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Activity-Dependent Synaptic Modifications

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Activity-Dependent Synaptic Modifications Input-Specific Metaplasticity by a Local Switch in NMDA Receptors by Ming-Chia Lee Department of Neurobiology Duke University Date:_______________________ Approved: ___________________________ Michael D. Ehlers, Advisor ___________________________ Anne E. West, Chair ___________________________ Rhohei Yasuda ___________________________ Benjamin D. Philpot Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Neurobiology in the Graduate School of Duke University 2009 ABSTRACT Input-Specific Metaplasticity by a Local Switch in NMDA Receptors by Ming-Chia Lee Department of Neurobiology Duke University Date:_______________________ Approved: ___________________________ Michael D. Ehlers, Advisor ___________________________ Anne E. West, Chair ___________________________ Rhohei Yasuda ___________________________ Benjamin D. Philpot An abstract of a dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Neurobiology in the Graduate School of Duke University 2009 Copyright by Ming-Chia Lee 2009 Abstract At excitatory synapses, NMDAR‐mediated synaptic plasticity occurs in response to activity inputs by modifying synaptic strength. While comprehensive studies have been focused on the induction and expression mechanisms underlying synaptic plasticity, it is less clear whether and how synaptic plasticity itself can be subjected to regulations. The presence of “plasticity of plasticity”, or meta‐plasticity, has been proposed as an essential mechanism to ensure a proper working range of plasticity, which may also offer an additional layer of information storage capacity. However, it remains elusive whether and how meta‐plasticity occurs at single synapses and what molecular substrates are locally utilized. Here, I develop systems allowing for sustained alterations of individual synaptic inputs. By implementing a history of inactivity at single synapses, I demonstrate that individual synaptic inputs control synaptic molecular composition homosynaptically, while allowing heterosynaptic integration along dendrites. Furthermore, I report that subunit‐ specific regulation of NMDARs at single synapses mediates a novel form of input‐ specific metaplasticity. Prolonged suppression of synaptic releases at single synapses enhances synaptic NMDAR‐mediated currents and increases the number of functional NMDARs containing NR2B. Interestingly, synaptic NMDAR composition is adjusted by spontaneous glutamate release rather than evoked activity. I also demonstrate that inactivated synapses with more NMDARs iv containing NR2B acquire a lower induction threshold for long‐term synaptic potentiation. Together, these results suggest that at single synapses, spontaneous release primes the synapse by modifying its synaptic state with specific molecular compositions, which in turn determine the synaptic gain in an input‐specific manner. v Dedication I would like to dedicate my Ph.D. thesis to my dear parents and beloved husband for their invaluable support and unconditional faith in me throughout my life. vi Table of Contents Abstract..................................................................................................................... iv List of Tables..........................................................................................................xii List of Figures........................................................................................................xiii List of Abbreviations............................................................................................ xv Acknowledgements ............................................................................................xvii Chapter 1. Introduction ...........................................................................................1 Heterogeneous synaptic inputs ...............................................................................3 Synaptic inputs as presynaptic vesicular release ...........................................4 Action potential dependent evoked release....................................................6 Spontaneous miniature release .........................................................................7 Dissociable evoked and spontaneous release .................................................8 Activity‐dependent synaptic modifications..........................................................9 Hebbian plasticity: modifications on synaptic strength..............................10 LTP............................................................................................................11 LTD ...........................................................................................................13 Metaplasticity: modifications on Hebbian plasticity ...................................14 Induction of metaplasticity........................................................................15 LTP‐facilitation .........................................................................................15 LTP‐inhibition and LTD‐facilitation ........................................................16 vii Synaptic NMDA receptors mediate activity‐dependent metaplastic regulations .................................................................................................................17 Subunit‐specific properties of NMDAR ........................................................18 Gating and kinetics ...................................................................................19 Synaptic locations .....................................................................................20 Protein interactions...................................................................................22 Activity modifies NMDAR subunit composition ........................................23 Developmental switch from NR2B to NR2A............................................24 Chronic activity influences NMDAR composition...................................25 Spontaneous releases and NMDAR composition .....................................27 Animal models with altered NMDAR composition..................................27 NMDAR composition is modulated in a cell‐wide manner......................28 NMDAR composition modifies synaptic plasticity .....................................29 Subunit composition determines the induction threshold of Hebbian plasticity....................................................................................................30 NMDAR composition as a substrate for metaplasticity ...........................31 Heterogeneity of synaptic NMDAR composition .....................................32 NMDAR composition as a substrate for metaplasticity: input‐specific? .33 Local activity manipulations..................................................................................34 Acute and local activity manipulations .........................................................34 Sustained local activity manipulation at individual synapses ...................35 Local activity manipulation and NMDAR composition .............................37 Experimental rationales and specific aims..........................................................37 viii AIM#1: To determine if activity inputs modify synaptic states at single synapses .............................................................................................................38 AIM#2: To determine if NMDAR composition serves as a substrate for input‐specific metaplasticity ...........................................................................39 Chapter 2. Materials and methods ......................................................................56 General strategy........................................................................................................56 Synaptic inactivation and single synapse resolution...................................56 Identify excitatory synapses............................................................................57 Materials and methods............................................................................................57 DNA constructs, antibodies and reagents.....................................................58 Chemical‐based inactivation......................................................................58 Tetanus toxin‐based inactivation ..............................................................58 Primary neuronal culture, transfection and viral infection ........................58 Immunocytochemistry and antibodies..........................................................59 Chemical‐based inactivation ...........................................................................60 FM loading assay ..............................................................................................61 Image analysis and quantification..................................................................62 Two‐photon microscopy..................................................................................63 Two‐photon uncaging and uEPSC recording...............................................64 Two‐photon uncaging and plasticity induction ...........................................66 Two‐photon uncaging and spine enlargement.............................................66 Chapter 3. Activity inputs modify synaptic states at single synapses.........74 Activity manipulation at single synapses............................................................75 ix Chemical inactivation:
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