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Pathobiological Mechanisms and Treatment of Electrophysiological Dysfunction Following Primary Blast-Induced Traumatic Brain Injury

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Pathobiological Mechanisms and Treatment of Electrophysiological Dysfunction Following Primary Blast-Induced Traumatic Brain Injury Pathobiological Mechanisms and Treatment of Electrophysiological Dysfunction Following Primary Blast-Induced Traumatic Brain Injury Edward Weigand Vogel III Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate School of Arts and Science COLUMBIA UNIVERSITY 2017 © 2017 Edward Weigand Vogel III All rights reserved ABSTRACT Pathobiological Mechanisms of Electrophysiological Dysfunction Following Primary Blast- Induced Traumatic Brain Injury Edward W. Vogel III Traumatic brain injury (TBI) is the signature injury of the ongoing military conflicts in the Middle East and Afghanistan, largely due to the use of improvised explosive devices (IEDs), which have affected soldiers and civilians alike. Blast-induced TBI (bTBI) biomechanics are complex and multiphasic. While research has clearly demonstrated the negative effects of penetrative (secondary blast) and inertia-driven (tertiary blast) injury, the effect of shock wave loading (primary blast) on the brain remains unclear. Combined primary-tertiary blast exposure in vivo has been reported previously to alter brain function, specifically hippocampal function; however, it is extremely difficult to deliver primary blast exposure in isolation with an in vivo injury model. The research presented in this thesis utilized a custom-designed in vitro blast injury model to deliver military-relevant shock wave exposures, in isolation, to organotypic hippocampal slice cultures (OHSCs). To contextualize blast-induced pathobiology with previous TBI studies, the first goal of this thesis was to characterize the deformation profile induced in OHSCs with our blast injury model experimentally. Using stereoscopic, high-speed cameras and digital image correlation to calculate strain, we found that our blast model induced low strain magnitudes (<9%) but at high strain rates (25-86s-1), which aligned closely with associated computational simulations of our model. The second aim was to determine if primary blast was capable of altering hippocampal electrophysiological function. We exposed OHSCs to a range of shock intensities and found, using a micro-electrode array system, that long-term potentiation (LTP), a measure of synaptic plasticity, was very sensitive to primary blast exposure; a threshold for disruption of LTP was found between 9 and 39 kPa•ms impulse. Alternative measures of basal electrophysiology were less sensitive than LTP. Blast exposure significantly reduced LTP between 1 and 24 hours post- injury, and this deficit persisted through 6 days post-injury. Depending on shock intensity, LTP spontaneously recovered 10 days post-injury. The third aim was to explore the cellular mechanisms for blast-induced LTP deficits. Using a chemical LTP induction protocol, blast exposure altered key proteins necessary for the induction of LTP by 24 hours post-injury including, postsynaptic density protein-95 (PSD-95), a major scaffolding protein that organizes the postsynaptic density (PSD), α-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid glutamate receptor 1 (AMPA-GluR1), and stargazin, an auxiliary GluR1 protein that binds AMPA-GluR1 to PSD-95. Modulation of the cyclic adenosine monophosphate (cAMP) pathway reversed the observed effects of blast on LTP. We theorized that blast-induced disruption of PSD-95 prevented translocation, and subsequent phosphorylation, of GluR1-containing AMPARs to the postsynaptic membrane, which, in turn, prevented potentiation. The final aim was to investigate the efficacy of phosphodiesterase-4 (PDE4) inhibitors, which block degradation of cAMP, as a therapeutic strategy. When delivered immediately following primary blast injury, multiple PDE4 inhibitors proved efficacious in restoring LTP measured 24 hours post-injury. Roflumilast, a Food and Drug Administration-approved PDE4 inhibitor, was effective when delivered at a clinically relevant concentration (1nM) and at a delayed time point (up to 6 hours). Roflumilast reversed blast-induced changes in expression/phosphorylation of the key LTP protein targets. We hypothesized that maintenance of PSD-95 drove the observed therapeutic effect. Greater work is necessary to determine how blast exposure degrades PSD-95 and how roflumilast prevented these detrimental effects. This thesis has shown that primary blast exposure can negatively alter neurological function, as well as protein expression and phosphorylation. These studies expand the understanding of primary blast injury mechanisms, provide computational models with important tissue-level tolerance criteria, inform protective equipment design, inform clinical care guidelines for bTBI, and present a promising therapeutic candidate for further clinical investigation. Table of Contents LIST OF FIGURES ..................................................................................................................... iv LIST OF TABLES ........................................................................................................................ v LIST OF ABBREVIATIONS ..................................................................................................... vi ACKNOWLEDGEMENTS ...................................................................................................... viii 1 INTRODUCTION ................................................................................................................. 1 1.1 BLAST-INDUCED TRAUMATIC BRAIN INJURY ................................................................................................ 2 1.2 BLAST-INDUCED DEFICITS IN BEHAVIOR AND COGNITION ............................................................................... 7 1.3 BLAST-INDUCED DEFICITS IN ELECTROPHYSIOLOGICAL FUNCTION .................................................................... 8 1.4 CELLULAR MECHANISMS OF BLAST-INDUCED ELECTROPHYSIOLOGICAL DYSFUNCTION .......................................... 9 1.5 NEUROPROTECTION THROUGH PHOSPHODIESTERASE-4 INHIBITION .............................................................. 11 1.6 SIGNIFICANCE .................................................................................................................................... 12 2 IN VITRO PRIMARY BLAST EXPOSURE INDUCED LOW-STRAIN, HIGH- STRAIN RATE DEFORMATION IN HIPPOCAMPAL SLICE CULTURES ................... 16 2.1 INTRODUCTION .................................................................................................................................. 16 2.2 MATERIALS AND METHODS .................................................................................................................. 18 2.2.1 Organotypic hippocampal slice cultures .................................................................................. 18 2.2.2 Cell death measurement .......................................................................................................... 19 2.2.3 Primary blast exposure ............................................................................................................. 19 2.2.4 High-speed videography and digital image correlation (DIC) .................................................. 21 2.3 RESULTS ........................................................................................................................................... 22 2.3.1 Primary blast exposure induced low strains ............................................................................. 22 2.3.2 Primary blast exposure induced high strain rates .................................................................... 25 2.3.3 Strain and rate thresholds for blast-induced LTP deficits ......................................................... 27 2.4 DISCUSSION ...................................................................................................................................... 27 3 ISOLATED PRIMARY BLAST INJURY TO IN VITRO ORGANOTYPIC HIPPOCAMPAL SLICE CULTURES INHIBITS LONG-TERM POTENTIATION ....... 34 3.1 INTRODUCTION .................................................................................................................................. 34 3.2 MATERIALS AND METHODS .................................................................................................................. 36 3.2.1 Organotypic hippocampal slice culture .................................................................................... 36 3.2.2 Primary blast exposure ............................................................................................................. 37 3.2.3 Cell death measurement .......................................................................................................... 38 3.2.4 Electrophysiology ..................................................................................................................... 39 3.2.5 Spontaneous activity ................................................................................................................ 40 3.2.6 Stimulus-response curves ......................................................................................................... 43 3.2.7 Paired-pulse ratios ................................................................................................................... 44 3.2.8 Long-term potentiation ............................................................................................................ 45 3.3 RESULTS ........................................................................................................................................... 45 i 3.3.1
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