Springer from messengers to molecules memories are made of these (neuroscience intelligence unit)

NEUROSCIENCE INTELLIGENCE UNIT

Gernot Riedel and Bettina Platt
RIEDEL • PLATT
NIU

From Messengers to Molecules:
Memories Are Made of These

From Messengers to Molecules:
Memories Are Made of These


NEUROSCIENCE
INTELLIGENCE
UNIT

From Messengers to Molecules:
Memories Are Made of These
Gernot Riedel, Ph.D.
Bettina Platt, Ph.D.
School of Medical Sciences
College of Life Sciences and Medicine
University of Aberdeen
Foresterhill, Aberdeen, U.K.

LANDES BIOSCIENCE / EUREKAH.COM
GEORGETOWN, TEXAS
U.S.A.

KLUWER ACADEMIC / PLENUM PUBLISHERS
NEW YORK, NEW YORK
U.S.A.


FROM MESSENGERS TO MOLECULES:
MEMORIES ARE MADE OF THESE
Neuroscience Intelligence Unit
Landes Bioscience / Eurekah.com
Kluwer Academic / Plenum Publishers
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From Messengers to Molecules: Memories Are Made of These, edited by Gernot Riedel and Bettina Platt,
Landes / Kluwer dual imprint / Landes series: Neuroscience Intelligence Unit
ISBN: 0-306-47862-5
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Library of Congress Cataloging-in-Publication Data
From messengers to molecules : memories are made of these /
[edited by] Gernot Riedel, Bettina Platt.
p. ; cm. -- (Neuroscience intelligence unit)
Includes bibliographical references and index.
ISBN 0-306-47862-5
1. Neurochemistry. 2. Neurotransmitters. 3. Neurotransmitter
receptors. I. Riedel, Gernot. II. Platt, Bettina. III. Series:
Neuroscience intelligence unit (Unnumbered)
[DNLM: 1. Memory--physiology. 2. Ion Channels. 3. Learning
--physiology. 4. Memory Disorders. 5. Neurotransmitters.
6. Transcription Factors. WL 102 F9308 2004]
QP356.3.F76 2004
612.8'042--dc22
2004001884


Dedication
To our children Daniel and Lisa Sophie,
for wonderful memories.


CONTENTS
Preface .................................................................................................. ix
Abbreviations ...................................................................................... xxi

Section 1. Ions and Ion Channels
1.1. Calcium .................................................................................................. 1
Miao-Kun Sun and Daniel L. Alkon
Ca2+ Influx ............................................................................................. 2
Neurotransmitter Release ...................................................................... 7
Modulation of Channel Activity ............................................................ 8
Signal Transduction Cascades ............................................................... 9
Alzheimer’s Disease ............................................................................. 14
1.2. Potassium ............................................................................................. 20
Jeffrey Vernon and Karl Peter Giese
How Can K+ Channels Contribute to Learning and Memory? ............ 22

Section 2. Principle Neurotransmitters
2.1. Glutamate Receptors ............................................................................ 39
Gernot Riedel, Jacques Micheau and Bettina Platt
Glutamate Receptor Function in Learning and Memory
Formation ....................................................................................... 43
2.2. γ-Amino-Butyric Acid (GABA) ............................................................. 72
Claudio Castellano, Vincenzo Cestari and Alessandro Ciamei
GABAergic Drugs and Memory Formation: Peripheral
Administrations ............................................................................... 73
GABAergic Drugs and Memory: Genotype-Dependent Effects ........... 75
GABAergic Drugs and the State-Dependency Hypothesis ................... 76
GABAergic Drugs and Memory Formation: Administrations
into Brain Structures ....................................................................... 77
Interaction with Other Systems ........................................................... 82
2.3. Acetylcholine: I. Muscarinic Receptors ................................................. 90
Giancarlo Pepeu and Maria Grazia Giovannini
Muscarinic Receptors .......................................................................... 93
Which Cognitive Processes Depend on the Activation

of Muscarinic Receptors? ................................................................. 98
Effects of Direct and Indirect Selective Muscarinic Receptor
Agonists on Learning and Memory: Therapeutic Implications ....... 103
2.4. Acetylcholine: II. Nicotinic Receptors ................................................ 113
Joyce Besheer and Rick A. Bevins
Neuronal nAChRs ............................................................................. 113
Memory ............................................................................................ 115
Attention ........................................................................................... 117
Rewarding/Incentive Effects .............................................................. 118
Other Effects ..................................................................................... 120


2.5. Serotonin ........................................................................................... 125
Marie-Christine Buhot, Mathieu Wolff and Louis Segu
Role of 5-HT in Memory: Global Strategies ...................................... 126
Serotonergic-Cholinergic Interactions ............................................... 128
5-HT Receptors in Memory Systems ................................................. 128
2.6. Dopamine .......................................................................................... 143
Jan P.C. de Bruin
Functional Studies Using a Systemic Approach ................................. 145
Functional Studies Using a Central Approach ................................... 148
2.7. Adrenaline and Noradrenaline ............................................................ 155
Marie E. Gibbs and Roger J. Summers
Pharmacology of α- and β-Adrenoceptors in the Central
Nervous System ............................................................................. 155
Factors Affecting Drug Action at Adrenoceptors ............................... 159
Memory Studies with Adrenoceptor Agonists and Antagonists
in Rats ........................................................................................... 160
Memory Studies with Adrenoceptor Agonists and Antagonists
in Chicks ....................................................................................... 163

