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Effects of Chronic Oxidative Stress on TRPM2 and TRPC3 Channels: Potential Implications for Bipolar Disorder

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Effects of Chronic Oxidative Stress on TRPM2 and TRPC3 Channels: Potential Implications for Bipolar Disorder Effects of Chronic Oxidative Stress on TRPM2 and TRPC3 Channels: Potential Implications for Bipolar Disorder by Angela Selina Roedding A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Pharmacology and Toxicology Department University of Toronto © Copyright by Angela Selina Roedding 2013 Effects of Chronic Oxidative Stress on TRPM2 and TRPC3 Channels: Potential Implications for Bipolar Disorder Angela Selina Roedding Doctor of Philosophy Department of Pharmacology and Toxicology University of Toronto 2013 Abstract Intracellular calcium and oxidative stress dyshomeostasis, which can be highly interactive, occur in bipolar disorder (BD), but the pathogenesis of these disturbances is unknown. The transient receptor potential (TRP) melastatin subtype 2 (TRPM2) and canonical subtype 3 (TRPC3) calcium-permeable non-selective ion channels, already implicated in BD, are involved in calcium and oxidative stress signalling. Thus, I sought to determine whether the expression and function of these channels are modulated by oxidative stress exposure in rat cortical neurons, astrocytes, and in human B lymphoblast cell lines (BLCLs), a cell model that reports diagnostically relevant abnormalities in BD. This thesis work demonstrated that TRPC3 expression and function are decreased after chronic, but not acute oxidative stress exposure in both human and rat cell models. TRPM2 expression, on the other hand, was increased after both acute and chronic stressor treatments in rat cortical neurons. In BLCLs, TRPM2-mediated calcium entry was blunted although no ii difference in TRPM2 mRNA expression was detected. Moreover, BLCLs from BD-I patients exhibited greater susceptibility to cell death and a differential sensitivity of TRPM2-mediated calcium influx to acute oxidative stress compared with healthy subjects, further supporting reduced cellular resilience in the pathophysiology of BD-I. I also demonstrated that TRPC3 protein is expressed in human brain from 8 days to 83 years old supporting an ongoing role in the developing and adult human brain. These findings support an important role for TRPM2 and TRPC3 in sensing and responding to oxidative stress, and in transducing oxidative stress signalling to intracellular calcium homeostatic and cellular stress responses, which have been implicated in the pathophysiology of BD. Finally, this work has highlighted an inherent difference in TRPM2 channel functionality in BD type I subjects compared with controls, adding functional evidence to the genetic and differential expression findings implicating TRPM2 dysfunction in BD. iii Acknowledgments The completion of my PhD program would not have been possible without the help and support of numerous people. First and foremost, Dr. Jerry Warsh, I would like to express my utmost gratitude for all of the guidance and instruction you have given me throughout my training. You gave me the opportunity to develop and hone my skills as a scientist under your excellent tutelage. Your mentorship and confidence in my ability enabled me to successfully tackle grant writing, project management, scientific writing, and mentorship of several excellent undergraduate project students. Dr. Peter Li was also instrumental in my training and advised me on elements of study design, acting as a valuable sounding board. I was also fortunate to work with a wonderful group of talented staff and students in the lab. Many thanks to Marty Green for sharing her RT-PCR expertise and her general resourcefulness around the lab; and to Clarissa Pasiliao for all of her help with the neuronal cell cultures and her companionship during the dissection process. I would also like to thank all of the undergraduate project students that helped in the execution of my project, Andrew Gao, Alex Wu, Wynne Au-Yeung, Tiffany Scarcelli, and Lydia Zhou, for their hard work and friendship. I really enjoyed sharing with you my enthusiasm for science and you taught me about how rewarding working as a team can be. I also really enjoyed working alongside Michael Tseng, Takuji Uemura, Steven Tong and Dharshini Ganeshan. Finally, the support of my family and friends has been vital to the successful completion of my research program. The strength and support of my loving husband, Landon Roedding, has allowed me to pursue my interests and given me the strength to continue after the birth of our beautiful daughter. I would also like to thank my wonderful little girl, Grace June Roedding, for her angelic temperament that enabled me to continue and complete my thesis writing after her arrival. The love and support of my families, both Harrison and Roedding, has given me the confidence (and child care) I needed to reach my goals. I am truly lucky to have such a wonderful group of people in my life. iv Table of Contents Acknowledgments .......................................................................................................................... iv Table of Contents ............................................................................................................................ v List of Tables.................................................................................................................................. ix List of Figures ................................................................................................................................. x List of Appendices ........................................................................................................................ xii List of Abbreviations.................................................................................................................... xiii 1 Introduction ................................................................................................................................ 1 1.1 Bipolar Disorder .................................................................................................................. 2 1.2 Evidence of altered cellular resilience in the neuropathology of bipolar disorder ............. 4 1.3 Oxidative stress and mitochondrial dysfunction in bipolar disorder ................................ 10 1.4 Calcium signalling disturbances in bipolar disorder ......................................................... 17 1.5 Transient receptor potential channels................................................................................ 19 1.5.1 TRPC channels ...................................................................................................... 22 1.5.2 TRPM channels ..................................................................................................... 27 1.5.3 TRP channels and oxidative stress ........................................................................ 33 1.6 Cellular models used for the study of bipolar disorder pathophysiology ......................... 36 1.7 Hypotheses and objectives ................................................................................................ 38 2 TRPC3 Protein is Expressed Across the Lifespan in Human Prefrontal Cortex and Cerebellum ............................................................................................................................... 41 2.1 Abstract ............................................................................................................................. 42 2.2 Introduction ....................................................................................................................... 42 2.3 Methods ............................................................................................................................. 44 2.3.1 Subjects ................................................................................................................. 44 v 2.3.2 Preparation of brain samples ................................................................................. 44 2.3.3 SDS-PAGE and Western blotting. ........................................................................ 44 2.3.4 Statistics ................................................................................................................ 45 2.4 Results ............................................................................................................................... 46 2.4.1 Subject demographics ........................................................................................... 46 2.4.2 TRPC3 immunodetection specificity and quantification ...................................... 48 2.4.3 TRPC3 expression in human prefrontal cortex and cerebellum ........................... 48 2.5 Discussion ......................................................................................................................... 52 3 Chronic Oxidative Stress Modulates TRPC3 and TRPM2 Channel Expression and Function in Rat Primary Cortical Neurons: Relevance to the Pathophysiology of Bipolar Disorder ....................................................................................................................... 54 3.1 Abstract ............................................................................................................................. 55 3.2 Introduction ....................................................................................................................... 56 3.3 Methods ............................................................................................................................. 58 3.3.1 Preparation of rat cortical neuron cultures ...........................................................
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