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Molecular Neurobiology of the Olfactory System Molecular, Membranous, and Cytological Studies
Molecular Neurobiology of the Olfactory System Molecular, Membranous, and Cytological Studies
Edited by
Frank L. Margolis Roche Institute of Molecular Biology Nutley, New Jersey
and
Thomas V. Getchell Wayne State University School of Medicine Detroit, Michigan
PLENUM PRESS • NEW YORK AND LONDON
Library of Congress Cataloging in Publication Data
Molecular neurobiology of the olfactory system: molecular, membranous, and cytological studies / edited by Frank L. Margolis and Thomas V. Getchell.
p. em. Includes bibliographies and index. ISBN-13: 978-1-4612-8280-8 e-ISBN-13: 978-1-4613-0989-5 001: 10.1007/978-1-4613-0989-5 1. Smell. 2. Molecular neurobiology. 3. Chemoreceptors. I. Margolis, Frank L. II.
Getchell, Thomas V. QP4S8.M64 1988 S99'.OI826-dcI9
© 1988 Plenum Press, New York Softcover reprint of the hardcover 1st edition 1988 A Division of Plenum Publishing Corporation 233 Spring Street, New York, N.Y. 10013
All rights reserved
88-14821 CIP
No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written permission from the Publisher
Contributors
Richard A. Akeson • Division of Basic Science Research, Children's Hospital Research Foundation, Cincinnati, Ohio 45229
Harriet Baker • Laboratory of Molecular Neurobiology, The Burke Rehabilitation Center, Cornell University Medical College, White Plains, New York 10605
Peter C. Barber • Department of Morbid Anatomy and Histology, Addenbrooke's Hospital, (:ambridge CB2 2QQ, England
Klaus Buchner • Institut fOr Zoologie, Technische Universitat Mlinchen, D-8046 Garching, Federal Republic of Germany
Alan R. Dahl • Inhalation Toxicology Research Institute, Lovelace Biomedical and Environmental Research Institute, Albuquerque, New Mexico 87185
Ted M. Dawson • Department of Neurology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania 19143
Valina L. Dawson • Departments of Pharmacology and Psychiatry, University of Utah School of Medicine, Salt Lake City, Utah 84132
John A. DeSimone • Department of Physiology, Virginia Commonwealth University, Richmond, Virginia 23298
Vincent E. Dionne • Division of Pharmacology, Department of Medicine, University of California, San Diego, La Jolla, California 92093
Richard L. Doty • Smell and Taste Center and Department of Otorhinolaryngology and Human Communication, School of Medicine, University of Pennsylvania, Philadephia, Pennsylvania 19104
Albert I. Farbman • Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois 60208
Marilyn L. Getchell • Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, Michigan 48201
Thomas V. Getchell • Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, Michigan 48201
Gerard L. Heck • Department of Physiology, Virginia Commonwealth University, Richmond, Virginia 23298
Steen Jensen • Institute of Anatomy B, University of Aarhus, Aarhus 8000-C, Denmark
Doran Lancet • Department of Membrane Research, The Weizmann Institute of Science, Rehovot 76 100, Israel
Frank L. Margolis • Department of Neuroscience, Roche Institute of Molecular Biology, Roche Research Center, Nutley, New Jersey 07110
Robert A. Maue • Division of Molecular Medicine, New England Medical Center, Boston, Massachusetts 02111
v
vi CONTRIBUTORS
James I. Morgan • Department of Neuroscience, Roche Institute of Molecular Biology, Roche Research Center, Nutley, New Jersey 07110
Randall B. Murphy • Department of Chemistry, New York University, New York, New York 10003; and Department of Psychiatry, Cornell University Medical College-Westchester Division-New York Hospital, White Plains, New York 10605
Krishna C. Persaud • Department of Physiology, Virginia Commonwealth University, Richmond, Virginia 23298
Jonathan Pevsner • Departments of Neuroscience, Pharmacology and Molecular Sciences, and Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
Pamela B. Sklar • Departments of Neuroscience, Pharmacology and Molecular Sciences, and Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
James B. Snow, Jr. • Smell and Taste Center and Department of Otorhinolaryngology and Human Communication, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
Solomon H. Snyder • Departments of Neuroscience, Pharmacology and Molecular Sciences, and Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
James K. Wamsley • Departments of Pharmacology and Psychiatry, University of Utah School of Medicine, Salt Lake City, Utah 84132
Dieter C. Weiss • Institut fur Zoologie, Technische Universitat Munchen, D-8046 Garching, Federal Republic of Germany
Barbara Zielinski • Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, Michigan 48201
Preface
The sense of smell and the olfactory system have been a subject of intrinsic interest for millenia. Inquiry into the structure and function of the olfactory system is based on a long tradition that dates back at least to the ancient Greeks. The mechanistic basis for the sensitivity and selectivity of this chemosensory detection system has always posed a challenge and remained largely a mystery. Recently, there has been a renaissance of interest in it and especially in the application of contemporary techniques of biochemistry and cellular and molecular biology. In this volume, current research utilizing these approaches is discussed in depth by a group of scientists who are among the current leaders in the applications of these techniques to the olfactory system. These authors address a wide range of questions that bear directly on the olfactory system but have broader biological implications as well. The various chapters have been grouped into five broad subject areas that emphasize diverse but related questions.