Roles for Adrenoceptor Subtypes in the LPO .................................... 169
2.8. Histamine .......................................................................................... 174
Rüdiger U. Hasenöhrl and Joseph P. Huston
The Histaminergic Neuron System ................................................... 174
The Role of the Tuberomammillary Nucleus Projection System
in Neural Plasticity and Functional Recovery ................................ 176
The Role of the Histaminergic Neuronal System in the Control
of Reinforcement ........................................................................... 178
The Role of the Histaminergic Neuronal System in the Control
of Learning and Mnemonic Processes ............................................ 181
Tuberomammillary Modulation of Hippocampal Signal Transfer ..... 187
2.9. Adenosine and Purines ....................................................................... 196
Trevor W. Stone, M-R. Nikbakht and E. Martin O’Kane
Origin of Adenosine in the Extracellular Fluid .................................. 196
Adenosine Receptors ......................................................................... 196
Adenosine and Learning .................................................................... 197
Adenosine and Synaptic Plasticity ...................................................... 199
Interactions between Adenosine and Cholinergic
Neurotransmission ........................................................................ 201
Interactions between Purines and Glutamate Receptors ..................... 203
Other Receptor Interactions .............................................................. 205
The Effects of Ageing on Adenosine Receptors .................................. 210
Trophic Functions of Nucleosides ..................................................... 210
Nucleotides and Synaptic Plasticity ................................................... 211


Section 3. Neuromodulators
3.1. Cannabinoids ..................................................................................... 224
Lianne Robinson, Bettina Platt and Gernot Riedel
Cannabinoid Receptors ..................................................................... 224

Cannabinoid Receptor Ligands ......................................................... 225
Cannabinoid Receptors Modulate Memory Formation ..................... 226
3.2. Opioids .............................................................................................. 246
Makoto Ukai, Ken Kanematsu, Tsutomu Kameyama
and Takayoshi Mamiya
Distribution of Opioid Peptides and Their Receptors
in the Hippocampus ...................................................................... 246
Effects of Opioid Receptor Ligands on Long-Term Potentiation
in Hippocampal Regions ............................................................... 249
Effects of Opioid Receptor Ligands on Learning and Memory
in Hippocampal Regions ............................................................... 251
Effects of Opioid Receptor Ligands on Learning
and Memory Tasks ........................................................................ 251
Ameliorating Effects of Opioid Receptor Ligands on Models
of Learning and Memory Impairment ........................................... 251
3.3. Neuropeptides .................................................................................... 256
David De Wied and Gábor L. Kovács
Posterior Pituitary Peptides (Vasopressin, Oxytocin) ......................... 256
ACTH/MSH and Opioid Peptides ................................................... 261
Hypophyseotropic Peptides (CRF, Somatostatin) .............................. 263
Brain-Gut Peptides (CCK, Neuropeptide Y, Galanin) ....................... 266
Substance P ....................................................................................... 270
Natriuretic Peptides, Angiotensin ...................................................... 272
Amyloid Peptides .............................................................................. 277
3.4. Nerve Growth Factors and Neurotrophins ......................................... 286
Catherine Brandner
Neurotrophin Expression and Regulation of Neurogenesis
during Development ..................................................................... 287
Neurotrophin Receptors .................................................................... 287
Nerve Growth Factor and the Basal Forebrain Cholinergic System ... 287

Behavioral Studies of NGF Administrations ...................................... 289
Discussion ......................................................................................... 295
3.5. Eph Receptors and Their Ephrin Ligands in Neural Plasticity ........... 300
Robert Gerlai
The Promiscuous Family of Eph Receptors ....................................... 300
Function of Eph Receptors in the Normal Brain: Role
in Plasticity and Memory .............................................................. 302
Mechanisms Mediating Eph Action: The First Working
Hypotheses .................................................................................... 306


3.6. Corticosteroids ................................................................................... 314
Carmen Sandi
Glucocorticoid Hormones and Receptors .......................................... 314
Role of Glucocorticoids on Memory Consolidation .......................... 317
Neural Mechanisms Involved in Glucocorticoid Actions
on Memory Consolidation ............................................................ 321
Effects of Chronic Exposure to Elevated Glucocorticoid
Levels on Cognitive and Neural Function ..................................... 324

Section 4. Second Messengers and Enzymes
4.1. Adenylyl Cyclases ............................................................................... 330
Nicole Mons and Jean-Louis Guillou
Adenylyl Cyclases and Memory Formation in Invertebrates .............. 331
The Drosophila System ..................................................................... 332
A Specific Role for Mammalian Adenylyl Cyclases in Learning
and Memory Processes: Heterogeneity of Mammalian
Adenylyl Cyclases .......................................................................... 333
4.2. Phospholipases and Oxidases ............................................................. 349
Christian Hölscher

Phospholipases .................................................................................. 350
Arachidonic Acid (ArA), a Second Messenger .................................... 351
Release of ArA ................................................................................... 352
Time Course of Release ..................................................................... 352
Targets of ArA ................................................................................... 352
ArA and Metabolites of ArA As Transmitters and ‘Retrograde
Messengers’ in Synaptic Plasticity .................................................. 353
Oxygenases That Are of Importance in Memory Formation .............. 357
Cyclooxygenases ................................................................................ 358
The Timing of Memory Formation ................................................... 362
Defined Steps in Memory Formation ................................................ 362
A Potential Role for Defined Time Windows of Messenger
Systems in Memory Formation ..................................................... 363
4.3. Protein Kinase A ................................................................................ 369
Monica R.M. Vianna and Ivan Izquierdo
Short- and Long-Term Memory ........................................................ 370
One-Trial Avoidance ......................................................................... 372
The cAMP/PKA Signaling Pathway .................................................. 372
PKA Involvement in Long-Term Memory Formation ....................... 373
PKA Involvement in Short-Term Memory Formation ...................... 375
PKA Involvement in Memory Retrieval ............................................. 378
PKA Involvement in Extinction ........................................................ 379


