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Mechanisms of Nmda Receptor Inhibition by Memantine and Ketamine

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Mechanisms of Nmda Receptor Inhibition by Memantine and Ketamine MECHANISMS OF NMDA RECEPTOR INHIBITION BY MEMANTINE AND KETAMINE by Nathan G. Glasgow Bachelor of Science, University of Toledo, 2010 Submitted to the Graduate Faculty of the Kenneth P. Dietrich School of Arts and Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2016 UNIVERSITY OF PITTSBURGH DIETRICH SCHOOL OF ARTS AND SCIENCES This dissertation was presented by Nathan G. Glasgow It was defended on April 21, 2016 and approved by Dr. Stephen D. Meriney, Professor, Department of Neuroscience Dr. Anne-Marie Oswald, Assistant Professor, Department of Neuroscience Dr. Elias Aizenman, Professor, Department of Neurobiology Dr. Michael S. Gold, Professor, Department of Anesthesiology Dr. Stephen F. Traynelis, Professor, Department of Pharmacology, Emory University Dissertation Advisor: Dr. Jon W. Johnson, Professor, Department of Neuroscience ii Copyright © by Nathan G. Glasgow 2016 iii MECHANISMS OF NMDA RECEPTOR INHIBITION BY MEMANTINE AND KETAMINE Nathan G. Glasgow, PhD University of Pittsburgh, 2016 NMDA receptors (NMDARs), a subfamily of ionotropic glutamate receptors, have unique biophysical properties including high permeability to Ca2+. Activation of NMDARs increases the concentration of intracellular Ca2+ that can activate a vast array of signaling pathways. NMDARs are necessary for many processes including synaptic plasticity, dendritic integration, and cell survival. Aberrant NMDAR activation is implicated in many central nervous system disorders including neurodegenerative disorders, neuronal loss following ischemia, and neuropsychiatric disorders. Hope that NMDARs may serve as useful therapeutic targets is bolstered by the clinical success of two NMDAR antagonists, memantine and ketamine. Memantine and ketamine act as open channel blockers of the NMDAR-associated ion channel, and exhibit similar IC50 values and kinetics. Memantine is approved for treatment of Alzheimer's disease and shows promise in treatments of Huntington's disease, and ischemia. Ketamine was initially approved for use as a general anesthetic, but has recently shown efficacy in treatment of depression and of pain. Notably, memantine is not effective in treatment of depression or pain. In addition, memantine is well tolerated, whereas ketamine induces psychotomimetic side effects. The basis for the divergent clinical profiles of memantine and ketamine is not clear. One recently-proposed hypothesis is that memantine and ketamine inhibit overlapping but distinct subpopulations of NMDARs. However, mechanisms underlying inhibition of distinct NMDAR subpopulations by memantine or by ketamine are not fully understood. We therefore examined and compared iv mechanisms of inhibition by memantine and by ketamine. We also describe a novel fast perfusion system optimized for brief synaptic-like glutamate applications to lifted cells. We found that: (1) inhibition by memantine and ketamine exhibit differential dependence on duration of receptor activation and on NMDAR subtype; (2) the dependence of memantine inhibition on duration of NMDAR activation results from stabilization of a Ca2+-dependent desensitized state; (3) the endogenous NMDAR open channel blocker Mg2+ slows the binding kinetics of both memantine and ketamine, and, unexpectedly, speeds recovery from memantine inhibition; (4) although inhibition by memantine was thought to be mediated by only the charged form of memantine, the uncharged form of memantine also binds to and inhibits NMDARs, and exhibits surprisingly slow unbinding kinetics. v TABLE OF CONTENTS PREFACE ................................................................................................................................. XIV 1.0 GENERAL INTRODUCTION ................................................................................... 1 1.1 BASIC PROPERTIES OF NMDA RECEPTOR FUNCTION ....................... 2 1.1.1 Diversity of NMDAR subtypes ....................................................................... 5 1.1.2 NMDAR desensitization and inactivation ..................................................... 6 1.1.3 Kinetic models of NMDAR activity ............................................................... 7 1.2 ROLE OF NMDA RECEPTORS IN THE CENTRAL NERVOUS SYSTEM ............................................................................................................................. 11 1.2.1 NMDAR expression and localization ........................................................... 11 1.2.2 Role of NMDARs in plasticity and neuronal signaling .............................. 12 1.3 ROLE OF NMDA RECEPTORS IN CENTRAL NERVOUS SYSTEM DISORDERS ....................................................................................................................... 