"Transduction and Ligand-Receptor Interactions" considers the biochemical bases of stimulus access, interaction, transduction, elimination, and information processing. What are the current views of the mechanisms that regulate the arrival of odorant molecules at the sensory cells? What role is played by the mucus interface and how is its composition regulated? Having gained access, how do odorant molecules interact with the olfactory neurons and convey their information to the cell? How is this information processed and transmitted to the central nervous system, where it will be used to form the basis for organismal response? Finally, what is known of the enzymatic or physical mechanisms that eliminate prior stimuli?
"Molecular Biophysics and Membrane Function" recognizes that the stimulus interactions with the olfactory neurons take place at, and induce initial changes in, the plasma membrane of the receptor cell. What are the biophysical changes associated with these initial events? How can they be studied at various levels within the tissue? What ion fluxes can be identified in the intact tissue? To what extent are they dependent on identified components of the transduction system? Which cell types are responsible for expressing the conductance changes and how are they regulated? Do membrane fragments manifest the entire phenomenon and can the individual molecular components be disassembled and reconstituted for detailed mechanistic studies?
"Biochemical-Molecular Biological Studies" addresses how the highly plastic properties of this system might be regulated. How do second-order neurons respond to disruption of normal input from the olfactory receptor cells? What happens to their ability to maintain normal cellular and synaptic function? Do these target cells recover when the receptor neuron population is reconstituted? What are the agents that are responsible for these events? How are trophic agents and other components delivered to the distant terminals and targets of these unmyelinated nerves? How is the presynaptic cell body
vii
viii PREFACE
informed about events at the synaptic terminals? Are the properties of these chemoreceptor neurons and the tissue in which they exist dependent upon the selective expression of a particular subset of genes? If so, how can they be identified and characterized?
"Development and Differentiation" considers normal olfactory ontogeny as well as the ability of the receptor neurons to be replaced from an endogenous population of stem cells. Is this property an example of tissue-specific neoteny in an adult animal? How can the various cell types be discriminated? Do the various cell types exhibit biochemical/immunological hallmarks? Are the cells of a given morphological/functional set all identical? Can they develop/survive/function in an ectopic location? What are the cellular and environmental requirements for morphological and functional development of the neurons?
"Biological Relevance of Olfactory Function" illustrates that, in addition to presenting a challenging series of questions in model systems, understanding the olfactory system has relevance for the human condition. What are the effects of age-dependent changes in olfactory function? Why is one of the first events associated with the onset of Alzheimer's-type dementia loss of the ability to identify odors? Will this information help us to create diagnostic, therapeutic, or research models of the disease based on its link to olfactory function?
Our intent in editing this volume has been threefold: First, to focus attention on the functional questions in the olfactory system that are currently in need of answers; second, to illustrate how contemporary techniques in biochemistry and cellular and molecular biology are being used to address these questions; and third, to identify future directions for research in which studies of the olfactory system will also contribute to the solution of broad biological problems. Any success this volume has in achieving these goals accrues to the chapter authors, who have labored creatively and diligently in pursuit of our mutual goal.