4.4. Protein Kinase C ................................................................................ 383
Xavier Noguès, Alessia Pascale, Jacques Micheau and Fiorenzo Battaini
Protein Kinase C: Who Is It? ............................................................. 384
PKC in Synaptic Plasticity ................................................................. 386
Evidence for the Involvement of PKC in Cognitive Processes ............ 389
PKC and Neuronal Pathologies Impairing Cognition ........................ 395

Pharmacological Modulation of PKC: The Goal of Isoenzyme
Selectivity ...................................................................................... 400
4.5. CaMKinase II..................................................................................... 411
Martín Cammarota and Jorge H. Medina
CaMKII: Synaptic Plasticity and Memory Processing ........................ 412
Downstream Effectors of the CaMKII Cascade ................................. 416
CaMKIV: A New (and Important) Player in the Plasticity Team ...... 418
4.6. MAP Kinases ...................................................................................... 425
Joel C. Selcher, Edwin J. Weeber and J. David Sweatt
Hippocampal Involvement in Learning ............................................. 429
ERK in Hippocampal Synaptic Plasticity .......................................... 433
A Necessity for ERK Activation for Mammalian Learning ................. 435
Specific Contributions of ERK Isoforms to LTP and Learning .......... 440
Biochemical Attributes That Make ERK Suited for Memory
Formation ..................................................................................... 442
4.7. Phosphatases ...................................................................................... 448
Pauleen C. Bennett and Kim T. Ng
Phosphorylation in Information Storage Processes ............................. 458
Phosphatase Involvement in Invertebrate Memory Models ................ 462
Protein Phosphatases in Aplysia Learning and Memory ..................... 463
Phosphorylation in Vertebrate Memory Models ................................ 464
4.8. Nitric Oxide ....................................................................................... 480
Kiyofumi Yamada and Toshitaka Nabeshima
Regulation of NO Synthesis in the Brain ........................................... 480
Role of NO in LTP and LTD ........................................................... 481
Role of NO in Memory Processes ...................................................... 483
Learning and Memory-Associated Changes in NO Production
in the Brain ................................................................................... 487

Section 5. Transcription Factors, Genes and Proteins
5.1. CREB ................................................................................................. 492
Paul W. Frankland and Sheena A. Josselyn
Structure ........................................................................................... 493
Activation .......................................................................................... 493
CREB and Electrophysiological Studies of Long-Term
Plasticity in Aplysia ........................................................................ 495
CREB and Memory in Drosophila ..................................................... 496
CREB and LTM in Mammals ........................................................... 496
Gaining Temporal and Spatial Control of CREB Function
in Mammals .................................................................................. 497
5.2. Immediate-Early Genes ...................................................................... 506
Jeffrey Greenwood, Pauline Curtis, Barbara Logan, Wickliffe Abraham
and Mike Dragunow
Learning Activates IEGs .................................................................... 507
A Link between Cholinergic System and IEGs .................................. 507
IEGs and Their Relation to Stress ..................................................... 508
5.3. Protein Synthesis: I. Pharmacology .................................................... 514
Oliver Stork and Hans Welzl
Asking about the ‘Where’ and ‘When’ of Learning-Related
Protein Synthesis ........................................................................... 514
Inhibitors of Protein Synthesis ........................................................... 516
Effects of Protein Synthesis Inhibitors on Memory Formation .......... 519
Principle Findings and Future Perspectives in Protein Synthesis
Inhibitor Research ......................................................................... 522
5.4. Protein Synthesis: II. New Proteins ................................................... 529
Radmila Mileusnic
Present Time ..................................................................................... 533

Section 6. Morphological Changes in Synapses and Neurones

6.1. Learning-Induced Synaptogenesis and Structural Synaptic
Remodeling ........................................................................................ 543
Yuri Geinisman, Robert W. Berry and Olga T. Ganeshina
Patterns of Synaptogenesis Elicited by Behavioral Learning ............... 543
Specific Synaptogenesis Related to Learning-Induced
Adult Neurogenesis ....................................................................... 547
Pattern of Structural Synaptic Remodeling Elicited
by Behavioral Learning .................................................................. 553
Enlargement of Postsynaptic Densities following Learning:
A Possible Morphological Correlate of the Conversion of
Postsynaptically Silent Synapses into Functional Synapses ............. 556


6.2. Cell Adhesion Molecules .................................................................... 564
Ciaran M. Regan
Is Net Synapse Formation a Correlate of Learning? ........................... 565
Do Cell Adhesion Molecules Have a Role in Learning? ..................... 566
Do Cell Adhesion Molecules Have a Temporal Role in Learning? ..... 567
Can Cell Adhesion Molecules Reveal Memory Pathway? ................... 569
What about Neurogenesis in Learning? ............................................. 572

