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Basal and Experience Dependent Ampar and Synapse Dynamics: Alterations in a Mouse Model of Fragile X Syndrome

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Basal and Experience Dependent Ampar and Synapse Dynamics: Alterations in a Mouse Model of Fragile X Syndrome University of Nebraska Medical Center DigitalCommons@UNMC Theses & Dissertations Graduate Studies Spring 5-6-2017 Basal and Experience Dependent Ampar and Synapse Dynamics: Alterations in a Mouse Model of Fragile X Syndrome Anand Suresh University of Nebraska Medical Center Follow this and additional works at: https://digitalcommons.unmc.edu/etd Part of the Molecular and Cellular Neuroscience Commons Recommended Citation Suresh, Anand, "Basal and Experience Dependent Ampar and Synapse Dynamics: Alterations in a Mouse Model of Fragile X Syndrome" (2017). Theses & Dissertations. 179. https://digitalcommons.unmc.edu/etd/179 This Dissertation is brought to you for free and open access by the Graduate Studies at DigitalCommons@UNMC. It has been accepted for inclusion in Theses & Dissertations by an authorized administrator of DigitalCommons@UNMC. For more information, please contact [email protected]. i BASAL AND EXPERIENCE DEPENDENT AMPAR AND SYNAPSE DYNAMICS: ALTERATIONS IN A MOUSE MODEL OF FRAGILE X SYNDROME By Anand Suresh A Dissertation Presented to the Faculty of The Graduate College in the University of Nebraska Medical Center In partial Fulfillment of the Requirements For the Degree of Doctor of Philosophy Biochemistry and Molecular Biology Under the supervision of Professor Anna Dunaevsky University of Nebraska Medical Center Omaha, Nebraska December 2016 ii Acknowledgements I would like to first thank my mentor, Dr. Anna Dunaevsky for her patience, support and guidance throughout my graduate studies. Her immense drive and passion towards biomedical research has been a constant source of inspiration for me and will remain so for the rest of my scientific career. I am also grateful for her endless investment in mine and other trainee’s professional advancement. Her mentorship and constant discussions of scientific literature, experimental designs and data analysis were invaluable. It was through her encouragement that I applied and received the American Heart Association pre-doctoral fellowship which meant a lot to me. Anna has been also very generous in sponsoring conferences and workshops which have been crucial in broadening my scientific and professional horizons for which I am very grateful. I would also like to thank the members of comprehensive exam committee: Dr. Parmender Mehta, Dr. Kaushik Patel and Dr. Dominic Cosgrove for their guidance and tutelage throughout my qualifying exams. I would take this opportunity to thank my supervisory committee: Dr. Hamid Band, Dr. Steve Caplan, Dr. Woo Yang Kim, Dr. Kaustubh Datta and Dr. Wallace Thoreson for their suggestion, guidance and immense support. I would like to thank all present and past member of the Dunaevsky lab for their help during my stay in the lab and in creating an environment of curiosity and endeavor. I first want to warmly thank our lab manager Yoosun Jung for helping me in the breeding, cloning and tissue cultures which were integral for this thesis. She was my very first teacher in the lab and I learnt a variety of techniques under her tutelage. Next, a big thank you to Dr. Padmashri Ragunathan whom I collaborated with on more than a couple of projects. Her meticulous attention to detail and work ethics are both an inspiration and a role-model for a young researcher. I would like to thank Dr. Benjamin Reiner for his contributions to the motor learning deficits in the fmr1 KO mouse study and for enlightening me on American culture. I would like to thank Dr. Gurudutt Pendyala and James Buescher (of Dr. Howard iii Fox’s lab) for sharing the protocols in synaptosomal preparations and troubleshooting during the biochemical experiments. Additionally, I am grateful to other members of the Dunaevsky lab including Dr. Pierluca Coiro, Lara Bergdolt, Shreya Roy for creating a warm and collegial work environment. Next, I want to thank members and labs within Munroe-Meyer Institute’s Department of Developmental Neuroscience. A special thank you to Jerri Dayton, my go-to person for almost all administrative issues and a wizard in solving complex organizational nightmares! A grateful thank you to Dr. Shelly Smith and for her overall mentorship in leading a budding department and her lab for all their support over the years. I would also like to thank Dr. Channabasavaiah Gurumurthy and Rolen Macky Quadros for their cloning of the td-Tomato constructs which formed the foundations of the in vivo experiments and support during the long and frustrating cloning saga of the SEP-GluA1 construct. Finally, a big thank you to Dr. Eunju Seong and Li Yuan of the Arrikath lab for sharing their wonder, enthusiasm, passion for science. I am grateful to have witnessed their never-say-die attitude and this has served as an inspiration to me. A very grateful thank you to Florent Maye, a developer from France who wrote the program for the neuronal analysis which saved me thousands of man hours and indirectly made possible this thesis. I would also like to thank the faculty and staff of my parent department; Biochemistry and Molecular Biology for their support over the years. Finally, a heartfelt thank you to Din, Gin, Biu and my parents for their unwavering support and constant encouragement that made this all possible. iv Table of Contents: Acknowledgements………………………………………………………………………….