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Characterization and Development of a Stroke Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2010 Characterization and development of a stroke-induced model of acquired epilepsy in organotypic hippocampal slice cultures: role of the cannabinoid CB1 receptors in modulation of neuronal excitation and inhibition Julie Ziobro Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Neurosciences Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/145 This Dissertation is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. CHARACTERIZATION AND DEVELOPMENT OF A STROKE-INDUCED MODEL OF ACQUIRED EPILEPSY IN ORGANOTYPIC HIPPOCAMPAL SLICE CULTURES: ROLE OF THE CANNABINOID CB1 RECEPTORS IN MODULATION OF NEURONAL EXCITATION AND INHIBITION A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University. by Julie Marie Ziobro Bachelor of Science Michigan State University December 2004 Advisor: Dr. Robert J. DeLorenzo, M.D., Ph.D., M.P.H. George Bliley Professor of Neurology Professor, Biochemistry, and Pharmacology and Toxicology Virginia Commonwealth University Richmond, Virginia November 2010 ii ACKNOWLEDGEMENTS Though many people have played a role in helping me achieve my professional and personal goals, my parents, Tim and Sue, have always shown unwavering support for everything I set out to accomplish. I dedicate my work to them, as they have dedicated much of their lives to helping me succeed. I cannot express enough gratitude for their support and encouragement, even at the times that they don’t really understand what I’m working for. I’m also extremely grateful for the support from the rest of my family and friends who always help me see the big picture. I’d like to thank my advisor, Dr. Robert DeLorenzo for his support and encouragement, even when the science wasn’t working. I truly appreciate that he allowed me to exercise creativity and follow my own interests. I am grateful to my committee members; Drs. Laura Sim-Selley, Sandra Welch, Kimberle Jacobs, and Linda Phillips for sharing their expertise and asking questions to help me think more critically about my science, I also truly appreciate the technical help and skills learned from Dr. Jacobs while rotating in her lab. I’d also like to thank Dr. John Bigbee for his dedication to his students as the director of the Neuroscience graduate program and Dr. Gordon Archer for his tireless work supporting the MD/PhD program. Members of the DeLorenzo lab have been crucial to my work and have made a wonderful impact on my life. First and foremost, I must thank Dr. Laxmikant Deshpande for his guidance, support, and assistance in most every aspect of my project. His willingness to answer questions, help solve problems, and edit (often) have been instrumental to my science and my personal growth as a researcher – and the fact that he does it with a smile makes him a wonderful person to work with! I’d also like to express sincere thanks to Drs. Robert Blair and Katherine Falenski whose previous work piqued my interest in their field of expertise and whose guidance has let me explore it as well. Thanks also to Dr. Dawn Carter for her help in the lab, as well as the pre-work morning runs! I would also like to thank past lab members Dr. Sompong Sombati and Elisa Attkisson. Dr. Nisha Nagarkatti has also been a wonderful friend since I joined the lab and I appreciate her advice and support as I “follow in her footsteps” so to speak! Finally, on a personal note, I’d like to thank my fellow MD/PhD students, especially Frances Saccoccio, Steve Bakos, and Bret Adams. It’s been wonderful to have the support of great friends going through similar experiences. Last, but definitely not least, I must thank Danny for his love and support for the past four years. His tireless work to improve our home and our lives has made it all the more possible for me to pursue my goals. I cannot express enough gratitude to him for helping me keep life in perspective. Lame as it may be, I also must thank my dogs, Melvin and Penny, who always know how to keep me smiling. iii TABLE OF CONTENTS LIST OF FIGURES ..............................................................................................................vii LIST OF ABBREVIATIONS ................................................................................................ix ABSTRACT ..........................................................................................................................xi I. GENERAL INTRODUCTION .........................................................................................1 A. Epilepsy ................................................................................................................1 B. Current treatments of epilepsy .............................................................................4 C. Stroke induced acquired epilepsy .........................................................................5 D. Glutamate in stroke ..............................................................................................6 E. Current models of epileptogenesis ........................................................................11 F. Organotypic hippocampal slice cultures ...............................................................14 G. History of Cannabis use to treat seizures ..............................................................16 H. The endocanabinoid system ..................................................................................18 I. Depolarization induced suppression of inhibition (DSI) and excitation (DSE) .....27 J. ∆-9-THC’s anti-seizure effects ...............................................................................31 K. Endocannabinoid system: protector against excitotoxicity ..................................33 L. Anti-seizure effects are CB1 mediated .................................................................35 M. CB1 receptor plasticity in disease states ..............................................................37 N. Cannabinoid pro-convulsant effects and tolerance ...............................................42 O. Future directions, potential therapies ....................................................................44 P. Summary and rationale ..........................................................................................46 Q. Central hypothesis ................................................................................................48 iv II. CHAPTER 1: 4-AMINOPYRIDINE TREATMENT CAUSES RECURRENT SPONTANEOUS SEIZURES IN AN ORGANOTYPIC HIPPOCAMPAL SLICE CULTURE MODEL OF ACQUIRED EPILEPSY ..............................................................50 A. Introduction ..........................................................................................................50 B. Methods .................................................................................................................52 Organotypic hippocampal slice culture preparation .......................................... 52 Field potential recording with acute 4-AP application .....................................53 4-AP injury........................................................................................................54 Neuronal death assay ........................................................................................54 Field potential recording for delayed seizures ..................................................55 Data analyses ....................................................................................................56 C. Results ...................................................................................................................59 4-AP acutely causes seizure activity .................................................................59 4-AP exposure causes cell death .......................................................................59 4-AP induces long-term changes in OHSC excitability ...................................60 D. Discussion .............................................................................................................73 III. CHAPTER 2: AN ORGANOTYPIC HIPPOCAMPAL SLICE CULTURE MODEL OF EXCITOTOXIC INJURY INDUCED SPONTANEOUS RECURRENT EPILEPTIFORM DISCHARGES .........................................................................................77 A. Introduction ...........................................................................................................77 B. Methods .................................................................................................................79 Organotypic hippocampal slice culture preparation .........................................79 Glutamate injury ...............................................................................................80 Neuronal death assay ........................................................................................80 Field potential recording ...................................................................................81 Intracellular recording .......................................................................................82 Drug perfusion ..................................................................................................83
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