Section 7. Learning about Memory by Studying Brain Dysfunction
7.1. Animal and Human Amnesia: The Cholinergic Hypothesis
Revisited ............................................................................................ 580
Robert Jaffard and Aline Marighetto
Identifying Memory Dysfunction ...................................................... 580
Acetylcholine and Memory: From a Key Neurotransmitter
to the Functional Dynamics of Interactive Processes ...................... 580
Cholinergic Alterations Induced by Learning and Memory
Testing .......................................................................................... 581

From Assessment to Alleviation of Age-Related Memory
Impairments in Mice ..................................................................... 583
7.2. Aging and the Calcium Homeostasis .................................................. 591
Wendy W. Wu and John F. Disterhoft
Altered Ca2+ Homeostasis in Aging .................................................... 592
Altered Ca2+ Homeostasis and Age-Related Learning Deficits ............ 594
Alterations in Ca2+-Mediated Plasticity in Aging: Implications
for Learning ................................................................................... 594
Paradigms Used to Study Age-Related Learning Deficits ................... 594
Learning-Related Changes in Hippocampal CA1 Pyramidal
Neurons—Postsynaptic Excitability Increases in Learning ............. 595
Mechanisms Underlying Aging-Related Enhancement
in the sIAHP .................................................................................... 598
sIAHP As a Link Between Age-Related Changes in Ca2+
Homeostasis and Learning ............................................................. 600
Index .................................................................................................. 607


EDITORS
Gernot Riedel, Ph.D.
Bettina Platt, Ph.D.
School of Medical Sciences
College of Life Sciences and Medicine
University of Aberdeen
Foresterhill, Aberdeen, U.K.
Chapters 2.1, 3.1

CONTRIBUTORS
Wickliffe Abraham
Department of Pharmacology

University of Auckland
Auckland, and
Department of Psychology
University of Otago
Dunedin, New Zealand
Chapter 5.2

Daniel L. Alkon
Blânchette Rockefeller Neurosciences
Institute
Rockville, Maryland, U.S.A
Chapter 1.1

Fiorenzo Battaini
Department of Neurosciences
University of Roma
Roma, Italy
Chapter 4.4

Pauleen Bennett
Department of Psychology
Monash University
Clayton, Victoria, Australia

Joyce Besheer
Department of Psychology
University of Nebraska - Lincoln
Lincoln, Nebraska, U.S.A.
Chapter 2.4

Rick A. Bevins
Department of Psychology
University of Nebraska - Lincoln
Lincoln, Nebraska, U.S.A.
Chapter 2.4

Catherine Brandner
Institut de Physiologie
Université de Lausanne
Lausanne, Switzerland
Chapter 3.4

Marie-Christine Buhot
Laboratory of Cognitive Neurosciences
Centre National de la Recherche
Scientifique UMR 5106
University of Bordeaux I
Talence Cedex, France
Chapter 2.5

Chapter 4.7

Robert W. Berry
Department of Cell and Molecular
Biology
Northwestern University Medical School
Chicago, Illinois, U.S.A.
Chapter 6.1

Martín Cammarota

Centro de Memória
Departamento de Bioquímica
Instituto de Ciências Básicas da Saúde
Universidade Federal do Rio Grande
do Sul
Porto Alegre, Brasil
Chapter 4.5


Claudio Castellano
Section of Psychopharmacology
Institute of Neuroscience
Rome, Italy
Chapter 2.2

Vincenzo Cestari
Section of Psychopharmacology
Institute of Neuroscience
Rome, Italy
Chapter 2.2

Alessandro Ciamei
Section of Psychopharmacology
Institute of Neuroscience
Rome, Italy
Chapter 2.2

Pauline Curtis
Department of Pharmacology
University of Auckland

Auckland, and
Department of Psychology
University of Otago
Dunedin, New Zealand
Chapter 5.2

Jan P.C. de Bruin
Graduate School Neurosciences
Amsterdam
Netherlands Institute for Brain Research
Amsterdam, The Netherlands
Chapter 2.6

David De Wied
Department of Medical Pharmacology
and Anatomy
Rudolf Magnus Institute
for Neurosciences
University Medical Center
Utrecht, The Netherlands

Mike Dragunow
Department of Pharmacology
University of Auckland
Auckland, and
Department of Psychology
University of Otago
Dunedin, New Zealand
Chapter 5.2

Paul W. Frankland
Programmes in Integrative Biology
and Brain and Behaviour
Hospital for Sick Children
Toronto, Ontario, Canada
Chapter 5.1

Olga T. Ganeshina
Department of Cell and Molecular
Biology
Northwestern University Medical School
Chicago, Illinois, U.S.A.
Chapter 6.1

Yuri Geinisman
Department of Cell and Molecular
Biology
Northwestern University Medical School
Chicago, Illinois, U.S.A.
Chapter 6.1

Robert Gerlai
Department of Psychology
University of Hawaii at Manoa
Honolulu, Hawaii, U.S.A.
Chapter 3.5

Marie Gibbs
Department of Pharmacology
Monash University

Clayton, Victoria, Australia
Chapter 2.7

Chapter 3.3

John F. Disterhoft
Department of Cell and Molecular
Biology
Northwestern University Medical School
Chicago, Illinois, U.S.A.
Chapter 7.2

Karl Peter Giese
Wolfson Institute for Biomedical
Research
University College London
London, U.K.
Chapter 1.2


Maria Grazia Giovannini
Department of Pharmacology
University of Florence
Florence, Italy
Chapter 2.3

Jeffrey Greenwood
Department of Pharmacology
University of Auckland
Auckland, and