Nutley and Detroit
Frank L. Margolis Thomas V. Getchell
Contents
I. TRANSDUCTION AND LIGAND-RECEPTOR INTERACTIONS
1. Olfactory Receptor Mechanisms: Odorant-Binding Protein and Adenylate Cyclase
Solomon H. Snyder, Pamela B. Sklar, and Jonathan Pevsner
1. Introduction..................................................... 3 2. An Odorant-Binding Protein. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 3. Odorant Selectivity in Stimulation of Adenylate Cyclase Activity ...... 11 4. Localization of GTP-Binding Proteins in Nasal Mucosa. . . . . . . . . . . . . . . 15 5. Concl usions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
2. Molecular Components of Olfactory Reception and Transduction
Doron Lancet
1. Introduction.................................................... 25 2. Olfactory Cilia: The Site of Olfactory Reception and Transduction. . . . . 25
2.1. Olfactory Cilia ............................................. 25 2.2. Isolated Cilia Preparations ................................... 26
3. Candidate Odorant Receptor Proteins in the Sensory Membrane. . . . . . . 28 3.1. Expected Properties of Olfactory Receptor Proteins .............. 28 3.2. Olfactory Receptor Candidates ............................... 30
4. Cyclic Nucleotide Enzymatic Cascade in Olfactory Transduction...... 31 4.1. Role of cAMP in Olfaction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 4.2. Olfactory GTP-Binding Protein ............................... 36 4.3. Transduction Components as Odorant Receptor Probes. . . . . . . . . . 39
5. Possible Mechanisms of Olfactory lon-Channel Modulation by Cyclic Nucleotides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 5.1. Protein Phosphorylation in Olfactory Epithelium ................ 43 5.2. Direct lon-Channel Gating. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
6. Conclusions.................................................... 45 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
ix
x CONTENTS
3. The Effect of Cytochrome P-4S0-Dependent Metabolism and Other Enzyme Activities on Olfaction
Alan R. Dahl
1. Relationships among the Fields of Inhalation Toxicology, Foreign Compound Metabolism, and Olfactory Physiology .................. 51
2. Xenobiotic Metabolizing Enzymes Identified in the Nose and Their Function. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 2.1. Nasal Enzymes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 2.2. Types of Metabolic Transformation. . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 2.3. Capacity of Nasal Enzymes .................................. 61 2.4. Interactions of Two or More Compounds with Nasal Enzymes .... 64 2.5. Fate of Inhaled Materials: Are Metabolites of Odorants Present in
Mucus? ................................................... 65 3. Possible Effects of Nasal Metabolism on Olfaction. . . . . . . . . . . . . . . . . . . 66 4. Research Needed to Relate Nasal Metabolism of Odorants to
Olfaction ...................................................... 67 5. Summary and Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
4. Odorant and Autonomic Regulation of Secretion in the Olfactory Mucosa
Marilyn L. Getchell, Barbara Zielinski, and Thomas V. Getchell
1. Introduction.................................................... 71 2. Organization and Characterization of the Cells in the Olfactory
Mucosa ....................................................... 71 3. Extrinsic Innervation of the Olfactory Mucosa. . . . . . . . . . . . . . . . . . . . . . . 75 4. Cellular Aspects of Secretion in Sustentacular Cells. . . . . . . . . . . . . . . . . . 81
4.1. Mucous Secretion .......................................... 81 4.2. Electrolyte and Water Transport and Secretion .................. 82 4.3. Agents That Induce Secretion from Sustentacular Cells. . . . . . . . . . . 82 4.4. Effects of Olfactory Nerve Section ............................ 85
5. Neuropharmacological Regulation of Glandular Secretion ............ 85 5.1. Agonist-Induced Secretion ................................... 85 5.2. Second Messengers and Modulators of Agonist-Induced Secretion. 87 5.3. Odorant-Induced Secretion .................................. 89 5.4. Neural Pathways of Agonist-Induced Secretion ................. 90
6. Implications for Sensory Transduction ............................. 91 6.1. Prereceptor Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 6.2. Postinteractive Events ....................................... 92
7. Conclusions and Research Needs ................................. 92 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
CONTENTS xi
5. Autoradiographic Localization of Drug and Neurotransmitter Receptors in the Olfactory Bulb
Valina L. Dawson, Ted M. Dawson, and James K. Wamsley
1. Introduction.................................................... 99 2. Light Microscopic Receptor Autoradiography ....................... 101 3. Distribution of Receptor Types in the Olfactory Bulb ................ 104
3.1. Cholinergic Receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 3.2. Biogenic Amines ........................................... 105 3.3. Amino Acids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 3.4. Neuropeptides ............................................. 108 3.5. Drug-Binding Sites. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 3.6. Miscellaneous.............................................. 111
