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Modulation of NMDA Receptor Activity During Physiological and Pathophysiological Events Christine Marie Emnett Washington University in St

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Modulation of NMDA Receptor Activity During Physiological and Pathophysiological Events Christine Marie Emnett Washington University in St Washington University in St. Louis Washington University Open Scholarship Arts & Sciences Electronic Theses and Dissertations Arts & Sciences Winter 12-15-2014 Modulation of NMDA Receptor Activity During Physiological and Pathophysiological Events Christine Marie Emnett Washington University in St. Louis Follow this and additional works at: https://openscholarship.wustl.edu/art_sci_etds Part of the Biology Commons Recommended Citation Emnett, Christine Marie, "Modulation of NMDA Receptor Activity During Physiological and Pathophysiological Events" (2014). Arts & Sciences Electronic Theses and Dissertations. 347. https://openscholarship.wustl.edu/art_sci_etds/347 This Dissertation is brought to you for free and open access by the Arts & Sciences at Washington University Open Scholarship. It has been accepted for inclusion in Arts & Sciences Electronic Theses and Dissertations by an authorized administrator of Washington University Open Scholarship. For more information, please contact [email protected]. WASHINGTON UNIVERSITY IN ST. LOUIS Division of Biology and Biomedical Sciences Neurosciences Dissertation Examination Committee: Steven Mennerick, Chair James Huettner Daniel Kerschensteiner Peter D. Lukasiewicz Joseph Henry Steinbach Modulation of NMDA Receptor Activity During Physiological and Pathophysiological Events by Christine Marie Emnett A dissertation presented to the Graduate School of Arts and Sciences of Washington University in partial fulfillment of the requirements for the degree of Doctor of Philosophy December 2014 Saint Louis, MO © 2014, Christine Marie Emnett Table of Contents List of Figures ................................................................................................................................ iv List of Abbreviations .................................................................................................................... vii Acknowledgments....................................................................................................................... .viii Abstract .......................................................................................................................................... x Chapter 1: Introduction ............................................................................................................... 1 References .................................................................................................................. 22 Chapter 2: Synaptic NMDA Receptors mediate hypoxic excitotoxic cell death ................... 30 Abstract .......................................................................................................................... 31 Introduction .................................................................................................................... 32 Materials and Methods ................................................................................................... 34 Results ............................................................................................................................ 40 Discussion ...................................................................................................................... 61 References ...................................................................................................................... 67 Chapter 3: Indistinguishable synaptic pharmacodynamics of NMDAR channel blockers, memantine and ketamine ............................................................................................. 72 Abstract .......................................................................................................................... 73 Introduction .................................................................................................................... 75 Materials and Methods ................................................................................................... 78 Results ............................................................................................................................ 84 Discussion .................................................................................................................... 107 References .................................................................................................................... 113 Chapter 4:Interaction between positive allosteric modulators and trapping blockers of the NMDA receptor channel ............................................................................................ 118 Abstract ........................................................................................................................ 119 Introduction .................................................................................................................. 120 ii Materials and Methods ................................................................................................. 123 Results .......................................................................................................................... 128 Discussion .................................................................................................................... 144 References .................................................................................................................... 151 Chapter 5: Novel chemical biology tools reveal new insights into ketamine’s antidepressant actions .......................................................................................................................... 156 Abstract ........................................................................................................................ 157 Introduction .................................................................................................................. 159 Materials and Methods ................................................................................................. 162 Results .......................................................................................................................... 167 Discussion .................................................................................................................... 180 References .................................................................................................................... 187 Chapter 6: Discussion and Future Directions ........................................................................ 191 References ............................................................................................................... 212 iii List of Figures Chapter 1 Figure 1.1: Schematic of NMDA Receptor ........................................................................6 Figure 1.2: Competing hypotheses regarding NMDAR contribution to excitotoxicity .....8 Figure 1.3: Structures of memantine and ketamine ......................................................... 12 Figure 1.4: Kinetic scheme of a trapped channel blocker ................................................14 Chapter 2 Figure 2.1: 10μM memantine protects against hypoxic insults ........................................41 Figure 2.2: Memantine shows significant trapping block of synaptic NMDARs during tonic activation ...................................................................................................................43 Figure 2.3: Progressive memantine block of synaptic receptors during repetitive stimulation of a microculture neuron .................................................................................46 Figure 2.4: Glutamate transporters protect from hypoxic insults .....................................48 Figure 2.5: Synaptic NMDAR block significantly protects against hypoxic and exogenous glutamate insults ..............................................................................................52 Figure 2.6: MK-801 partial protection results from non-NMDAR related toxicity and not from MK-801 unblock .................................................................................................55 Figure 2.7: Decreasing synaptic activity during preblock still yields protection .............57 Figure 2.8: Specificity of glutamate pyruvate transaminase for tonic but not synaptic glutamate ............................................................................................................................58 Figure 2.9: Glutamate pyruvate transaminase protects against exogenous glutamate damage but does not protect against hypoxic damage .......................................................60 Chapter 3 Figure 3.1: Memantine and ketamine have indistinguishable IC50s ..................................84 Figure 3.2: .Memantine and ketamine effects on NMDAR EPSCs are indistinguishable ............................................................................................................... 86 Figure 3.3: Memantine and ketamine reach maximal synaptic block with similar time- course .................................................................................................................................87 iv Figure 3.4: Memantine and ketamine block extrasynaptic NMDARs equally .................89 Figure 3.5: Memantine exhibits a significantly larger fast component of voltage- dependent re-equilibration following a voltage-pulse depolarization ...............................92 Figure 3.6: Simulations demonstrate that low Po slows voltage-dependent re- equilibration of blocker ......................................................................................................95
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