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University of Florida Thesis Or Dissertation Formatting ANIMAL MODELS AND PATHOPHYSIOLOGY OF RAPID-ONSET DYSTONIA- PARKINSONISM AND RESTLESS LEGS SYNDROME By MARK P. DEANDRADE A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2014 © 2014 Mark P. DeAndrade To my parents, Avito and Neola, for their love and support; my brothers, Kevin and James, for their inspiration and motivation to strive for excellence; and in memory of my grandparents Louis and Helena Pereira de Andrade and Michael and Lydia Abreo. ACKNOWLEDGMENTS I would like to thank first and foremost Dr. Yuqing Li and the past and present members of his laboratory, including but not limited to, Dr. Fumiaki Yokoi, Dr. Lin Zhang, Dr. Li Zhang, Chad C. Cheetham, Atbin Doroodchi, Miki Jino, and Kelly Dexter, for all their assistance and guidance. I would like to thank my numerous collaborators who have helped make this work possible. Dr. Thomas van Groen assisted in teaching me how to conduct several of the behavioral experiments in this dissertation, alongside providing the equipment necessary to carry the experiments out. Dr. J. David Sweatt, Dr. Steven N. Roper, and their respective laboratories helped in conducting the electrophysiological experiments. Drs. J. Michael Wyss and Ning Peng helped in the implantation of the biopotential electrodes in the polysomnography and electromyographic studies, and provided the equipment to carry out and analyze the data from these experiments. Dr. Karen L. Gamble provided the wheel running setup used for the Btbd9 knockout animal studies, assisted in analyzing the data from these experiments, and served on my committee when I was a Master degree student at the University of Alabama at Birmingham. Dr. Erica L. Unger assisted in analyzing striatal tissue for iron levels by atomic absorption spectroscopy. Dr. Jerry B. Lingrel graciously supplied the Atp1a3 knockout mice. I would like to thank the members of the Departments of Neurology and Neuroscience, in particular Drs. Tetsuo Ashizawa, Lucia Notterpek, Wolfgang J. Streit, Jennifer Bizon, Harry S. Nick, Jada Lewis, Ms. Linda Kilgore, Ms. Shuri Pass, and Ms. Betty J. Streetman, for their advice, support, and patience. I would also like to thank Dr. Paul Gulig and his staff in the Office of Graduate Education in the College of Medicine, in particular Ms. Teresa Richardson and Ms. Susan Gardner, for their advice and 4 support. I would like to thank Drs. Pedro Fernandez-Funez, Suming Huang, Ronald J. Mandel, and Michael S. Okun for serving on my graduate supervisory committee, provide useful insight, and positive critiques with the aim of making me a better scientist. I have a heartfelt appreciation to Mónica Santisteban for her invaluable and indispensible support, sage advice, and constant encouragement throughout my graduate studies. Lastly, I would like to thank the funding sources for Dr. Yuqing’s laboratory [NIH NINDS (NS47692, NS54246, NS57098, NS47466, NS37406 and NS65273) and startup funds from the Department of Neurology (UAB, UF) and Tyler’s Hope for a Dystonia Cure, Inc.]. Without the above-mentioned people and funding sources, the work in this dissertation would not be possible. 5 TABLE OF CONTENTS page ACKNOWLEDGMENTS .................................................................................................. 4 LIST OF TABLES ............................................................................................................ 9 LIST OF FIGURES ........................................................................................................ 10 LIST OF ABBREVIATIONS ........................................................................................... 12 ABSTRACT ................................................................................................................... 15 CHAPTER 1 INTRODUCTION .................................................................................................... 17 Animal Models ........................................................................................................ 17 Rapid-Onset Dystonia-Parkinsonism ...................................................................... 18 Clinical Features and Classification .................................................................. 18 Dopaminergic System in Dystonia .................................................................... 19 Genetics of Rapid-Onset Dystonia-Parkinsonism ............................................. 21 Alternating Hemiplegia in Childhood and Rapid-Onset Dystonia- Parkinsonism ................................................................................................. 22 Restless Legs Syndrome ........................................................................................ 22 Clinical Features, Prevalence, and Comorbidities ............................................ 22 Dopaminergic System in Restless Legs Syndrome .......................................... 23 Iron Homeostasis in Restless Legs Syndrome ................................................. 25 Genetics of Restless Legs Syndrome .............................................................. 26 Goals and Significance ........................................................................................... 27 2 MATERIALS AND METHODS ................................................................................ 28 General Considerations .......................................................................................... 28 Mice ........................................................................................................................ 28 Atp1a3 Knockout Mice ..................................................................................... 28 Btbd9 Knockout Mice ....................................................................................... 29 Behavior Paradigms ............................................................................................... 30 Restraint Stress Protocol .................................................................................. 30 Beam-walking Test ........................................................................................... 31 Rotarod Test ..................................................................................................... 31 Grip Strength Test ............................................................................................ 32 Open Field Test ................................................................................................ 32 Wheel Running Test ......................................................................................... 32 Tail Flick Test ................................................................................................... 33 Fear Conditioning Memory Assessment ........................................................... 34 Polysomnography ............................................................................................. 35 6 Electromyography ............................................................................................ 36 High Performance Liquid Chromatography ............................................................. 37 Iron Measurements ................................................................................................. 38 Colorimetric Assay for Serum Iron .................................................................... 38 Atomic Absorption Spectroscopy for Iron in Striatal Tissue .............................. 39 Electrophysiology .................................................................................................... 39 Field Recordings .............................................................................................. 39 Whole-cell Recordings...................................................................................... 40 Western Blot ........................................................................................................... 42 RT-PCR .................................................................................................................. 43 Statistics ................................................................................................................. 44 3 PART1: CHARACTERIZATION OF ATP1A3 KNOCKOUT MICE AS A MODEL FOR RAPID-ONSET DYSTONIA-PARKINSONISM ............................................... 45 Motor Deficits in Female Heterozygous Atp1a3 Mutant Mice ................................. 45 Beam-walking test ............................................................................................ 45 Accelerated Rotarod Test ................................................................................. 46 Grip Strength Test .................................................................................................. 46 Activity Levels of Heterozygous Atp1a3 Mutant Mice ............................................. 46 Spontaneous activity levels .............................................................................. 46 Voluntary activity levels .................................................................................... 47 Sensory Deficits in Heterozygous Atp1a3 Mutant Mice .......................................... 47 No Alterations in Striatal Neurochemical Levels ..................................................... 48 4 PART 2: CHARACTERIZATION OF BTBD9 KNOCKOUT MICE AS A POTENTIAL MODEL FOR RESTLESS LEGS SYNDROME .................................. 55 Generation of Btbd9
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