4. Conclusions.................................................... 112 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 3
II. MOLECULAR BIOPHYSICS AND MEMBRANE FUNCTION
6. Membrane Probes in the Olfactory System: Biophysical Aspects of Initial Events
Randall B. Murphy
1. Introduction.................................................... 121 2. The Role of Biophysical Models within a Receptor-Mediated Model of
the Initial Events in Olfaction..................................... 121 2.1. Possible Mechanisms ....................................... 122 2.2. Evidence for Nonspecific Mechanisms. . . . . . . . . . . . . . . . . . . . . . . . . 123 2.3. Further Experimental Evidence ............................... 124
3. Surface Potential and Single Ionic Channels ........................ 127 4. Physical Methods of Probing Initial Chemoreceptive Mechanisms ..... 128
4.1. General Considerations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 4.2. Photophysical Methods. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 4.3. Electron Spin Resonance .................................... 131
5. Biophysical Studies of Olfactory Epithelium ........................ 131 5.1. ESRStudies ................................................ 131 5.2. Fluorescence Studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 5.3. Raman and Infrared Spectroscopy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 5.4. Difference Absorption Spectrophotometry. . . . . . . . . . . . . . . . . . . . . . 133 5.5. Biophysical Studies Using Artificial Membranes. . . . . . . . . . . . . . . . . 134
6. Summary...................................................... 137 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 38
xii CONTENTS
7. Membrane Properties of Isolated Olfactory Receptor Neurons
Robert A. Maue and Vincent E. Dionne
1. Introduction.................................................... 143 1 .1. Basis of Interest in Olfactory Receptor Neurons ................. 143 1.2. Obstacles to Studying Receptor Neuron Membrane Currents. . . . . . 143 1.3. Advantages to Patch-Clamping Isolated Receptor Neurons. ..... .. 144 1.4. Focus of Initial Patch-Clamp Studies .......................... 144
2. Experimental System ............................................ 145 2.1. Preparation of Isolated Olfactory Receptor Neurons ............. 145 2.2. Patch-Clamp Technique and Data Analysis...... ............... 147 2.3. Perfusion System and Odorant Application ..................... 148
3. Results........................................................ 148 3.1. Ion Channels in Olfactory Receptor Neurons................... 148 3.2. Response of Receptor Neurons to Odorants .................... 151
4. Discussion..................................................... 152 4.1. Roles of Ion Channels in Receptor Neuron Activity. . . . . . . . . . . . . . 152 4.2. Future Directions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
8. Voltage-Clamp Studies of the Isolated Olfactory Mucosa
John A. DeSimone, Krishna C. Persaud, and Gerard L. Heck
1. Introduction.................................................... 159 1.1. Chemoreception: A Property of Every Cell ..................... 159 1.2. Chapter Organization ....................................... 160
2. Ion-Transporting Epithelia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160 2.1. Asymmetrical Structure: Consequences for Function. . . . . . . . . . . . . 160 2.2. Special Membrane-Transport Systems ......................... 161 2.3. Paracellular Shunts ......................................... 161
3. Electrophysiological Methods. . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . 162 3.1. The Short-Circuit Method (Ussing Method) ..................... 162 3.2. Radioisotopes and Active Ion Transport. . . . . . . . . . . . . . . . . . . . . . . . 163 3.3. Other Methods. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
4. Theoretical Methods ............................................ 164 4.1. Nonequilibrium Thermodynamics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164 4.2. Kinetic Approaches ......................................... 165
5. Ion Transport and Chemoreception. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166 5.1. The Sodium Taste Receptor .................................. 166 5.2. Other Ions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
6. The Olfactory Mucosa. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167 6.1. Materials and Methods ...................................... 168 6.2. Active Ion Transport in the Steady State ....................... 169
CONTENTS xiii
6.3. The Current-Voltage Relationship ............................ 170 6.4. Odorant-Evoked Current Transients under Voltage Clamp ........ 170 6.5. Dose-Response Relationship. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172
7. Cyclic Nucleotide Modulation of Olfactory Transduction. . . . . . . . . . . . . 173 7.1. cAMP Evokes an Inward Current Transient. . . . . . . . . . . . . . . . . . . . . 174 7.2. cAMP Enhances Odorant-Evoked Current Transients. . . . . . . . . . . . . 175 7.3. Evidence for a Stimulatory G Protein. . ... . . .. . . ... . ... . . . . . . . . 176 7.4. cGMP Inhibits Odorant-Evoked Current Transients .............. 176
