Chemical Neurotransmission -...

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.

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

Learning Objectives

• Describe the structure and function of neurons

• Explain the anatomical basis of synaptic

neurotransmission

• Explain the chemical basis of synaptic

neurotransmission

Structure and Function

of Neurons

dendrites

dendritic spines cell body (soma)

axon en passant

presynaptic

axon terminals

presynaptic

axon terminals

General Structure of the Neuron

Another General Structure of the Neuron

dendritic spines

dendrites

cell body (soma)

dendritic

pyramidal

cell body

recurrent

collateral

(axon)

presynaptic

axon terminal

motor cortex

Realistic Pyramidal Cell

pyramidal

cell body

apical dendrite

basal dendrites

presynaptic

axon terminal

Icon of Pyramidal Cell

Synaptic Neurotransmission and

the Anatomically Addressed

Nervous System

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

Time Course of Neurodevelopment

development

conception

12 wks

16 wks

20 wks

24 wks

28 wks

32 wks

18 yrs

competitive elimination

synaptogenesis

differentiation and myelination

migration from ventricular zone

neuronal selection

neurogenesis

Overview of Neurodevelopment

immature

neurons

neurogenesis

eliminated

selection migration differentiation

synaptogenesis

(presynaptic;

axonal

growth &

connections)

synaptogenesis

(postsynaptic;

dendritic

arborization)

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

Adult Neurogenesis in the Dentate Region of

the Hippocampus

pyramidal neuron

in CA1 and CA3

dentate neuron

(granule cell neuron)

stem cell

dentate region

proliferation migration

differentiation

cell loss/atrophy

Adult Neurogenesis in the Hippocampus: Effects of Stress, Depression, and Aging

pyramidal neuron

in CA1 and CA3

dentate neuron

stem cell

stress

depression

dentate region

Adult Neurogenesis in the Hippocampus: Effects of Learning, Exercise, Growth Factors, Antidepressants

pyramidal neuron

in CA1 and CA3

dentate neuron

stem cell learning

exercise

growth factors

antidepressants

dentate region

cell growth

= defective neuron

= healthy neuron

good neuronal selection

= defective neuron

= healthy neuron

bad neuronal selection

= defective neuron

= healthy neuron

good migration bad migration

necrosis

neuronal assassination

apoptosis

neuronal suicide

normal

growth

attractive

growth factor

repulsive

growth factor

normal

growth

attractive

growth factor

guidepost

glial cell

target neuron

attractive

growth factor

repulsive

growth factor

undeveloped neuron

growth factor

(protein)

undeveloped neuron

developmental

disease or

no stimulation

normal

development

adult degenerative

disease

Pretest Question 3

Synapses form only at axodendritic

locations.

1. True

2. False

dendritic

axodendritic synapse

axosomatic synapse

axoaxonic (initial segment) synapse

axoaxonic (terminal) synapse

postsynaptic dendrite

postsynaptic

density

dendrite

dendritic spines

Overview of Formation of a Synapse

hemisynapse

trial contact

ordering

supplies

erecting

synaptic

scaffolding

erecting intra-

neuronal

scaffolding

decorating

structure

Strengthening the Synapse With Neuronal Activity:

The Neurons That Fire Together Wire Together

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

dendrites in need

of "pruning"

normal "pruning"

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

birth age 6 age 14–16

Signal Transduction and the

Chemically Addressed Nervous

System

Pretest Question 5

Communication between human CNS

neurons at synapses is:

1. Chemical

2. Electrical

Classical Synaptic Neurotransmission: Fast Communication

reception

integration chemical encoding

electrical encoding

signal propagation

signal transduction

neurotransmitter

hormone

nerve impulse

Classical Synaptic Neurotransmission: Fast Communication

reception

integration chemical encoding

electrical encoding

signal propagation

signal transduction

neurotransmitter

hormone

nerve impulse

neurotransmitter

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

Classical Neurotransmission Versus Retrograde Neurotransmission

(Short Feedback Loop)

classical

A retrograde

CB1 receptor

cGMP targets

classical

A retrograde

CB1 receptor

cGMP targets

classical

A retrograde

CB1 receptor

cGMP targets

NO (nitric oxide)

NGF (nerve growth factor)

Pretest Question 7

All chemical neurotransmission requires a

synapse.

1. True

2. False

Volume Neurotransmission

DA neuron

receptors

synaptic neurotransmission at 1 and diffusion to 2 and 3

3-6 dendritic monoamine

synaptic vesicle

autoreceptor

3-6 dendritic monoamine

synaptic vesicle

autoreceptor

first messenger 1

second messenger

third messenger kinase

third messenger

phosphatase

activation / inactivation

of fourth messengr phosphoprotein

diverse biological responses

first messenger 1

second messenger

third messenger kinase

third messenger

phosphatase

fourth

messenger

activation / inactivation

of fourth messenger phosphoprotein

diverse biological responses

Time Course of Signal Transduction

response

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

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

first messenger

receptor

G protein

The first messenger causes the receptor to change.

G protein can now bind to the receptor.

Once bound to the receptor, the G protein

changes shape so it can bind to an enzyme capable

of synthesizing a second messenger.

Once this binding takes place, the second

messenger will be released.

Activating a Third Messenger Kinase Through Cyclic AMP

first messenger – neurotransmitter

second messenger

Activating a Third Messenger Kinase Through Cyclic AMP

second messenger

inactive protein kinase

activation third messenger –

active

protein kinase

Third Messenger Kinases Put Phosphates on Critical Proteins

messenger –

kinase

messenger

second

messenger

regulatory

enzymes 4

Third Messenger Kinases Put Phosphates on Critical Proteins

messenger –

kinase

messenger

second

messenger

voltage-gated

ion channel 4

ligand-gated

ion channel 4

regulatory

enzymes

voltage-gated

ion channel

ligand-gated

ion channel 4

Third Messenger Phosphatases Undo What Kinases Create — Take Phosphates Off Critical Proteins

regulatory

enzymes

voltage-gated

ion channel

ligand-gated

ion channel 4

second

messenger

inactive

calcineurin

3 third messenger –

active calcineurin

(phosphatase)

regulatory

enzymes

voltage-gated

ion channel

ligand-gated

ion channel 4

second

messenger

inactive

calcineurin

3 third messenger –

active calcineurin

(phosphatase)

Third Messenger Activating a Transcription

Factor for an Early Gene

inactive

transcription factor

activated "early"

transcription factor

transcription factor –

(inactive)

RNA polymerase

(inactive)

cell nucleus

protein kinase

enhancer promoter coding

Gene is off

activated

transcription factor –

RNA polymerase

cell nucleus

enhancer promoter coding

Transcription factor is activated; gene is turning on

RNA polymerase

activated

cell nucleus

DNA Gene is activated

protein

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

nucleus

FOS – fifth messenger

JUN – fifth messenger

3-27,28

sixth messenger

ZIPPER

FOS JUN nucleus

nucleus

late gene

3-27,28

sixth messenger

ZIPPER

FOS JUN nucleus

nucleus

late gene late gene

product

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

Chemical Neurotransmission -...

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