Department of Psychology
University of Otago
Dunedin, New Zealand
Chapter 5.2

Ivan Izquierdo
Departamento de Bioquimica
Instituto de Ciências Básicas da Saúde
Universidade Federal do Rio Grande
do Sul
Porto Allegre, Brazil
Chapter 4.3

Robert Jaffard
Laboratory of Cognitive Neurosciences
Centre National de la Recherche
Scientifique UMR 5106
University of Bordeaux I
Talence Cedex, France
Chapter 7.1

Jean-Louis Guillou
Laboratory of Cognitive Neurosciences
Centre National de la Recherche
Scientifique UMR 5106
University of Bordeaux I
Talence Cedex, France

Sheena A. Josselyn
Programmes in Integrative Biology

and Brain and Behaviour
Hospital for Sick Children
Toronto, Ontario, Canada

Chapter 4.1

Chapter 5.1

Rüdiger U. Hasenöhrl
Department of Psychology
University of Hertfordshire
Hatfield Herts, U.K.

Tsutomu Kameyama
Department of Chemical Pharmacology
Meijo University, and
Japan Institute of Psychopharmacology
Nagoya, Japan

Chapter 2.8

Chapter 3.2

Christian Hölscher
Department of Cognitive Neuroscience
University of Tuebingen
Tuebingen, Germany

Ken Kanematsu
Research Institute of Meijo University

Nagoya, Japan

Chapter 4.2

Chapter 3.2

Joseph P. Huston
Institute of Physiological Psychology
and Center for Biological
and Medical Research
University of Düsseldorf
Düsseldorf, Germany

Gábor L. Kovács
Institute of Diagnostics and Management
University of Pécs
Szombathely, Hungary

Chapter 2.8

Barbara Logan
Department of Pharmacology
University of Auckland
Auckland, and
Department of Psychology
University of Otago
Dunedin, New Zealand

Chapter 3.3

Chapter 5.2


Takayoshi Mamiya
Department of Chemical Pharmacology
Meijo University
Nagoya, Japan
Chapter 3.2

Toshitaka Nabeshima
Department of Neuropsychopharmacology and Hospital Pharmacy
Nagoya University Graduate School
of Medicine
Nagoya, Japan

Aline Marighetto
Laboratory of Cognitive Neurosciences
Centre National de la Recherche
Scientifique UMR 5106
University of Bordeaux I
Talence Cedex, France

Chapter 4.8

Chapter 7.1

Chapter 4.7

Jorge H. Medina
Instituto de Biología Celular y

Neurociencias
Universidad de Buenos Aires
Buenos Aires, Argentina

M-R. Nikbakht
Institute of Biomedical and Life Sciences
University of Glasgow
Glasgow, U.K.

Kim T. Ng
Department of Psychology
Monash University
Clayton, Victoria, Australia

Chapter 2.9

Chapter 4.5

Jacques Micheau
Laboratory of Cognitive Neurosciences
Centre National de la Recherche
Scientifique UMR 5106
University of Bordeaux I
Talence Cedex, France

Xavier Noguès
Laboratory of Cognitive Neurosciences
Centre National de la Recherche
Scientifique UMR 5106
University of Bordeaux I

Talence Cedex, France
Chapter 4.4

Chapters 2.1, 4.4

Radmila Mileusnic
Department of Biological Sciences
The Open University
Milton Keynes, U.K.

E. Martin O’Kane
Institute of Biomedical and Life Sciences
University of Glasgow
Glasgow, U.K.
Chapter 2.9

Chapter 5.4

Nicole Mons
Laboratory of Cognitive Neurosciences
Centre National de la Recherche
Scientifique UMR 5106
University of Bordeaux I
Talence Cedex, France
Chapter 4.1

Alessia Pascale
Department of Experimental
and Applied Pharmacology
University of Pavia

Pavia, Italy
Chapter 4.4

Giancarlo Pepeu
Department of Pharmacology
University of Florence
Florence, Italy
Chapter 2.3


Ciaran M. Regan
Department of Pharmacology
University College Dublin
Dublin, Ireland

Roger Summers
Department of Pharmacology
Monash University
Clayton, Victoria, Australia

Chapter 6.2

Chapter 2.7

Lianne Robinson
School of Medical Sciences
College of Life Sciences and Medicine
University of Aberdeen
Foresterhill, Aberdeen, U.K.

Miao-Kun Sun
Blânchette Rockefeller Neurosciences
Institute
Rockville, Maryland, U.S.A
Chapter 1.1

Chapter 3.1

Carmen Sandi
Brain and Mind Institute
Ecole Polytechnique Federale
de Lausanne
Lausanne, Switzerland
Chapter 3.6

Louis Segu
Laboratory of Cognitive Neurosciences
Centre National de la Recherche
Scientifique UMR 5106
University of Bordeaux I
Talence Cedex, France
Chapter 2.5

Joel C. Selcher
Division of Neuroscience
Baylor College of Medicine
Houston, Texas, U.S.A.
Chapter 4.6

Trevor W. Stone

Institute of Biomedical and Life Sciences
University of Glasgow
Glasgow, U.K.