8. Summary and Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 78
III. BIOCHEMICAL-MOLECULAR BIOLOGICAL STUDIES
9. Neurotransmitter Plasticity in the Juxtaglomerular Cells of the Olfactory Bulb
Harriet Baker
1. Introduction.................................................... 185 1 . 1. Overview ................................................. 1 85 1.2. Anatomy.................................................. 186
2. Alterations in Olfactory Bulb Structure and Function following Receptor Afferent Lesions ................................................ 187 2.1. Changes in the Size of the Olfactory Bulb. . . . . . . . . . . . . . . . . . . . . . 187 2.2. Biochemical Alterations in the Olfactory Bulb .................. 187 2.3. Immunocytochemical Observations in the Deafferented Olfactory
Bulb.... . ........ . . . . . . .. . . . . . . . . . .. . . . .. . . . ... . . . ... . . . . . 188 3. Development and Plasticity ...................................... 200
3.1. Inductive Capacity of the Olfactory Epithelium ................. 200 3.2. Strain Differences in Transmitter Expression in the Olfactory Bulb. 200
4. Transneuronal Transport of Exogenous Materials from the Olfactory Epithelium to Brain ............................................. 203 4.1. Transport of Lectins in the Olfactory System. . . . . . . . . . . . . . . . . . . . 203 4.2. Transneuronal Transport of Lectin to the Forebrain .............. 204 4.3. Implications of Transneuronal Transport for Disease Processes .... 205
5. Conclusions.................................................... 205 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212
10. Axoplasmic Transport in Olfactory Receptor Neurons
Dieter G. Weiss and Klaus Buchner
1. Introduction.................................................... 217 2. The Olfactory Receptor Neuron as a Specialized Neuronal System .... 217 3. Transport of Low-Molecular-Weight Material ....................... 221
xiv CONTENTS
4. Transport of Bulk Proteins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224 4.1. Rapid Transport ............................................ 224 4.2. Slow Transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
5. Transport of Characterized Proteins ............................... 227 6. Retrograde Transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227 7. Organelle Movement Studied with AVEC-DIC Microscopy.... .... .... 228 8. Transneuronal Transport and the Spread of Virus. . . . . . . . . . . . . . . . . . . . 232 9. The Study ofAxoplasmic Transport Using the Olfactory Receptor
Neuron... .......... . ..... . .... .... ... . .... ........ . .. .... .... . 233 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
11. Molecular Cloning of Olfactory-Specific Gene Products
Frank L. Margolis
1. Introduction.................................................... 237 2. Anatomical Organization ........................................ 238 3. Biochemical Properties .......................................... 239 4. Olfactory Marker Protein ........................................ 240
4.1. Overview ................................................. 240 4.2. Amino Acid Sequence ...................................... 241 4.3. Hypothetical Approaches to the Function of Olfactory Marker
Protein. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242 4.4. Characterization and Cloning of the mRNA and Gene. . . . . . . . . . . 243 4.5. Future Directions for Olfactory Marker Protein. . . . . . . . . . . . . . . . . . 246
5. Lesion-Induced Changes in mRNAs ............................... 246 5.1. In Vitro Translation ......................................... 246 5.2. Cloning of Additional mRNAs from Nasal/Olfactory Tissue ...... 250
6. Carnosine Synthetase. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256 6.1. Overview ................................................. 256 6.2. Characterization............................................ 257 6.3. Monoclonal Antibodies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
7. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
IV. DEVELOPMENT AND DIFFERENTIATION
12. Monoclonal Antibody Mapping of the Rat Olfactory Tract
James I. Morgan
1. Introduction.................................................... 269 1 .1. Scope..................................................... 269
2. Strategies for Monoclonal Antibody Production ..................... 269
CONTENTS xv
2.1. General Considerations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269 2.2. Monoclonal Antibodies to Adult and Embryonic Epithelium. . . . . . . 270 2.3. Monoclonal Antibodies Raised against Membranes from Olfactory
Epithelium. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271 2.4. Antibodies to Carnosine Synthetase ........................... 272
3. Applications of Monoclonal Antibodies. . . . . . . . . . . . . . . . . . . . . . . . . . . . 273 3.1. Studies of the Structure of the Olfactory Epithelium ............. 273 3.2. Monoclonal Antibody Studies of Ontogeny in the Olfactory
Epithelium. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276 3.3. Monoclonal Antibody Studies of Regeneration in the Olfactory
