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Neurotoxicity of Tri-Cresyl Phosphate : Impairment of Glutamate Signaling

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Neurotoxicity of Tri-Cresyl Phosphate : Impairment of Glutamate Signaling Neurotoxicity of tri-cresyl phosphate - Impairment of glutamate signaling in mouse central nervous system neurons in vitro Dissertation to obtain the degree Doctor Rerum Naturalium (Dr. rer. nat.) at the Faculty of Biology and Biotechnology Ruhr-University Bochum Leibniz Research Centre for Working Environment and Human Factors Neurotoxicology and Chemosensation submitted by Vanessa Hausherr from Sprockhövel, Germany Bochum October 2015 1. Supervisor: PD. Dr. C. van Thriel 2. Supervisor: Prof. Dr. H. Lübbert Neurotoxizität von Tri-cresylphosphaten - Beeinflussung der glutamatergen Signaltransduktion in murinen Neuronen des zentralen Nervensystems in vitro Dissertation zur Erlangung des Grades eines Doktors der Naturwissenschaften der Fakultät für Biologie und Biotechnologie an der Internationalen Graduiertenschule Biowissenschaften an der Ruhr-Universität Bochum angefertigt im Leibniz-Institut für Arbeitsforschung Neurotoxikologie und Chemosensorik vorgelegt von Vanessa Hausherr aus Sprockhövel, Deutschland Bochum Oktober 2015 1. Betreuer: PD. Dr. C. van Thriel 2. Betreuer: Prof. Dr. H. Lübbert Index of Contents Summary _________________________________________________________ IV Zusammenfassung _________________________________________________ VI Abbreviations ____________________________________________________ VIII 1 Introduction__________________________________________________ 1 1.1 Central and peripheral nervous system ___________________________________ 5 1.2 Neurite outgrowth and neurite degeneration _____________________________ 6 1.3 Neurotransmitter systems and ion channels ______________________________ 8 1.3.1 Glutamate receptors ________________________________________________________ 8 1.3.2 GABA receptors ___________________________________________________________ 13 1.3.3 Voltage-gated calcium channels ______________________________________________ 14 1.3.4 TRP Channels _____________________________________________________________ 15 1.4 Neurotransmission and activity-dependent plasticity ______________________ 16 1.5 Organophosphate-induced delayed neuropathy __________________________ 18 1.5.1 Chemistry of OPIDN inducing compounds ______________________________________ 19 1.5.2 Neuropathology and clinical signs of OPIDN ____________________________________ 19 1.6 Tri-cresyl phosphate _________________________________________________ 20 1.6.1 Structure of TCPs __________________________________________________________ 20 1.6.2 Metabolism of TCPs ________________________________________________________ 21 1.6.3 Toxicity of TCPs ___________________________________________________________ 23 1.6.4 Human TCP poisoning ______________________________________________________ 24 1.7 The aerotoxic syndrome ______________________________________________ 24 1.8 Objectives _________________________________________________________ 26 2 Material and methods ________________________________________ 27 2.1 Material __________________________________________________________ 27 2.1.1 Chemical Reagents and Kits __________________________________________________ 27 2.1.2 Primary Antibodies ________________________________________________________ 29 2.1.3 Secondary Antibodies ______________________________________________________ 29 2.1.4 Consumables _____________________________________________________________ 30 2.1.5 Technical Equipment _______________________________________________________ 31 2.2 Methods __________________________________________________________ 32 2.2.1 Animals __________________________________________________________________ 32 2.2.2 Preparation and cell culture of primary mouse cortical neurons ____________________ 32 I Index of Contents 2.2.3 Preparation and cell culture of primary rat cortical neurons ________________________ 33 2.2.4 Preparation and cell culture of mouse dorsal root ganglia neurons __________________ 33 2.2.5 Treatment conditions ______________________________________________________ 34 2.2.6 CellTiter-Blue® cell viability assay _____________________________________________ 34 2.2.7 Immunocytochemistry ______________________________________________________ 35 2.2.8 Quantitative analysis of neurite outgrowth and neurite degeneration _______________ 36 2.2.9 Quantitative analysis of neurite morphology ____________________________________ 36 2.2.10 Network Formation Assay _________________________________________________ 37 2.2.11 Calcium Imaging ________________________________________________________ 38 2.2.12 RNA Isolation ___________________________________________________________ 39 2.2.13 cDNA Synthesis _________________________________________________________ 39 2.2.14 