15 1.3.1 NMDAR-mediated excitotoxicity ................................................................. 15 1.3.2 NMDARs as targets for drug therapy ......................................................... 17 1.4 BASIC MECHANISMS OF ACTION OF MEMANTINE AND KETAMINE ........................................................................................................................ 20 1.4.1 Properties of open channel blockers ............................................................ 20 1.4.2 Inhibition of NMDARs by memantine and ketamine ................................ 23 vi 1.4.3 Memantine and ketamine inhibit distinct subpopulations of NMDARs .. 29 2.0 WHOLE-CELL PATCH-CLAMP ANALYSIS OF RECOMBINANT NMDA RECEPTOR PHARMACOLOGY USING BRIEF GLUTAMATE APPLICATIONS ...... 32 2.1 OVERVIEW ....................................................................................................... 32 2.2 INTRODUCTION ............................................................................................. 33 2.3 MATERIALS ..................................................................................................... 35 2.3.1 Cell Culture and Transfection ...................................................................... 35 2.3.2 Fast Perfusion System ................................................................................... 36 2.3.3 Whole-Cell Recordings.................................................................................. 37 2.4 METHODS ......................................................................................................... 38 2.4.1 Fast Perfusion System Design ....................................................................... 39 2.4.1.1 Brief Application Strategy .................................................................. 40 2.4.1.2 Changing Solutions Flowing Through Barrels ................................. 40 2.4.2 Transient Transfection of tsA201 Cells ....................................................... 41 2.4.3 Performing Brief Glutamate Applications in Control Solution ................ 42 2.4.3.1 Estimating Duration of Brief Applications ....................................... 42 2.4.3.2 Whole-Cell Recording from Lifted Cells .......................................... 45 2.4.3.3 Quantification of Receptor Response Time Course ......................... 47 2.4.3.4 Fast Perfusion System Optimization ................................................. 49 2.4.4 Performing Brief Glutamate Applications in Presence of Channel Blockers ....................................................................................................................... 51 2.5 NOTES ................................................................................................................ 56 vii 3.0 MEMANTINE AND KETAMINE DIFFERENTIALLY ALTER NMDA RECEPTOR DESENSITIZATION KINETICS ...................................................................... 60 3.1 OVERVIEW ....................................................................................................... 60 3.2 INTRODUCTION ............................................................................................. 61 3.3 MATERIALS AND METHODS ...................................................................... 64 3.3.1 Cell culture and transfection ........................................................................ 64 3.3.2 Electrophysiology........................................................................................... 65 3.3.3 Fast perfusion system .................................................................................... 66 3.3.4 Kinetic modeling ............................................................................................ 67 3.3.5 Analysis ........................................................................................................... 68 3.4 RESULTS ........................................................................................................... 71 3.4.1 Glutamate concentration does not strongly affect inhibition by memantine or ketamine ................................................................................................................. 71 3.4.2 Inhibition depends on duration of glutamate exposure and on NMDAR subtype ........................................................................................................................ 75 3.4.3 Memantine enhances desensitization of GluN1/2A receptors ................... 83 3.4.4 Memantine stabilizes a Ca2+-dependent desensitized state of GluN1/2A receptors ...................................................................................................................... 92 3.4.5 Memantine and ketamine differentially alter desensitization kinetics of
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