Dopaminergic Neuron Transplantation in the Weaver Mouse Model of Parkinson's Disease

Dopaminergic Neuron Transplantation in the Weaver Mouse Model of Parkinson's Disease

ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY Editorial Board: NATHAN BACK, State University of New York at Buffalo IRUN R. COHEN, The Weizmann Institute of Science DAVID KRITCHEVSKY, Wistar Institute ABEL LAJTHA, N.S. Kline Institutefor Psychiatric Research RODOLFO PAOLETTI, University of Milan Recent Volumes in this Series Volume 506 LACRIMAL GLAND, TEAR FILM, AND DRY EYE SYNDROME 3: BASIC SCIENCE AND CLINICAL RELEVANCE Edited by David A. Sullivan, Michael E. Stern, Kazuo Tsubota, Darlene A. Dartt, Rose M. Sullivan, and B. Britt Bromberg Volume 507 EICOSANOIDS AND OTHER BIOACTIVE LIPIDS IN CANCER, INFLAMMATION, AND RADIATION INJURY 5 Edited by Kenneth V. Honn, Lawrence J. Marnell, Santosh Nigam, and Charles Serhan Volume 508 SENSORIMOTOR CONTROL OF MOVEMENT AND POSTURE Edited by Simon C. Gandevia, Uwe Proske and Douglas G. Stuart Volume 509 IRON CHELATION THERAPY Edited by Chiam Hershko Volume 510 OXYGEN TRANSPORT TO TISSUE XXIII: OXYGEN MEASUREMENTS IN THE 21 ST CENTURY: BASIC TECHNIQUES AND CLINICAL RELEVANCE Edited by David F. Wilson, John Biaglow and Anna Pastuszko Volume 511 PEDIATRIC GENDER ASSIGNMENT: A CRITICAL REAPPRAISAL Edited by Stephen A. Zderic, Douglas A. Canning, Michael C. Carr and Howard McC. Snyder III Volume 512 LYMPHOCYTE ACTIVATION AND IMMUNE REGULATION IX: LYMPHOCYTE TRAFFIC AND HOMEOSTASIS Edited by Sudhir Gupta, Eugene Butcher and William Paul Volume 513 MOLECULAR AND CELLULAR BIOLOGY OF NEUROPROTECTION IN THE CNS Edited by Christian Alzheimer Volume 514 PHOTO RECEPTORS AND CALCIUM Edited by Wolfgang Baehr and KrzysztofPalczewski Volume 515 NEUROPILIN: FROM NERVOUS SYSTEM TO VASCULAR AND TUMOR BIOLOGY Edited by Dominique Bagnard Volume 516 TRIPLE REPEAT DISORDERS OF THE NERVOUS SYSTEM Edited by Lubov T. Timchenko Volume 517 DOPAMINERGIC NEURON TRANSPLANTATION IN THE WEAVER MOUSE MODEL OF PARKINSON'S DISEASE Edited by Lazaros C. Triarhou Volume 518 ADVANCES IN MALE MEDIATED DEVELOPMENTAL TOXICITY Edited by Bernard Robaire and Barbara F. Hales A Continuation Order Plan is available for this series. A continuation order will bring delivery of each new volume immediately upon publication. Volumes are billed only upon actual shipment. For further information please contact the publisher.

Dopaminergic Neuron Transplantation in the Weaver Mouse Model ofparkinson's Disease By Lazaros C. Triarhou University of Macedonia Thessaloniki. Greece Springer Science+Business Media, LLC

Library of Congree Cataloginh-in-Publication Data Triarhou, Lazaros Constantinos, 1957- Dopaminergic neuron transplantation in the weaver mouse model ofparkinson's disease I Lazaros C. Triarhou. p. cm. -- (Advances in experimental medicine and biology; v. 517) IncJudes bibliographical references and index. ISBN 0-306-47418-2 (alk. paper) 1. Parkinson's disease. 2. Dopaminergic neurons--transplantation. 3. Parkinson's disease--surgery. I. Title. II. Series. RC382.T75 2000 617.4'810592--dc21 00-046207 ISBN 978-1-4613-5201-3 ISBN 978-1-4615-0699-7 (ebook) DOI 10.1007/978-1-4615-0699-7 2002 Springer Science+Business Media New York 10 9 8 7 6 5 4 3 2 A c.i.p. record for this book is available from the Library ofcongress. All rights reserved. No part ofthis book may be reproduced, stored in a retrieval system, or transmitted in any fonn or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written pennission from the PubJisher.