Quantitative Real-Time PCR _______________________________________________ 40 2.2.15 Statistical Analysis _______________________________________________________ 41 3 Results _____________________________________________________ 42 3.1 Morphology of mouse primary cortical neurons at different stages of the in vitro culture __________________________________________________________________ 42 3.2 Impairment of cell viability ___________________________________________ 43 3.2.1 TCP isomers and TCP mixture impair cell viability ________________________________ 43 3.2.2 ToCP impairs cell viability ___________________________________________________ 44 3.2.3 CBDP impairs cell viability ___________________________________________________ 45 3.3 Impairment of neurite outgrowth and neurite degeneration ________________ 46 3.3.1 Inhibition and degeneration of neuronal networks by TCP isomers __________________ 46 3.3.2 Inhibition and degeneration of neuronal networks by ToCP ________________________ 47 3.3.2.1 Time course of neurite outgrowth inhibition – Network Formation Assay ________ 50 3.3.3 Inhibition and degeneration of neuronal networks CBDP __________________________ 51 3.4 Effects of TCPs on neurochemical processes ______________________________ 52 3.4.1 TCP isomers impair glutamate signaling ________________________________________ 53 3.4.2 ToCP impairs glutamate signaling _____________________________________________ 57 3.4.2.1 ToCP affects glutamate receptor expression ________________________________ 65 3.4.3 Recovery of the glutamate sensitivity after ToCP exposure ________________________ 66 3.4.4 Effects of the ToCP metabolite CBDP on glutamate signaling _______________________ 70 3.4.5 ToCP induced effects on glutamate signaling in rat cortical neurons _________________ 71 3.4.6 ToCP effects on non-glutamatergic signaling ____________________________________ 72 3.4.7 Direct receptor-mediated action of tri-cresyl phosphates and the metabolite CBDP ____ 74 3.4.8 Mechanism and target of ToCP-induced block of glutamate responses _______________ 78 3.4.8.1 ToCP affects NMDA receptor-mediated responses ___________________________ 79 3.4.8.2 ToCP affects AMPA receptor-mediated responses ___________________________ 81 II Index of Contents 4 Discussion __________________________________________________ 82 4.1 Impairment of glutamate signaling _____________________________________ 83 4.1.1 Direct receptor-mediated action of ToCP _______________________________________ 83 4.1.2 ToCP impairs glutamate sensitivity in a time- and concentration dependent manner ___ 86 4.1.3 Regeneration capacity of pCNs after ToCP treatment _____________________________ 89 4.1.4 Is the reduced glutamate sensitivity a specific mode of action of ToCP? ______________ 90 4.1.5 Impairment of glutamate signaling by CBDP ____________________________________ 92 4.1.6 Impairment of glutamate signaling by TCP isomers _______________________________ 92 4.1.7 Increased basal calcium levels as an endpoint of TCP-induced neurotoxicity __________ 93 4.2 Impairment of neurite outgrowth and neurite degeneration ________________ 94 4.3 ToCP, TCPs and the aerotoxic syndrome _________________________________ 97 4.4 Conclusion _________________________________________________________ 99 5 List of Figures ______________________________________________ 102 6 List of Tables _______________________________________________ 104 7 References _________________________________________________ 105 8 Publication List _______________________________________________ 1 9 Curriculum Vitae ______________________________________________ 4 10 Danksagung ________________________________________________ 5 III Summary Summary The nervous system is characterized by its ability to transmit and process incoming information from extrinsic and intrinsic stimuli via specialized neuronal networks consisting of interconnecting neurites and synapses. The developing as well as the adult brain had an astonishing capacity to reorganize its connectivity on structural and functional levels to adapt to changing environmental conditions and based on behaviorally experience, which is called activity-dependent plasticity. As a result of incoming information and learning and memory mechanisms, synapses are strengthened and weakened during life changes. Synaptic strength is based on changes in trafficking, subunit composition, and signaling of AMPAR and NMDAR as fundamental processes. The nervous system with its strictly regulated processes is a highly sensitive target structure of a variety of toxins. Neurotoxins can cause alterations in a variety of pathways, which lead to adverse outcomes when sufficiently perturbed. Tri-ortho cresylphosphate is a well-known neurotoxin, which cause after high dose exposure organophosphate-induced delayed neuropathy. The main objective of the present thesis
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