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Download The The Role of DHHC5-Mediated Palmitoylation of δ-Catenin in Cadherin Stability and Synapse Plasticity by Gian Stefano Brigidi B.Sc., McGill University, 2007 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Neuroscience) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) December 2014 © Gian Stefano Brigidi, 2014 Abstract Synapses of the Central Nervous System are specialized junctions of cell-cell contact that transmit signals from one neuron to another in a rapid and efficient manner. Synapses are highly plastic structures that can be continually modified in response to fluctuations in neuronal activity. Changes in the number, size, and protein composition of synapses have been observed following alterations in neuronal activity in vitro and following the learning of specific tasks in vivo. Thus, elucidating the molecular mechanisms underlying activity-mediated trafficking of proteins to and from synaptic compartments is essential for our understanding of brain function. Previous work has demonstrated a requirement for the cadherin-adhesion complex in activity-induced enhancements in synapse strength, however the molecular mechanisms that translate synaptic activation into enhanced cadherin-based adhesion and synapse strengthening remain unknown. This dissertation discusses work that unravels how synaptic activity coordinates the enhancement of cadherin surface stabilization, enlargement of dendritic spines, and increased surface insertion of AMPA receptors. This work demonstrates that increased synaptic activity enhances the palmitoylation of a brain-specific component of the cadherin-adhesion complex, δ-catenin, which in turn causes δ-catenin to traffic toward the synaptic membrane in spines where it associates with and stabilizes surface N-cadherin. This results in enhancements in synapse structure and efficacy, and is correlated with the acquisition of contextual fear memories. Furthermore, we show that palmitoylation of δ-catenin is mediated by the palmitoyl acyl- transferase DHHC5, and that DHHC5 drives activity-induced increases in surface AMPA receptor levels through the palmitoylation of δ-catenin. Finally, we demonstrate that the activity- induced palmitoylation of δ-catenin by DHHC5 is accomplished through the rapid trafficking of DHHC5 out of the synapse and into the dendritic shaft where it can associate with and palmitoylate δ-catenin, resulting in δ-catenin’s synaptic recruitment. This work provides new insights into the cellular and molecular mechanisms that underlie activity-induced synapse plasticity. ii Preface The content in chapter 1.5, entitled “Cadherin-catenin Adhesion Complexes at CNS synapses” is a review that has been published as: Brigidi, G.S., and S.X. Bamji. 2011. Cadherin-catenin adhesion complexes at the synapse. Current Opinion in Neurobiology 21:208-214. The manuscript was written and figures prepared by me under the supervision of the senior author, Dr. Shernaz X. Bamji. The work in chapter 2, entitled “Palmitoylation of δ-catenin by DHHC5 Mediates Activity- Induced Synapse Plasticity” has been published as: Brigidi, G.S., Y. Sun, D. Beccano-Kelly, K. Pitman, M. Mobasser, S.L. Borgland, A.J. Milnerwood, and S.X. Bamji. 2014. Palmitoylation of delta-catenin by DHHC5 mediates activity-induced synapse plasticity. Nature Neuroscience 17:522-532. All experiments and data analysis for this manuscript was done by myself with following exceptions: Immunocytochemical experiments in Figure 2.12 were done by co-authors Yu Sun and Mahsan Mobasser. Electrophysiology experiments in Figure 2.8 were designed by co- authors and collaborators Dr. Austen Milnerwood and Dr. Stephanie Borgland, and done by co- authors Dayne Beccano-Kelly and Kimberley Pitman. The manuscript was written and figures prepared by me under the supervision of the senior author, Dr. Shernaz X. Bamji. The work in chapter 3, entitled “Activity-Regulated Trafficking of the Palmitoyl Acyl- Transferase DHHC5” is currently under revision as: iii Brigidi G.S., Santyr B, Shimell J, Jovellar B, and S.X. Bamji (2014). Activity-Regulated Trafficking of the Palmitoyl Acyl-Transferase DHHC5. Manuscript under revision. All experiments and data analysis for this manuscript were done by myself with following exceptions: Immunocytochemical experiments and data analysis in Figures 3.1-3.5 were done with assistance from co-authors Brendan Santyr, Jordan Shimell, and Blair Jovellar. The experiment in Figure 3.3D was done by Brendan Santyr. The manuscript was written and figures prepared by me under the supervision of the senior author, Dr. Shernaz X. Bamji. iv Table of Contents Abstract….. .................................................................................................................................... ii Preface…… ................................................................................................................................... iii Table of Contents .......................................................................................................................... v List of Tables ............................................................................................................................... viii List of Figures ............................................................................................................................... ix List of Abbreviations ................................................................................................................... xii Acknowledgements ..................................................................................................................... xiv Chapter 1: Introduction ............................................................................................................... 1 1.1 The Hippocampus as a Model System ............................................................................ 1 1.2 Excitatory Synapses of the Central Nervous System ...................................................... 3 1.2.1 Composition of the Presynaptic Compartment ........................................................... 4 1.2.2 Composition of the Postsynaptic Compartment .......................................................... 8 1.2.2.1 AMPA Receptors .............................................................................................. 10 1.2.2.2 NMDA Receptors .............................................................................................. 11 1.2.3 Dendritic Spines ........................................................................................................ 14 1.2.3.1 Spine Morphology ............................................................................................. 15 1.2.3.2 Structure–Function Relationship ....................................................................... 18 1.2.3.3 Spine Abnormalities and Neuropsychiatric Disease ......................................... 20 1.3 Inhibitory CNS Synapses .............................................................................................. 22 1.4 Synapse Plasticity .......................................................................................................... 25 1.4.1 Long-Term Potentiation ............................................................................................ 26 1.4.1.1 Functional LTP .................................................................................................. 27 1.4.1.2 Structural LTP ................................................................................................... 28 1.4.2 Long-Term Depression ............................................................................................. 31 1.4.2.1 Functional LTD ................................................................................................. 31 1.4.2.2 Structural LTD .................................................................................................. 32 1.4.3 LTP and LTD in Learning and Memory ................................................................... 33 1.5 Cadherin-Catenin Adhesion Complexes at CNS Synapses ........................................... 35 1.5.1 Cadherins in Synapse Formation ............................................................................... 36 1.5.1.1 Cadherin Functions at Presynaptic Compartments ........................................... 37 1.5.1.2 Cadherin Functions at Postsnaptic Compartments ............................................ 39 1.5.2 Regulation of Cadherin-Based Adhesion at the Synapse .......................................... 43 1.6 δ-Catenin at the Synapse ............................................................................................... 46 1.6.1 Postsynaptic Signaling Pathways of δ-Catenin ......................................................... 46 1.6.2 Aberrant δ-Catenin Function and Cognitive Performance ........................................ 49 1.7 Neuronal Protein Palmitoylation ................................................................................... 50 1.7.1 Palmitoyl Acyl-Transferases: The DHHC Family of Proteins .................................. 53 1.7.2 DHHC Proteins in Cognitive Function and Neurological Disease ........................... 57 v 1.7.3 Dynamic Palmitoylation of Synaptic Substrates ....................................................... 59 1.8 Rationale and Hypothesis .............................................................................................
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