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Synaptic Mechanisms Underlying Treatment of Depression and Bipolar Disorder Approved by Supervisory Committee

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Synaptic Mechanisms Underlying Treatment of Depression and Bipolar Disorder Approved by Supervisory Committee SYNAPTIC MECHANISMS UNDERLYING TREATMENT OF DEPRESSION AND BIPOLAR DISORDER APPROVED BY SUPERVISORY COMMITTEE __________________________________________ Lisa Monteggia, Ph.D. __________________________________________ Mark Goldberg, M.D. __________________________________________ Ege Kavalali, Ph.D. __________________________________________ Adrian Rothenfluh, Ph.D. Dedicated to my parents, Heinrich and Jo Ann, my brothers Chris and Adam and their families, my grandfather Linwood, my dog Lina, my boyfriend Jerry, and the rest of my family and friends for their unending love and support. ii SYNAPTIC MECHANISMS UNDERLYING TREATMENT OF DEPRESSION AND BIPOLAR DISORDER by ERINN SOMMER GIDEONS DISSERTATION Presented to the Faculty of the Graduate School of Biomedical Sciences The University of Texas Southwestern Medical Center at Dallas In Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY The University of Texas Southwestern Medical Center Dallas, Texas August 2016 iii Copyright by Erinn Sommer Gideons, 2016 All Rights Reserved iv ACKNOWLEDGEMENTS I would first like to thank my advisor Dr. Lisa Monteggia for her continual support, guidance, and patience during my time at UT-Southwestern. She has taught me how to be a successful scientist on many levels and is a true role model of a successful woman in science. I am extremely grateful for her mentorship and guidance. I would also like to thank Dr. Ege Kavalali not only for his experimental advice, but also for the many conversations about topics not dealing with science. I would not be an electrophysiologist without his influence. I want to think the current and past members of the Monteggia and Kavalali labs, especially Dr. Megumi Adachi, Dr. Anita Autry, and Pei-Yi Lin for taking me under their wings and teaching me about science and their continued friendship. In addition, I want to thank Dr. Melissa Mahgoub for being my rock in and out of lab. I would not have made it through the many steps and missteps of my Ph.D. without her unending support. I also want to thank my closest classmates Austin Reese and Aroon Karra for their friendship, conversations, and scientific insights as we navigated graduate school together. I would like to thank the members of my thesis committee, Dr. Adrian Rothenfluh, Dr. Mark Goldberg, and Dr. Ege Kavalali for their feedback and advice over the years. Many special thanks to Dr. Stuart Ravnik for his insight and advice on many topics, and encouragement of my time with STARS. Finally, I want to thank the University of Texas Southwestern Medical Center at Dallas, the Graduate School of Biomedical Sciences, and the entire Departments of Psychiatry and Neuroscience for providing top notch training, and the National Institute of Neurological Diseases and Stroke for funding and monetary support. Also thank you to UTSW WISMAC for travel support. I must also thank my gym family, including the members and coaches of Tiger’s Den Crossfit, Crossfit Bovine, and Heat Barbell Club, especially JD Thorne, Colin and Rebecca Bilodeau, Meghan Courtney, Dr. Blake Wu, Melissa McIntyre, and Calren Moore. I would never have survived the past four years without the love and friendship I have received from being a part of this extended family. In the end, I would not be where I am and who I am without the love and support of my family. Thank you to my parents Heinrich and Jo Ann for always believing in me and pushing me to succeed. Also, thank you to both of my brothers, Chris and Adam, I would not be the resilient person I am without both of your influences. Thank you also to Valli and Kerri for being the sisters that I always wanted. Thank you to all of the Carter Girls, especially the original Carter Girl my grandma Louise Garland Carter, for showing me how to be a strong woman in all aspects of life. I must also thank my Opi, Linwood Gideons, for his love and gracious character. I also want to thank my dog Lina for always putting a smile on my face at the end of a long day. Finally, I want to thank my boyfriend, Jerry Rodriguez, for your unending love, patience, and support during this stressful time. vi vii SYNAPTIC MECHANISMS UNDERLYING TREATMENT OF DEPRESSION AND BIPOLAR DISORDER Erinn S. Gideons, Ph.D. The University of Texas Southwestern Medical Center at Dallas, 2016 Supervising Professor: Lisa Monteggia, Ph.D. Ketamine is a N-methyl-D-aspartate receptor (NMDAR) antagonist that elicits rapid antidepressant responses in depressed patients. However, ketamine can also produce psychotomimetic effects, which limits its widespread use. The field has been exploring the mechanism of ketamine’s antidepressant action to assist in identifying