J. David Sweatt
Division of Neuroscience
Baylor College of Medicine
Houston, Texas, U.S.A.
Chapter 4.6

Makoto Ukai
Department of Chemical Pharmacology
Meijo University
Nagoya, Japan
Chapter 3.2

Jeffrey Vernon
Wolfson Institute for Biomedical
Research
University College London
London, U.K.
Chapter 1.2

Monica R.M. Vianna
Departamento de Bioquimica
Instituto de Ciências Básicas da Saúde
Universidade Federal do Rio Grande
do Sul
Porto Allegre, Brazil
Chapter 4.3

Chapter 2.9

Oliver Stork
Institute of Physiology
University of Magdeburg
Magdeburg, Germany
Chapter 5.3

Edwin J. Weeber
Division of Neuroscience
Baylor College of Medicine
Houston, Texas, U.S.A.
Chapter 4.6


Hans Welzl
Neuroanatomy and Behavior Group
Institute of Anatomy
University of Zurich
Zurich, Switzerland

Wendy W. Wu
Department of Cell and Molecular
Biology
Northwestern University Medical School
Chicago, Illinois, U.S.A.

Chapter 5.3

Chapter 7.2

Mathieu Wolff
Laboratory of Cognitive Neurosciences
Centre National de la Recherche
Scientifique UMR 5106
University of Bordeaux I
Talence Cedex, France

Kiyofumi Yamada
Laboratory of Neuropsychopharmacology
Department of Clinical Pharmacy
Kanazawa University
Kanazawa, Japan

Chapter 2.5

Chapter 4.8


PREFACE

M

emory formation is one of the most important achievements of
life, and a main determinant of evolutionary success. For us
humans, our present experiences are determined by their relation
to our personal past. Recall of memories, new evaluation of their meaning in
light of recent achievements, events or problems is therefore a fundamental
element of our conscious activities. On a more trivial level, remembering an

important phone number or the way to the next shop is essential for our
ability to manage day to day life. Failure of the neural mechanisms supporting these functions, as observed in varying levels of severity in different types
of dementia, has devastating consequences and leads, in many cases, to a loss
of a patient’s personality.
This illustrates the importance of memory for the human species, and
it also justifies why understanding the mechanisms of memory formation
and memory malfunction is in great demand.
While the present book concentrates mostly on pharmacological aspects of memory, we had to neglect the taxonomy of memory, i.e., what
forms of memories can be distinguished in humans and what are their counterparts in animals? In the traditional laboratory experiment, the behavioural
task is shaped to address specifically one form of memory, for example spatial memory or fear memories in order to avoid confounding influences of
other forms of memory, say procedural memory. In a more natural setting,
however, forms of memory are mixed and interact, and the recent emergence of neuroecology to understand the brain in relation to native behavior
is a clear reflection of this awareness and will be of great benefit in future
work. Meanwhile however, we follow the traditional categorization that specific brain regions or neuronal circuits subserve specific forms of memory.
So what are the cellular events underlying memory formation? To put
it in simple terms, a learning event will lead to neuronal excitation, activation of ion channels and transmitter receptors in a specific subset of neurones.
This will trigger intracellular cascades leading eventually to the activation of
transcription factors and genes. The product is the formation of new proteins, which can be used to remodel synapses in their morphology and thus
making them more efficient.
While this clearly is an over-simplification, this book follows the general route outlined above and looks at the many different components that
are known to contribute to the chain of events, and reveals a number of
interactions at different levels.
The book has seven themes. Section one deals with ions and ion channels and concentrates on both calcium and potassium. Section two is dedicated to the principle neurotransmitters and their receptors including excitatory and inhibitory systems. Neuromodulators and their receptor function are summarised in section three. They do not directly activate ion channels and thus impinge on intracellular protein cascades and enzymes via


second messengers. These are then covered in section four which looks at
various kinases and phosphatases that are crucial for long-term memory formation and can be linked to the activation of transcription factors and genes,
as described in section five. Such gene activation should generate novel proteins and these may be incorporated during the formation of new connections between nerve cells, i.e., the process of synaptogenesis, outlined in
section six. The final section gives two examples of how pharmacological
knowledge can be used to understand malfunction of memory systems, and

we return to the outset of this book, namely the roles of ions and ion channels in learning and memory formation.
We are grateful to all our colleagues and friends for contributing to
this book despite their tight schedules and multitudes of commitments. With
as little interference from us as possible, each chapter is written in such a way
that it can be read independently and provides a thorough review of the
respective field. We trust that this compendium will appeal to memory researchers, both students and scientists alike. It may hopefully provide a useful overview of the diverse components relevant to memory and other aspects of neuronal plasticity, and serve as a comprehensive introduction for
those new in the field and as a source of reference. Finally, we would hope
that this summary of cellular mechanisms underlying memory formation
may give an impetus for new research in order to strengthen this exciting
scientific field.
Gernot Riedel
Bettina Platt


ABBREVIATIONS
2-DG
5-HETE
5-HPETE
5-HT
6-OHDA
7-NI
8-OH-DPAT
11-HSD
12-HETE
12-HKETE
12-HPETE
ACE
ACh
ACPD
ACTH

AMPA
AMPA-R
Ang I
Ang II
Ang IV
ANP
Anti-Svg-30
AP-1
AP5
APP
ArA
Arc
AST
ATP
AVP
AVP
BC264
BDNF
BLA
BNP
BOC
Ca2+
CalA
CaM
CAM
CaMk
CaMKII
CaMK-II
cAMP
CCK

