University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2014 Investigation Of The Molecular Mechanisms Of Synaptic Tagging And Capture Jung Whan Park University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Biology Commons, and the Neuroscience and Neurobiology Commons Recommended Citation Park, Jung Whan, "Investigation Of The Molecular Mechanisms Of Synaptic Tagging And Capture" (2014). Publicly Accessible Penn Dissertations. 1399. https://repository.upenn.edu/edissertations/1399 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/1399 For more information, please contact [email protected]. Investigation Of The Molecular Mechanisms Of Synaptic Tagging And Capture Abstract Memory formation is continuously influenced by past, present, and future experiences. Memories linked to events that require more attention or involve emotional arousal are more persistent than ordinary memories. Information from multiple inputs that consist of memory is integrated in the hippocampus, a brain region responsible for memory storage. As a form of hippocampal long-term potentiation, pathway- specific synaptic tagging and capture (STC) has been proposed as a synaptic model of memory because it illustrates the interaction of two independent sets of synapses. This pathway-specificity is a emarkabler property of neuronal signaling because it requires highly coordinated cellular signaling only at the activated synapses. However, elucidating the mechanism that is responsible for this specificity is a big challenge in the field. In my dissertation, I focused on PKA anchoring and RNA-binding proteins because they can contribute to STC through compartmentalization of PKA signaling and regulation of dendritic expression of RNAs, respectively. In Chapter 1, I review the mechanism of STC and discuss how compartmentalized PKA signaling contributes to STC. PKA is involved in the process of STC by orchestrating the activity of synaptic molecules and by mediating gene expression. In Chapter 2, I combine genetic and pharmacological approaches to determine the role of PKA anchoring in STC and memory. The results from electrophysiological, biochemical and behavioral experiments suggest that presynaptically anchored PKA contributes to STC and memory by regulating the size of the readily releasable pool of synaptic vesicles. In Chapter 3, I perform genetic and viral approaches to define whether an RNA-binding protein translin (also known as testes-brain RNA-binding protein, TBRBP) is involved in STC and memory. The data from electrophysiological, behavioral and gene expression studies suggest that translin mediates STC and memory via RNA processing. Taken together, my thesis work provides evidence that presynaptic PKA anchoring-mediated synaptic vesicle release and postsynaptic processing of specific RNAs by translin are critical for STC and memory. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Biology First Advisor Ted Abel Keywords Memory, PKA, PKA anchoring protein, RNA-binding protein, Synaptic tagging and capture, Translin Subject Categories Biology | Neuroscience and Neurobiology This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/1399 INVESTIGATION OF THE MOLECULAR MECHANISMS OF SYNAPTIC TAGGING AND CAPTURE Jung Whan Park A DISSERTATION in Biology Presented to the Faculties of the University of Pennsylvania in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy 2014 Supervisor of Dissertation ______________________ Ted Abel Brush Family Professor of Biology Graduate Group Chairperson _____________________ Doris Wagner Professor of Biology Dissertation Committee Dejian Ren, Associate professor of Biology Nancy Bonini, Professor of Biology Gregory Carlson, Assistant Professor of Neuroscience in Psychiatry Marc Schmidt, Associate professor of Biology ACKNOWLEDGMENT My graduate life in the Abel lab had been a continuum of scientific challenges and excitement. I would like to express my sincere gratitude to Dr. Ted Abel for giving me the opportunity to work in this great scientific environment. Ted’s enthusiasm for science and broad knowledge in science inspired me throughout my dissertation and shaped me as a scientist. He is clearly my role model as a scientist and as a mentor. I sincerely thank my thesis committee: Dr. Dejian Ren, Dr. Nancy Bonini, Dr. Gregory Carlson, Dr. Marc Schmidt. Their support and guidance were invaluable. By giving me ideas and comments on my progress, they helped me to finish my dissertation. I thank the past and current Abel lab members. In the lab, they were willing to help and discuss each other’s work. Outside of the lab, they were friends to share fun. Let’s go play paintball again guys. Dr. Ted Huang and Dr. Chris Vecsey – thank you for teaching me slice electrophysiology. Dr. Robbert Havekes – thank you for the guidance and teaching me experiments. Finally, I cannot thank enough to my parents and wife for their unconditional support and love. I am grateful to my parents for giving me advice that has helped my development as a scientist and as a person. My wife Hyojin – thank you for coming down to Philly from NYC almost every weekend and bearing with me. ii ABSTRACT INVESTIGATION OF THE MOLECULAR MECHANISMS OF SYNAPTIC TAGGING AND CAPTURE Jung Whan Park Ted Abel Memory formation is continuously influenced by past, present, and future experiences. Memories linked to events that require more attention or involve emotional arousal are more persistent than ordinary memories. Information from multiple inputs that consist of memory is integrated in the hippocampus, a brain region responsible for memory storage. As a form of hippocampal long- term potentiation, pathway-specific synaptic tagging and capture (STC) has been proposed as a synaptic model of memory because it illustrates the interaction of two independent sets of synapses. This pathway-specificity is a remarkable property of neuronal signaling because it requires highly coordinated cellular signaling only at the activated synapses. However, elucidating the mechanism that is responsible for this specificity is a big challenge in the field. In my dissertation, I focused on PKA anchoring and RNA-binding proteins because they can contribute to STC through compartmentalization of PKA signaling and regulation of dendritic expression of RNAs, respectively. In Chapter 1, I review the mechanism of STC and discuss how compartmentalized PKA signaling contributes to STC. PKA is involved in the process of STC by orchestrating the activity of synaptic molecules and by mediating gene expression. In Chapter 2, I combine genetic and pharmacological approaches to determine the role of PKA anchoring in STC and memory. The results from electrophysiological, biochemical and behavioral experiments suggest that presynaptically anchored PKA contributes to STC and memory by regulating the size iii of the readily releasable pool of synaptic vesicles. In Chapter 3, I perform genetic and viral approaches to define whether an RNA-binding protein translin (also known as testes-brain RNA- binding protein, TBRBP) is involved in STC and memory. The data from electrophysiological, behavioral and gene expression studies suggest that translin mediates STC and memory via RNA processing. Taken together, my thesis work provides evidence that presynaptic PKA anchoring-mediated synaptic vesicle release and postsynaptic processing of specific RNAs by translin are critical for STC and memory. iv TABLE OF CONTENTS ACKNOWLEDGMENT ............................................................................................................ ii ABSTRACT ............................................................................................................................... iii TABLE OF CONTENTS........................................................................................................... v LIST OF FIGURES ................................................................................................................ viii CHAPTER 1: Overview of PKA and PKA anchoring in synaptic tagging and capture ......................................................................................................................................... 1 Abstract ................................................................................................................................................. 1 1.1 Introduction .................................................................................................................................... 2 1.2 The role of PKA in synaptic plasticity and memory formation ............................................. 4 1.3 The role of PKA in synaptic tagging and capture .................................................................... 5 1.4 Other potential tagging mechanisms possibly mediated by PKA ........................................ 6 1.5 Plasticity related products ........................................................................................................... 8 1.6 The role of PKA anchoring in synaptic plasticity and memory ........................................... 10 1.7 Examples of AKAPs modulating neuronal function .............................................................. 11 1.8 PKA-centric unified model of synaptic tagging and capture ..............................................