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PDE1B KO Confers Resilience to Acute Stress-Induced Depression-Like Behavior

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PDE1B KO Confers Resilience to Acute Stress-Induced Depression-Like Behavior PDE1B KO confers resilience to acute stress-induced depression-like behavior A dissertation submitted to the Graduate School of the University of Cincinnati in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Molecular and Developmental Biology Program of the College of Medicine by Jillian R. Hufgard B.S. Rose-Hulman Institute of Technology April 2017 Committee Chair: Charles V. Vorhees, Ph.D. ABSTRACT Phosphodiesterases (PDE) regulate secondary messengers such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) by hydrolyzing the phosphodiester bond. There are over 100 PDE proteins that are categorized into 11 families. Each protein family has a unique tissue distribution and binding affinity for cAMP and/or cGMP. The modulation of different PDEs has been used to treat several disorders: inflammation, erectile dysfunction, and neurological disorders. Recently, PDE inhibitors were implicated for therapeutic benefits in Alzheimer’s disease, depression, Huntington’s disease, Parkinson’s disease, schizophrenia, and substance abuse. PDE1B is found in the caudate-putamen, nucleus accumbens, dentate gyrus, and substantia nigra–areas linked to depression. PDE1B expression is also increased after acute and chronic stress. Two ubiquitous Pde1b knockout (KO) mouse models, both removing part of the catalytic region, decreased immobility on two acute stress tests associated with depression-like behavior; tail suspension test (TST) and forced swim test (FST). The decreases in immobility suggest resistance to depression-like behavior, and these effects were additive when combined with two current antidepressants, fluoxetine and bupropion. The resistance to induced immobility was seen when PDE1B was knocked down during adolescence or earlier. Expression of Pde1b mRNA and protein showed that Pde1b is localized to dopaminergic and glutamatergic post-synaptic cells. Serotonin transporter, dopamine transporter, and dopamine receptor D1a (Drd1a) Cre drivers were tested and only Pde1b KO in Drd1a specific cells was sufficient to reproduce the immobility phenotype in TST. Intrastriatal injections of dopamine receptor, D1, agonist (SKF38393) and antagonist (SCH23390) revealed an additive immobility effect of Pde1b KO and dopamine receptor antagonism. The D1 agonist reversed the genotype immobility phenotype. The results suggest that reduction of PDE1B causes resistance to acute stress-induced depression-like behaviors through the dopamine pathways. ii iii ACKNOWLEDGEMENTS I would like to thank my advisor, Dr. Charles Vorhees, for providing the opportunity to learn and perform research in his laboratory, his encouragement and guidance, and for his dedication to leading his students through the roller coaster that is graduate school. I would also like to thank Dr. Michael Williams and Dr. Matthew Skelton for their constant technical support throughout this entire process. In addition I would like to thank the Vorhees, Williams, and Skelton laboratory members both past and present, especially Chiho Sugimoto for her willingness to always help. The entirety of my committee also deserves significant acknowledgements for their advice and guidance of the following research. I would like to thank my family for their encouragement and support in this process and in life. An additional thank you is extended to those in Cincinnati, both friends and dogs, that became my family during this process. Their companionship, lovingness and confidence in me provided the strength necessary to complete this process. And lastly, I would like to thank Shaun Wendel for being my rock during this process and his constant reminders to make sure I enjoy whatever I am doing. iv TABLE OF CONTENTS ABSTRACT ................................................................................................................................. ii ACKNOWLEDGEMENTS .......................................................................................................... iv TABLE OF CONTENTS ............................................................................................................. 1 LIST OF TABLES AND FIGURES .............................................................................................. 4 LIST OF SYMBOLS ................................................................................................................... 6 CHAPTER 1 The Role of Phosphodiesterases in Major Depressive Disorder ................................................. 8 Major Depressive Disorder ..................................................................................................... 9 Brain development in the pathophysiology of depression ......................................................10 Current antidepressant treatments ........................................................................................13 Postsynaptic targets for MDD treatment ................................................................................14 Regulation of secondary messengers by phosphodiesterases ..............................................16 PDE1 .................................................................................................................................17 PDE4 .................................................................................................................................19 PDE10A .............................................................................................................................22 Phosphodiesterases in dopaminergic pathways ....................................................................24 Conclusion ............................................................................................................................25 References ............................................................................................................................27 Tables ...................................................................................................................................36 Figures ..................................................................................................................................38 1 CHAPTER 2 Phosphodiesterase-1b (Pde1b) knockout mice are resistant to forced swim and tail suspension test induced immobility and show upregulation of Pde10a* .......................................................41 Abstract .................................................................................................................................42 Introduction ...........................................................................................................................43 Methods ................................................................................................................................45 Results ..................................................................................................................................50 Discussion .............................................................................................................................53 References ............................................................................................................................58 Tables ...................................................................................................................................66 Figures ..................................................................................................................................69 Acknowledgments .................................................................................................................74 CHAPTER 3 Phosphodiesterase-1b deletion confers depression-like behavioral resistance separate from stress-related effects in mice .....................................................................................................75 Abstract .................................................................................................................................76 Introduction ...........................................................................................................................77 Methods ................................................................................................................................78 Results ..................................................................................................................................85 Discussion .............................................................................................................................87 References ............................................................................................................................91 Figures ..................................................................................................................................99 2 Acknowledgements ............................................................................................................. 113 CHAPTER 4 PDE1B is implicated in dopamine pathways and its deletion in dopamine receptor 1a cells confers an immobility-resistant phenotype in forced swim and tail suspension tests ............... 114 Abstract ............................................................................................................................... 115 Introduction ......................................................................................................................... 116 Methods .............................................................................................................................
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