PREFACE Parkinson's disease, a degenerative brain disorder, affects an estimated 0.25-0.50% of the population. Symptoms result from neuronal degeneration in the nigrostriatal dopaminergic pathway and include tremor, rigidity and gradual slowness of spontaneous movement. The cause of Parkinson's disease is only partially understood; both environmental factors and a genetic predisposition have been implicated in its etiopathogenesis. Neural transplantation is being used experimentally for providing an alternative biological source of dopamine both in animal studies and in experimental clinical trials. This book is the result of 15 years of research on the transplantation of dopaminergic neurons in the striatum of the weaver mouse, a neurological mutant characterized by genetically-determined degeneration of midbrain dopamine neurons. The weaver mouse constitutes the only available laboratory model with a chronic progressive disease that mimics Parkinsonism. The other two models currently used to investigate dopaminergic mechanisms rely on the use of the neurotoxins 6- hydroxydopamine and methylphenyltetrahydropyridine for the selective removal of dopaminergic neurons from an otherwise healthy organism. Structural and functional aspects of transplantation of mesencephalic dopaminergic grafts into the striatum of weaver mice are reviewed, including histochemical correlates of graft survival and integration, numerical aspects of donor neuron survival, ultrastructural findings on synaptogenesis, neurochemical indices of dopamine uptake function and receptor binding, gene expression of several structural and neurotransmitter-receptor related molecules, the levels of striatal amino acid receptors, and the behavioral effects of unilateral and bilateral neuronal transplantations. One finding of particular interest is that weaver hosts appear to offer a suboptimal environment for dopamine cell survival compared to wild-type hosts subjected to 6-hydroxydopamine lesions. While the weaver brain permits the survival and histotypic differentiation of donor dopaminergic neurons to a degree sufficient for bringing about functional improvement, there may be micro environmental factor(s) putatively influencing the final number of surviving dopamine cells in the grafts. It is pertinent to mention that at birth, many young neurons undergo degeneration in the weaver striatum just beneath the subependymal plate, and by one year of age an estimated 22% of medium-sized striatal neurons have been lost. The possibility that the disease process exerts an influence on graft survival has been repeatedly brought up in clinical transplantation studies in Parkinsonism. Such considerations add value to the weaver mutant as a model of nigrostriatal dopamine degeneration, particularly in studying host-graft interactions. v

ACKNOWLEDGMENTS The author thanks all of his collaborators and co-authors of the original studies, particularly those who have devotedly shared the laboratory bench, for making this work possible; special thanks for that matter to Drs. Patrik Brundin, Guy Doucet, Walter Low, Lupe Mengod, Adamantia Mitsacos, Jay Simon, Carme Sola, Lefteri Tsoukalas and Thomas Witt. Words of deep gratitude are extended to Drs. Shirley Bayer, Anders Bjorklund, Manuel del Cerro, Joseph Hingtgen, Elias Kouvelas and Chema Palacios for expanding the author's scientific horizons; to Drs. Biagio Azzarelli, Ben Boukai, Jans Muller and Sidney Ochs for inspired discussions; to the American Society for Neural Transplantation and Repair for the exciting forum it has created and maintained; to the Bodossakis Foundation, Athens, for honoring this research with the bestowal of its Science Award; to the following agencies and foundations for supporting the author's scientific efforts over the years: the Association for the Advancement of Mental Health Research and Education, the Ataxia-Telangiectasia Children's Project, Eli Lilly and Company, the National Ataxia Foundation, the National Institutes of Health, and the Research and Sponsored Programs ofindiana University; and to Dr. Ronald Landes personally and the staff of Landes Bioscience for their encouragement, understanding and care during the composition of this monograph. vii

CONTENTS 1. INTRODUCTION... 1 Dopamine and Parkinson's Disease... 1 Experimental Models of Parkinsonism in Laboratory Animals... 5 Graft-Assisted Neural Reconstruction ("Brain ware Engineering"?)... 7 References... 8 2. BIOLOGY AND PATHOLOGY OF THE WEAVER MUTANT MOUSE 15 Introduction... 15 Cellular and Molecular Genetics of the Weaver Mutation... 15 Alterations of the Mesotelencephalic Dopamine Projection System... 16 Cerebellar Phenotype of the Weaver Mutant... 29 Hippocampal Morphology... 31 Biology of Normal H Mutant Cell Associations... 32 Behavioral Phenotype... 34 Structural Clues to the Weaver Riddle... 35 References... 36 3. HISTOCHEMICAL PROPERTIES OF INTRASTRIATAL MESENCEPHALIC GRAFTS... 43 Introduction... 43 Methodological Considerations... 43 Expression of Catecholaminergic Neurotransmitter-Related Molecules and Quantitative Aspects of Dopaminergic Neuron Survival... 47 Comparative Survival of Dopaminergic Neurons in Grafts Placed in Weaver and in 6-0HDA Lesion Hosts... 51 Expression of Neuropeptides and Structural Proteins... 53 References... 56 4. STRUCTURAL CORRELATES OF PROCESS OUTGROWTH AND CIRCUIT RECONSTRUCTION... 63 Axonal Reinnervation of the Host Striatum... 63 Synaptic Investment of Graft-Derived Dopamine Terminals... 65 Compartmental Specificity of the Striatal Reinnervation... 73 Innervation of Nonstriatal Regions by the Grafts... 74 ix

x COlltellts Chemoaffinity and Axon-Target Recognition in Development and in Transplantation... 76 Dendrite Extension from the Graft into the Host Striatum... 77 Expression of Molecules Related to Axonal and Dendritic Outgrowth... 78 References... 83 5. NEUROCHEMICAL INDICES OF FUNCTIONAL RESTORATION... 89 Dopamine Uptake Markers... 89 Autoradiography of [3H)Dopamine Uptake... 89 Dopamine Receptors... 96 Neurotensin Receptors ~... 100 Excitatory and Inhibitory Amino Acid Receptors... 100 References... 102 6. BEHAVIORAL RECOVERY OF FUNCTIONAL RESPONSES... 107 Unilateral Grafts and Circling Behavior... 107 Correlation of Turning Bias with Structural and Biochemical Parameters... 109 Dissociation of the Functional Contribution of Graft-Derived Axons and Dendrites in Rotational Asymmetry... 112 Enhancement of Motor Performance after Bilateral Transplantation... 118 References... 122 7. DIRECTIONS FOR FUTURE RESEARCH... 127 Introduction... 127 Analysis of Early Events in Graft-Host Interactions... l29 Trophic Considerations... 131 Neurotransmitter Mechanisms... 134 Supplemental Restoration of the Interrupted Nigro-Striato-Nigral Loop by StriatallNigral Double Grafts... 135 References... 138 INDEX... 145