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Learning, Memory, and Synaptic Plasticity in Alzheimer’S Model Mice

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Learning, Memory, and Synaptic Plasticity in Alzheimer’S Model Mice LEARNING, MEMORY, AND SYNAPTIC PLASTICITY IN ALZHEIMER’S MODEL MICE by JASON KNIGHT CLARK (Under the Direction of John J. Wagner) ABSTRACT Alzheimer’s disease (AD) is a neurodegenerative disease of aging thought to be initiated by production of Amyloid-β peptide, which leads to synaptic dysfunction and progressive memory loss, and the eventual formation of β-Amyloid plaques and neurofibrillary Tau tangles. Working memory is one of the first cognitive impairments in AD. We therefore wanted to explore the cellular mechanisms underlying working memory impairments in AD utilizing a well-known triple transgenic mouse model of Alzheimer’s disease (3xTg-AD) carrying mutations in APP, PS1, and Tau. We evaluated working memory using an 8-arm radial maze, and synaptic transmission and plasticity using an ex vivo hippocampal slice preparation to measure field Excitatory Post-Synaptic Potentials (fEPSP) in the CA1 region of ventral hippocampus. Unexpectedly, young 3xTg-AD mice at 3 months of age, typically considered to be presymptomatic, were significantly impaired in the spatial working memory task compared to Nontransgenic (NonTg) control mice. Measurements of fEPSPs to evaluate Long-Term Potentiation (LTP) as an indicator of long-term synaptic plasticity showed the NMDA receptor-dependent component of LTP (NMDAR LTP) was reduced in 3xTg-AD mice compared to NonTg mice. The remaining non-NMDA receptor- dependent component of LTP (non-NMDAR LTP) however was increased, resulting in a total LTP that was not different between 3xTg-AD and NonTg mice. At 8 months of age, 3xTg-AD mice were again significantly impaired in the spatial working memory task, and NMDAR LTP was again reduced in 3xTg-AD mice. The non-NMDAR LTP however was also reduced in 3xTg-AD mice, resulting in a total LTP that was now reduced in 3xTg- AD mice. The majority (>90%) of non-NMDAR LTP is mediated by Voltage-Dependent Calcium Channels (VDCC), and attempts to block LTP using NMDAR and VDCC antagonists were unsuccessful, indicating 3xTg-AD mice have compensatory mechanisms for LTP expression that occur independently of NMDAR or non-NMDAR dependent mechanisms. In addition, 3xTg-AD mice also showed impairments in short- term synaptic plasticity and basal synaptic transmission at both 3 and 8 months of age. These impairments in synaptic transmission and plasticity coincide with impairments in spatial working memory, and understanding the nature of these altered mechanisms may lead to therapeutic targets for disorders such as AD. INDEX WORDS: Alzheimer’s disease, Synaptic Plasticity, Working Memory, LTP, Radial Maze, Amyloid-β, Hirano Body LEARNING, MEMORY, AND SYNAPTIC PLASTICITY IN ALZHEIMER’S MODEL MICE by JASON KNIGHT CLARK B.S., Georgia Southern University, 1998 M.S., The University of Georgia, 2007 A Dissertation Submitted to the Graduate Faculty of The University of Georgia in Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY ATHENS, GEORGIA 2016 © 2016 Jason Knight Clark All Rights Reserved LEARNING, MEMORY, AND SYNAPTIC PLASTICITY IN ALZHEIMER’S MODEL MICE by JASON KNIGHT CLARK Major Professor: John J. Wagner Committee: Julie Coffield James Lauderdale Electronic Version Approved: Suzanne Barbour Dean of the Graduate School The University of Georgia May 2016 DEDICATION To my family, for their support, encouragement, and patience. iv ACKNOWLEDGEMENTS I would like to begin by acknowledging and thanking Dr. John Wagner for the opportunity to learn, grow, and develop as a scientist under his guidance and direction throughout my graduate training. To the members of the Wagner Lab, whose discussions and contributions have been an invaluable source of creative thought. I would also like to thank Dr. Marcus Fechheimer and Dr. Ruth Furukawa. A portion of this work has been in collaboration with their research group, and they have been instrumental in the completion of this work. I would like to thank the members of my graduate committee, Dr. Jim Lauderdale and Dr. Julie Coffield, whose input is always valuable, and whose discussions always lead to new perspectives of my work. I would also like to thank the faculty and staff of the UGA department of Physiology and Pharmacology, who were always willing to help out in any way necessary, providing technical support and advice, and whose interactions made my time at UGA an enjoyable and engaging experience. Thank you all. v TABLE OF CONTENTS Page ACKNOWLEDGEMENTS ............................................................................................... v CHAPTER 1 INTRODUCTION AND LITERATURE REVIEW .............................................. 1 1.1 Historical Perspective ......................................................................... 1 1.2 General Overview of Alzheimer’s Disease .......................................... 3 1.3 General Overview of Learning and Memory ..................................... 16 1.4 Memory and Synaptic Plasticity ........................................................ 22 1.5 Cellular Mechanisms of Synaptic Plasticity ....................................... 27 1.6 NMDA Receptors in Complex Learning and Memory ....................... 41 1.7 Synaptic Impairment in Alzheimer’s Disease .................................... 50 1.8 Final Thoughts .................................................................................. 61 References .............................................................................................. 64 Figures ................................................................................................... 102 2 ALTERATIONS IN SYNAPTIC PLASTICITY COINCIDE WITH DEFICITS IN SPATIAL WORKING MEMORY IN 3xTg-AD MICE .................................... 118 Abstract .................................................................................................. 119 2.1 Introduction ..................................................................................... 120 2.2 Methods .......................................................................................... 122 2.3 Results ............................................................................................ 130 vi 2.4 Discussion ...................................................................................... 136 References ............................................................................................ 146 Figures ................................................................................................... 152 3 ALTERATIONS IN SYNAPTIC TRANSMISSION AND SYNAPTIC PLASTICITY IN YOUNG 3xTg-AD MICE .................................................... 160 Abstract .................................................................................................. 161 3.1 Introduction ..................................................................................... 162 3.2 Methods .......................................................................................... 164 3.3 Results ............................................................................................ 168 3.4 Discussion ...................................................................................... 173 References ............................................................................................ 183 Figures ................................................................................................... 187 4 OPEN FIELD BEHAVIOR IN YOUNG 3xTg-AD MICE ................................ 194 Abstract .................................................................................................. 195 4.1 Introduction ..................................................................................... 196 4.2 Methods .......................................................................................... 197 4.3 Results ............................................................................................ 199 4.4 Discussion ...................................................................................... 201 References ............................................................................................ 205 Figures ................................................................................................... 206 5 IMPAIRMENTS IN SPATIAL WORKING MEMORY IN A NOVEL MOUSE MODEL OF HIRANO BODY EXPRESSION ............................................... 207 Abstract .................................................................................................. 208 vii 5.1 Introduction ..................................................................................... 209 5.2 Methods .......................................................................................... 212 5.3 Results ............................................................................................ 223 5.4 Discussion ...................................................................................... 229 References ............................................................................................ 238 Figures ................................................................................................... 244 6 CONCLUSIONS AND FINAL THOUGHTS ................................................. 260 6.1 Summary of Experimental Findings ................................................ 260 6.2 The Big Picture ............................................................................... 262 6.3 Where do we go from here? ........................................................... 264 6.4 A Final Thought on the Future of Alzheimer’s Disease
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