Epithelium. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279 3.4. Monoclonal Antibodies to Specific Proteins .................... 281 3.5. Monoclonal Antibody Studies of Cultures of the Olfactory
Epithelium. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282 3.6. The Use of Monoclonal Antibodies in the Identification and
Isolation of Novel Olfactory Tract Antigens .................... 288 4. Discussion..................................................... 292 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293
13. Primary Olfactory Neuron Subclasses
Richard A. Akeson
1. Introduction.................................................... 297 2. Olfactory Neuron Subclasses ..................................... 298
2.1. Morphological Subclasses ................................... 298 2.2. Carbohydrate Expression Subclasses. . . . . . . . . . . . . . . . . . . . . . . . . . . 299 2.3. Other Defined Subclasses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306
3. Perspectives on Research Directions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309 3.1. Clonal Olfactory Neurons ................................... 309 3.2. Direct Approaches to Molecular Olfactory Receptors ............ 312 3.3. Genetic Approaches ........................................ 31 3
4. Summary...................................................... 314 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 5
14. Cellular Interactions in the Development of the Vertebrate Olfactory System
Albert I. Farbman
1. Introduction.................................................... 319 2. Early Development and Formation of the Olfactory Placode .......... 320
2.1. Experimental Analysis of Induction of the Olfactory Placode. . . . . . 320 3. Effect of Olfactory Receptor Cells on Early Formation of the Olfactory
Bulb.......................................................... 322 4. Effect of the Olfactory Bulb on Differentiation of Receptor Cells in a
Regenerating System ............................................ 322
xvi CONTENTS
5. Effect of Olfactory Bulb on Receptor Cell Development .............. 325 5.1. Organ Culture Method ...................................... 325 5.2. Bulbar Effects on OMP Synthesis ............................. 325 5.3. Bulbar Effects on Ciliogenesis ................................ 327 5.4. Does the Bulb Exert a Tropic Effect? .......................... 327
6. Cell-Culture Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327 7. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
15. Olfactory Tissue Interactions Studied by Intraocular Transplantation
Peter C. Barber and Steen Jensen
1. Introduction.................................................... 333 2. Organization of Olfactory Sensory Epithelial Grafts In Oculo ......... 334 3. Indicators of Neuronal Maturation In Oculo ........................ 337 4. Factors Affecting Neuronal Maturation In Oculo .................... 339
4.1. Epithelial Organization ...................................... 340 4.2. Neurotrophic Influence of the Iris. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341 4.3. Innervation of the Graft from the Iris .......................... 341 4.4. Presence of Co-transplanted Central Nervous Tissue ..... . . . . . . . . 342
5. Factors Affecting Overall Growth of Olfactory Epithelium in Oculo .... 346 6. Effects of Olfactory Epithelium In Oculo on Co-transplanted CNS ..... 346
6.1. Maturation of CNS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346 6.2. Innervation of Co-transplant by Olfactory Axons ................ 347 6.3. Innervation of Olfactory Tissue from the CNS .................. 349
7. Conclusions and Directions ...................................... 350 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350
V. BIOLOGICAL RELEVANCE OF OLFACTORY FUNCTION
16. Age-Related Alterations in Olfactory Structure and Function
Richard L. Doty and James B. Snow, Jr.
1. Introduction.................................................... 355 2. Human Olfactory Perception in Later Life .......................... 356
2.1. Odor Identification ......................................... 356 2.2. Odor Detection ............................................ 356 2.3. Suprathreshold Odor Intensity Perception ...................... 357 2.4. Odor Discrimination. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 358 2.5. Odor Pleasantness. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359
3. Human Olfactory Perception in Age-Related Diseases ............... 359 3.1. Alzheimer's Disease ........................................ 360
CONTENTS xv;;
3.2. Parkinson's Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363 4. Age-Related Alterations in the Structure and Function of the Nose and
the Olfactory System ............................................ 365 4.1. Airflow and General Nasal Considerations ..................... 365 4.2. Olfactory Neuroepithelium .................................. 366 4.3. Olfactory Bulb. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367 4.4. Higher Centers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369
5. Summary and Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 370
Index........................ .......................... .......... 375