CCK-4
CCK-8
CCK-8s

2-deoxygalactose
5-hydroxyeicosatetraenoic acid
5-hydroperoxyeicosatetraenoic acid
serotonin
6-hydroxydopamine
7-nitroindazole
8-hydroxy-2(di-n-propyloamino)tetralin
11beta-Hydroxysteroid dehydrogenase
12-hydroxyeicosatetraenoic acid
12-keto-5,8,10,14-eicosatetraenoic acid ibuprofen
12-hydroperoxyeicosatetraenoic acid
angiotensin converting enzyme
acetylcholine
1S,3R-1-amino-cyclopentyl-1,3-dicarboxylic acid
adrenocorticotropic hormone
α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor
angiotensin I
angiotensin II
angiotensin IV
atrial natriuretic peptide
antisauvagine-30
activating protein
2-amino-5-phosphonovaleric acid
amyloid precursor protein
arachidonic acid

activity-regulated cytoskeleton associated protein
aristolochic acid
adenosine triphosphate
[Arg8]-vasopressin
arginine vasopressin
Tyr(SO3H)-gNle-mGly-Trp-(NMe)Nle-Asp-Phe-NH2
brain-derived neurotrophic factor
basolateral nucleus of the amygdala
brain natriuretic peptide
tert-butoxycarbonyloxiimino protective group
calcium ion
calyculin A
calmodulin
cell adhesion molecule
calmodulin-calcium dependent kinase
Ca2+/calmodulin-dependent protein kinase
calcium-calmodulin dependent kinase-type II
cyclic adenosin monophosphate
cholecystokinin
C-terminal tetrapeptide of cholecystokinin
C-terminal octapeptide of cholecystokinin
sulphated C-terminal octapeptide of cholecystokinin


CCK-8US
CEA
CGP42112A
ChAT
CLIP
CNP

CNQX
CNS
Cort
CREB
CRF
CRH
CyA
DA
DAG
DAG
DARPP-32
D-MPRG
DNMTP
DNMTS
DOPAC
EDRF
eNOS
EPSPs
FF
GABA
GAP
GAP-43
GluR
GluR-A
GPII
GR 73632
GR
HFS
HMA
HODI

HPA
HR
HVA
ic
icv
IEG
IgG
IMHV
INDO
INH-1
INH-2
iNOS
IP3
K+

unsulphated C-terminal octapeptide of cholecystokinin
central nucleus of the amygdala
nicotinic acid-Tyr-(N-benzoylcarbonyl-Arg)-Lys-His-Pro-Ile-OH
choline acetyl-transferase
corticotropin-like intermediate lobe peptide
C-type natriuretic peptide
6-cyano-7-nitroquinoxaline-2,3-dione
central nervous system
corticosterone
cAMP-responsive element-binding protein
corticotropin releasing factor
corticotropin releasing hormone
cyclosporin A
dopamine
diacylglycerate

1,2-diacylglycerol
dopamine- and cAMP-regulated phosphoprotein of 32 kD weight
D-Met-Pro-Arg-Gly-NH2
delayed non-matching to place
delayed non-matching to sample
3,4-dihydroxyphenylacteic acid
endothelium-derived relaxing factor
endothelial NOS
excitatory postsynaptic potentials
Fimbria /Fornix
γ-aminobutyric acid
GTPase activating protein
growth associated protein of ~50 kD weight
glutamate receptor
glutamate receptor subtype A
glycosylphosphatidylinositol
D-ALA-[l-Pro9,Me-Leu8]substance P-(7-11)
glucocorticoid receptor
high frequency stimulation
hydroxymyristic acid
homozygous diabetes insipidus
hypothalamo-pituitary-adrenal
hightened locomotor response
homovanillic acid
intracerebral
intracerebroventricular
immediate early gene
immunoglobulin G
intermediate medial hyperstriatum ventrale
indomethacin

inhibitor-1
inhibitor-2
inducible NOS
inositol 1,4,5-triphosphate
potassium ion


L1
L-365,260
LHRH
L-NA
L-NAME
L-NAME
L-NMMA
LPH
LPO
LR
LS
LTD
LTP
LTS
M35
MAGUK
MAP2
MAPK
MARCKS
MeA
mGluR
MK-801
MR

mRNA
MS
MSB
MSH
MWM
[Nle1]-Ang IV
NA
NaCl
NAME
NARG
NBM
NC-1900
NCAM
NCDC
NDGA
NGF
NK
NKKB
NMDA
NMDA-R
nNOS
NO
NOS
NPY
OA
OLETF

a cell adhesion molecule
3R(+)-N-(2,3-dihydroxy-1-methyl-2-oxo-5-phenyl-1-H-1,
4-benzodiazepine-3-yl)

luteinizing hormone releasing hormone
NG-nitro-L-arginine
NG-nitro-L-arginine methyl ester
nomega-nitro-L-arginine methylester-hydrochloride
NG-monomethyl-L-arginine acetate
lipotropin
lobus parolfactorius
locomotor response
lateral septum
long-term depression
long-term potentiation
long-term sensitisation
galanin-(1-13)-bradykinin-(2-9)amide
membrane-associated guanylate kinase
microtubule-associated protein 2
mitogen-activated protein kinase
myristoylated alanine-rich C kinase substrate
methylanthranilate
metabotropic glutamate receptor
dizocilpine
mineralocorticoid receptor
messenger ribonucleic acid
medial septal nucleus
multiple synapse bouton
melanocyte stimulating hormone
Morris water maze
norleucine-1-angiotensin IV
noradrenalin
sodium chloride, saline
NG-nitro-L-arginine methyl ester

N-nitro-L-arginine
nucleus basalis magnocellularis
pGlu-Asn-Ser-Pro-Arg-Gly-NH2 acetate
neural cell adhesion molecule
2-nitro-4-carboxylphenyl-N,N-diphenylcarbamate
nordihydroguaiaretic acid
nerve growth factor
neurokinin
nuclear factor kB
N-methyl-D-aspartate
N-methyl-D-aspartate receptor
neuronal NOS
nitric oxide
nitric oxide synthase
neuropeptide Y
okadaic acid
Otsuka Long-Evans Tokushima fatty rat