drugs that may also produce the rapid effects without the potential side effects. Memantine is a NMDAR antagonist similar to ketamine in many regards but does not produce antidepressant effects in patients. Behavioral experiments in mice recapitulated clinical findings showing that ketamine but not memantine has antidepressant-like effects in two common antidepressant viii efficacy tests. Ketamine and memantine effectively blocked NMDAR-mediated mEPSCs in the absence of Mg2+. However, in physiological levels of extracellular Mg2+ only ketamine was able to block the NMDAR at rest. This difference between ketamine and memantine extended to intracellular signaling coupled to NMDAR at rest, in that ketamine inhibits the phosphorylation of eukaryotic elongation factor 2 (eEF2) resulting in an augmentation of subsequent protein expression of brain-derived neurotrophic factor (BDNF), that is not triggered by memantine These results demonstrate significant differences between the efficacies of ketamine and memantine on NMDA receptor mediated neurotransmission that impacts downstream intracellular signaling which is hypothesized as the trigger for rapid antidepressant responses. In a subsequent study, the therapeutic effect of lithium, a mood stabilizer and a common treatment for Bipolar Disorder (BD) is being investigated. Lithium has antidepressant and antimanic effects in patients with BD that can be recapitulated in animal models. While lithium is effective as a mood stabilizer, the mechanisms that underlie its therapeutic effect are unclear. Lithium has previously been shown to decrease the overall phosphorylation status of eEF2, which increases BDNF protein translation at the synapse. In this study, clinically effective doses of lithium were shown to result in antidepressant and antimanic-like effects in mice. We report that neither eEF2 kinase nor BDNF are necessary for the antidepressant effects of lithium. Additionally, eEF2 kinase is not required for the antimanic effects of lithium. However, BDNF appears to be necessary for lithium’s antimanic actions. To begin to understand whether this requirement of BDNF in lithium’s anti-manic action was due to synaptic changes we performed electrophysiological analysis on ix primary hippocampal neurons treated with lithium. Chronic lithium treatment caused a significant decrease in AMPAR-mEPSC amplitude, which requires both BDNF and its high affinity receptor, TrkB. Additionally, chronic lithium treatment caused a significant decrease in surface expression of the GluA1 subunit of the AMPAR. Collectively, this data demonstrates that BDNF is required for the antimanic effects of lithium, and that lithium’s effects on the regulation of AMPARs are BDNF and TrkB dependent, which may underlie its behavioral effect. x TABLE OF CONTENTS Dedication ........................................................................................................................... ii Acknowledgements ..............................................................................................................v Abstract ............................................................................................................................ viii Table of Contents ............................................................................................................... xi Prior Publications .............................................................................................................. xii List of Figures .................................................................................................................. xiii List of Abbreviations ....................................................................................................... xiv Chapter 1: Introduction ........................................................................................................1 Treatments for MDD and BD ..................................................................................4 Molecular mechanisms underlying Ketamine’s rapid antidepressant effects .......................................................................................................................7 Molecular mechanisms of lithium still under debate .............................................11 Concluding Remarks ..............................................................................................16 Chapter 2: Mechanisms Underlying the Differential Effectiveness of Memantine and Ketamine in Rapid Antidepressant Responses ................................................19 Introduction ............................................................................................................19 Materials and Methods ...........................................................................................21 Results ....................................................................................................................25
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