neurotransmitter

A

B

3-1

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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