…i Table of content…………………………………………………………………………….….iv Abstract..………………………………………………………………………………………...1 Chapter 1. 1.1 Introduction………………………………………………………………………………....3 1.2 Dendritic spines………………………………………………………..……..5 1.2a Structure and organization …………...…………………….........7 1.2b Glutamate Receptors ....…………...…...…….………..……......9 1.2c Synaptic plasticity……………….………………………………..12 1.2d Structural plasticity…………………..……………..……............16 1.2e Relationship between functional and structural plasticity…….19 1.3 Fragile X syndrome………………...……………………..…….…………..23 1.3a Clinical classification and diagnosis…………………………….23 1.3b Structural brain studies in humans ……..…….……….……… 26 1.3c Molecular basis of Fragile X……...………………………….…..28 1.3d Mouse models of Fragile X…………………...………………....31 1.3e Synaptic plasticity in fmr1 KO mouse…………………..……....37 1.4: Organization of motor system in humans and mice………..………......41 1.5: Goals of this study………………………..……………………….............43 v Chapter 2. Relationship between AMPAR and Synapse dynamics in vivo; alterations in a mouse model of Fragile X syndrome 2.1 Introduction………………………………………………………..............44 2.2 Materials and Methods 2.2a Animals……………………………………………………………....46 2.2b DNA constructs……………………….……………………….…....46 2.2c In utero electroporation………………………………………........46 2.2d Tissue preparation and immunohistochemistry…..…................47 2.2e Cranial window…………………….……………………………….47 2.2f Imaging………………………………………………………..……..47 2.2g Image analysis………………………………………………..…....48 2.2h Statistics……………………………………...…………….…….....51 2.3 Results 2.3a Repeated in vivo imaging of dendritic spines and SEP-GluA2………………………………….…..52 2.3b Altered spine density, size, and dynamics in the primary motor cortex of fmr1 KO mice……………………….…..55 2.3c Spine fates and AMPAR levels……………………………….......59 2.3d sGluA2 dynamics within stable spines…………………………...63 2.3e sGluA2 in newly formed and eliminated spines………………....68 2.4 Discussion 2.4a AMPAR and spine dynamics………………………………….…..72 2.4b Fragile X spine and AMPAR dynamics……………………….....74 2.5 Supplementary figures……………………………………………………..77 vi Chapter 3. Altered functional plasticity of synaptic GluA1 with motor learning in the Fragile X mouse. 3.1 Introduction……..………………………………………………………....82 3.2 Materials and methods 3.2a Mice…………………………………….…..……………………....84 3.2b Motor skill training……………………………………...............….85 3.2c Preparation of synaptosomes from the motor cortex………….86 3.2d Surface biotinylation assay……………………………...……….92 3.2e Statistics……………………………………………………….…...92 3.3 Results 3.3a fmr1 KO mice have a motor learning deficit in a single forelimb reaching task…………………………..93 3.3b Motor skill training-induced synaptic delivery of GluA1 is impaired in fmr1 KO mice……………………95 3.4 Discussion………………………………………………………..…...…..99 Chapter 4. Appendices 4.1 Appendix A Abbreviations…………………………………………….….103 4.2 Appendix B References……………………………………..……….…..105 vii Table of Figures Figure 1: Repeated in vivo imaging of doubly transfected layer 2/3 neurons of M1 cortex………………………………………………………………………………….……...54 Figure 2: Altered dendritic spine properties in the fmr1 KO mice………………………………………………………………….………………………..56 Figure 3: Altered spine size and GluA2 content in the fmr1 KO mice…………………………………………………………………………………………...58 Figure 4: sGluA2 levels predict spine fate………………………………………………….…………………………………………61 Figure 5: sGluA2 is dynamic within stable spines……………………………………………………………………………….………...65 Figure 6: Newly formed spines gradually accumulated sGluA2 over time…………………………………………………………………………………..………..69 Figure 7: Eliminated spines have decrease in sGluA2 immediately before elimination…………………………………………………………………………………....71 Figure S1: Experimental approach to measure sGluA2 and spine intensity……………………………………………………………………………………….77 Figure S2: sGluA2 overexpression does not alter spine density or GluA2 expression profile………………………………………………………………………………………….78 Figure S3: sGluA2 content predicts spine fate in k-means analysis and local rank predicts fate for all but the smallest spines………………………………………………………………………...……………….79 Figure S4: total sGluA2 levels and mean spine intensity do not change over time…………………………………………………………………………………………….80 Figure S5: New spines are small and initial sGluA2 content does
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