ORG 2766
PAF
PAG
PAL
PAT
PG
PI3
PIP2
PKA
PKC
PKG

PLA2
PLC
POMC
PP1
PP2A
PP2B
PP2C
PPIase
PSA
PSD
PST
PTP
PVN
RA
RAM
RM
RT-PCR
SDHACU
Ser/Thr
sGC
SHS
SNAP
SNAP
SPRC
STS
STX
SVZ
TF
TRIM
TX

US
VDB
VDCC
WIN 62577
WM

[Met(O2),D-Lys,Phe9]-α-MSH-(4-9)
platelet activating factor, 1-O-alkyl-2-acyl-sn-3-phosphocholine
periaqueductal grey matter
passive-avoidance learning
passive avoidance task
prostaglandins
1-Phosphatidylinositol 3-Kinase
phosphoinosytolbisphosphate
protein kinase A
protein kinase C
cGMP-dependent protein kinase, protein kinase G
phospholipase A2
phospholipase C
proopiomelanocortin
protein phosphatase 1
protein phosphatase 2A
protein phosphatase 2B (also called calcineurin)
protein phosphatase 2C
peptidyl prolyl cis/trans isomerase (also called immunophilins)
polysialic acid
post-synaptic density
polysialyltransferase ST8SiaIV
protein tyrosine phosphatase
paraventricular nucleus

retinoic acid
radial arm maze
reference memory
reverse transcriptase polimerase chain reaction
sodium-dependent high affinity choline uptake
serine/threonine
soluble guanylyl cyclase
septo-hippocampal system
S-nitroso-N-acetylpenicillamine
soluble N-ethylmaleimide-sensitive factor attachment protein
synapse-associated polyribosomal complexes
short-term sensitisation
polysialyltransferase ST8SiaII
subventricular zone
transcription factor
1-(2-trifluoromethylphenyl)imidazole
thromboxanes
unconditioned stimulus
vertical diagonal band
voltage-dependent calcium channels
17-Hydroxy-17-ethynyl-D-4-androstano[3.2-b]pyrimido[1,2]benzimidazole (non-peptide NK1 tachykinin receptor antagonist)
working memory


CHAPTER 1.1

Calcium
Miao-Kun Sun and Daniel L. Alkon

Abstract

C

a2+ plays an essential role in a variety of intracellular signaling cascades, which underlie mechanisms essential for the dynamic control of cell functions. In cognition, Ca2+
participates in control of not only the formation and development of neural structures
that cognition depends on, but also signal processing and synaptic plasticity that define learning and memory. The dramatic influence of Ca2+ on neural functions relies on the fact that its
concentrations and changes are rapidly sensed and recognized by many intracellular molecules,
including proteins that trigger neurotransmitter exocytosis and Ca2+-binding enzymes and kinases. Ca2+ homeostasis is thus tightly controlled and involves a balance of mechanisms controlling Ca2+ entry through the plasma membrane, intracellular storage and release, and sequestration. Each of these mechanisms can be impaired in diseases, by drugs, and in aging,
leading to derangement of Ca2+ homeostasis. Thus, abnormal Ca2+ signaling contributes in
important ways to neurological and cognitive disorders. Effective cognitive therapies cannot be
achieved without a comprehensive understanding of the roles and mechanisms of Ca2+ ions in
cognition and without valid strategies for correcting the Ca2+ abnormalities. These and other
issues are briefly discussed in the chapter.

Introduction

Ca2+, a ubiquitous intracellular messenger, controls almost everything we do (from fertilization to death), including how our minds organize thoughts sufficiently well to investigate our
own existence, and for an exceptional few, a clear view of the beginning of our universe. In
neurons, for instance, Ca2+ regulates development, excitability, secretion, learning, memory,
aging, and death.6,15 Information about the mechanisms regulating Ca2+ concentrations and
mechanisms regulated by Ca2+ is therefore critical for our understanding neural functions and
memory.
Intracellular Ca2+ signaling is characterized by two phenomena: a broad spectrum of functional roles and precise control of intracellular concentrations. A long-standing question in cell
Ca2+ signaling is how Ca2+, with its abundant and varied intracellular targets, is able to achieve
specificity and activate only a subset of those targets. Temporal and spatial control of Ca2+
signaling through the neural networks involved in learning and memory are fundamental for
cognitive capacities. The Ca2+ signals can not only spread through neurons as global Ca2+
waves, but can also be highly localized within micro-domains of sub-cellular compartments
such as at close appositions of mitochondria and the endoplasmic reticulum (ER), dendritic
spines, or presynaptic terminals.68,100

Losing effective control of cytosolic free Ca2+ concentration ([Ca2+]c) according to functional demands undoubtedly contributes to neurological and memory disorders, and aging.
Abnormally high or low levels of [Ca2+]c can be cytotoxic. Although high [Ca2+]c attracts most
of attention, there is evidence that neuronal cell injury/death can also be associated with a
decrease of [Ca2+]c (for review see ref. 95). For instance, growth factor deprivation induces cell
From Messengers to Molecules: Memories Are Made of These, edited by Gernot Riedel
and Bettina Platt. ©2004 Eurekah.com and Kluwer Academic / Plenum Publishers.