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Probing the Role of Neuronal Nicotinic Acetylcholine Receptors in Modulating in Vitro Hippocampal Network Dynamics

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Probing the Role of Neuronal Nicotinic Acetylcholine Receptors in Modulating in Vitro Hippocampal Network Dynamics PROBING THE ROLE OF NEURONAL NICOTINIC ACETYLCHOLINE RECEPTORS IN MODULATING IN VITRO HIPPOCAMPAL NETWORK DYNAMICS A Dissertation submitted to the Faculty of the Graduate School of Arts and Sciences of Georgetown University in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Pharmacology By Sarra Djemil, M.S. Washington, D.C. April 5, 2018 Copyright 2018 by Sarra Djemil All Rights Reserved ii PROBING THE ROLE OF NEURONAL NICOTINIC ACETYLCHOLINE RECEPTORS IN MODULATING IN VITRO HIPPOCAMPAL NETWORK DYNAMICS Sarra Djemil, M.S. Thesis Advisor: Rhonda Dzakpasu, Ph.D. ABSTRACT Nicotinic acetylcholine receptors (nAChRs), the first receptors to be identified, play varying and essential roles throughout the CNS. Both the endogenous ligand, acetylcholine, and exogenous ligand, nicotine, have been found to induce a wide range of effects on neurotransmitters. On the systems level, nAChRs are involved in the maintenance of hippocampal gamma and theta oscillations, and these oscillations are associated with cognitive functions, facilitating attention, learning and memory. As such, the aberrant nicotinic transmission has been implicated in many neuropathological and psychiatric disorders as they impact the dynamics of select neuronal oscillations such as Alzheimer’s disease, Parkinson’s disease, and schizophrenia. In the following studies, I used cultured hippocampal neurons plated on multi-electrode arrays to investigate how nicotine modulates spiking and network bursting activity, the latter of which is necessary for reliable information transmission in the hippocampus. In the first study, intermediate and high doses of nicotine were used as a tool to investigate the impact of activation and desensitization of nicotinic receptors on network dynamics. My results suggest that the high dose of nicotine activates nAChRs, which enhances firing of action potentials as well as facilitates synchronized bursting activity, whereas the intermediate dose had minimal effects on network spiking activity but appeared to desensitize iii the network to a higher dose. These effects are absent in hippocampal networks where nAChRs were initially treated with a low nicotine concentration, suggesting that stochastic activation of nAChRs may protect the network from pathological synchronization. The last part of my thesis focuses on determining the nAChR subtypes involved in nicotine’s effect on hippocampal network dynamics. To elucidate their contribution to the observed effects, I blocked the conductance of discrete nAChR subtypes and then stimulated the network with nicotine. My results suggest that β4-containing nAChRs are necessary for the observed increases in spiking, bursting and synchrony, whereas α7 nAChRs play a role in mediating the impact of nicotine. Lastly, to address the role of synaptic N-methyl-D-aspartate receptors (NMDARs) and group I metabotropic glutamate receptors (mGluRs) in these dynamics, I blocked either NMDARs or group I mGluRs, then stimulated the network with nicotine. iv ACKNOWLEDGMENTS “I will never stop being ravenously hungry for science, no matter how well it feeds me.” Hope Jahren, Lab Girl Many people have played an instrumental role in my development as a scientist, and to whom I feel a deep sense of gratitude. To attempt to do justice to the gratitude, I feel towards these individuals would make this section the longest in my thesis. Therefore, these acknowledgments reflect a sense and not the magnitude of gratitude that I feel. First and foremost, I would like to thank my thesis advisor, Dr. Rhonda Dzakpasu. Dr. Dzakpasu’s brimming passion for science makes research in her lab a continuous source of excitement. She is always willing to consider new ideas and quick to embrace them. I feel that Dr. Dzakpasu pushed my abilities as a scientist by prompting me to explore, encouraging me to be independent, and to develop my own ideas and creativity in research. For these reasons, and for many more, I will always be grateful for her mentorship. I have been very fortunate to be a member of the Pharmacology and Physiology Department, where research is highly collaborative, and the faculty, staff, and students are incredibly helpful. In particular, I would also like to thank my thesis committee members Dr. Gerard Ahern, Dr. Kathy Conant, Dr. Ken Kellar, Dr. Dan Pak, and Dr. Barry Wolfe, whose support and advice was pivotal to my success. I am especially thankful to Dr. Ahern for teaching me Ca2+ imaging. To Dr. Conant for graciously agreeing to serve as my outside committee member. To Dr. Kellar for teaching me how to perform radioligand neurotransmitter release assays. To Dr. Pak for teaching me how to culture primary neurons but also shared with me his hippocampal cultures. To Dr. Wolfe for his expertise in experimental design and statistical analysis, and for serving as my v committee chair. I also appreciate the contributions of Dr. Bob Yasuda, who as far as I am concerned served as an additional committee member. Importantly, many of experiments that I conducted could not have been performed without the generosity Dr. Stefano Vicini, who kindly allowed us the use of his MEA2100 system. No words will sufficiently convey my gratitude for his generosity. My understanding of pharmacology has grown exponentially since the day that I joined the Ph.D. program. For this growth, I must thank the late Dr. Jarda Wroblewski, a great teacher, and pharmacologist. I am forever indebted to him and to Dr. Wolfe for teaching me the principles of pharmacology. I would also like to specifically thank Dr. Xin Chen, whose substantial insights into neural network dynamics field have contributed to this project. I am also grateful for the help and support I received from Dr. Gustavo Rodriguez, who was generally helpful when I first joined the lab. I will always be grateful to the many friends that I made in Georgetown who made the good times more joyful, and the difficult times more bearable. I would also like to thank Dr. Nancy L. Greenbaum, my undergraduate mentor, as well as Dr. Victoria Luine and Janerie Rodriguez, of the MBRS-RISE program at Hunter College, for believing in me, and for giving me the opportunity and the means to flourish as a scientist. My parents, husband, sisters, brothers, and children have been an amazing support system. They understand my passion for science, and always encourage me to strive to be the best that I can be. I am especially thankful to my parents for teaching me the value of hard work and the art of preserverence. Above all, Ahmed my husband and best friend has been a constant source of inspiration and support. He understands me like no other and is always there for me when I am in need. Thank you for all you have done. vi DEDICATION The research and writing of this thesis is dedicated to everyone who helped along the way. Thank you, Sarra Djemil vii TABLE OF CONTENTS CHAPTER I: INTRODUCTION .................................................................................................... 1 Nicotinic Acetylcholine Receptors: Discovery ........................................................................... 2 Nicotinic Acetylcholine Receptors: Structure ............................................................................ 2 Nicotinic Acetylcholine Receptors: Pharmacology .................................................................... 3 Nicotinic Acetylcholine Receptors: Localization Within the Hippocampus .............................. 6 The Functional Role of Hippocampal Nicotinic Cholinergic Transmission .............................. 8 The Role of nAChRs in Modulating in vitro Hippocampal Neuronal Network Dynamics ....... 9 Studying Neuronal Networks In Vitro ...................................................................................... 10 Introduction to Thesis Project ................................................................................................... 11 CHAPTER II: MATERIALS AND METHODS .......................................................................... 17 Cell Culture ............................................................................................................................... 18 Multi-electrode Array Recordings ............................................................................................ 18 Data Acquisition ................................................................................................................... 18 Drugs ..................................................................................................................................... 19 Drug Application: Chapter III ............................................................................................... 19 Drug Application: Chapter IV .............................................................................................. 20 Data Analysis ........................................................................................................................ 20 Statistics ................................................................................................................................ 22 CHAPTER III: STOCHASTIC ACTIVATION OF NICOTINIC ACETYLCHOLINE RECEPTORS PREVENTS INDUCED SYNCHRONIZATION WITHIN IN VITRO HIPPOCAMPAL NETWORKS ................................................................................................... 24 Introduction ............................................................................................................................... 25 Results ......................................................................................................................................
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