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Tpa PROMOTES POSTNATAL CORTICAL NEURON SURVIVAL I

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Tpa PROMOTES POSTNATAL CORTICAL NEURON SURVIVAL I tPA PROMOTES POSTNATAL CORTICAL NEURON SURVIVAL i Tissue plasminogen activator (tPA) promotes postnatal cortical neuron survival in vitro via JAK2- and mTOR-dependent mechanisms by Julia A. Grummisch A thesis submitted to the Faculty of Graduate and Postdoctoral Affairs in partial fulfillment of the requirements for the degree of Master of Science in Neuroscience Carleton University Ottawa, Ontario © 2015 Julia A. Grummisch tPA PROMOTES POSTNATAL CORTICAL NEURON SURVIVAL ii Abstract Tissue plasminogen activator (tPA) is the only approved drug for ischemic stroke in Canada but is limited in its clinical efficacy due to its short therapeutic window. This study sought to determine the effect of tPA on postnatal primary cortical neuron viability and aimed to identify the relevant cellular signalling mechanisms underlying the tPA-mediated effects in vitro. The data revealed that tPA significantly increased the propensity for cell survival within a time latency window of up to 3 hours. tPA-induced neuroprotective effects were significantly dependent upon the mTOR and JAK/STAT signalling pathways, while the MEK and PKA signalling pathways were found to play a less critical role. Immunocytochemical staining showed a marked increase in p-S6 expression following treatment with tPA, substantiating the vital role of mTOR activation in tPA-mediated neuroprotection. These results suggest the possibility of targeting the defined mechanisms to expand the therapeutic window of tPA in stroke recovery. tPA PROMOTES POSTNATAL CORTICAL NEURON SURVIVAL iii Acknowledgments My sincerest thanks goes to everyone who has helped me along this educational journey. I would like to appreciate my thesis supervisor, Dr. Patrice Smith, as well as the members of my thesis committee, Drs. Alfonso Abizaid and John Stead, for their time, support, insight and advice. I would also like to thank past and present members of the Smith lab for their help, encouragement, and laughter along the way. I would also like to thank the staff in Animal Care for their flexibility and patience. Last but certainly not least, I would like to thank my close friends and family, especially my Mom and Oma, for their unwavering support, encouragement, and avid belief in me. tPA PROMOTES POSTNATAL CORTICAL NEURON SURVIVAL iv Table of Contents Title Page ........................................................................................................................................ i Abstract .......................................................................................................................................... ii Acknowledgments ........................................................................................................................ iii Table of Contents ......................................................................................................................... iv List of Tables ................................................................................................................................ vi List of Figures .............................................................................................................................. vii List of Abbreviations ................................................................................................................. viii Introduction ................................................................................................................................... 1 Development of the nervous system ........................................................................................... 1 Growth and survival factors within the developing nervous system .......................................... 2 Naturally occurring cell death ..................................................................................................... 4 Apoptosis and its mechanisms of cell death ............................................................................ 4 Alternative forms of naturally occurring cell death ................................................................. 9 Necrosis, an alternative form of cell death...........................................................................9 Autophagy and its role in cell viability ...............................................................................13 Promotion of cell survival and the vital role of cellular signalling mechanisms ...................... 15 JAK/STAT Pathway .............................................................................................................. 16 Raf/MEK/ERK Pathway........................................................................................................ 19 cAMP/PKA/CREB Pathway ................................................................................................. 22 PI3K/PTEN/Akt/mTOR Pathway .......................................................................................... 26 Stroke ........................................................................................................................................ 30 Tissue plasminogen activator (tPA) .......................................................................................... 31 tPA’s pleiotropic role in neuronal viability ........................................................................... 32 tPA-induced neurotoxicity .................................................................................................34 tPA-induced neuroprotection .............................................................................................36 Research Objectives .................................................................................................................. 40 Major Hypotheses ..................................................................................................................... 40 Methods ........................................................................................................................................ 40 Animals ..................................................................................................................................... 40 Tissue isolation and primary neuronal cell culture ................................................................... 41 Plating........................................................................................................................................ 42 tPA time course and inhibitor treatments .................................................................................. 42 Immunocytochemistry ............................................................................................................... 42 Cell quantification ..................................................................................................................... 43 Statistical analyses..................................................................................................................... 44 Results .......................................................................................................................................... 44 tPA increases postnatal cortical neuron survival in vitro .......................................................... 44 tPA promotes postnatal cortical neuron survival via mTOR and JAK/STAT pathway activation ................................................................................................................................... 47 tPA-induced signalling mechanisms at 3 DIV show marked activation of p-S6 expression .... 53 Discussion..................................................................................................................................... 56 tPA-induced cell survival .......................................................................................................... 57 Mechanisms underlying tPA-induced neuroprotection ............................................................. 62 Limitations and future directions .............................................................................................. 74 tPA PROMOTES POSTNATAL CORTICAL NEURON SURVIVAL v References .................................................................................................................................... 79 tPA PROMOTES POSTNATAL CORTICAL NEURON SURVIVAL vi List of Tables Table 1. Mean raw cell counts per well and percentage of control cell survival levels for the tPA- or ddH2O-treated groups treated with one or more inhibitor solutions ............................... 52 tPA PROMOTES POSTNATAL CORTICAL NEURON SURVIVAL vii List of Figures Figure 1. The apoptotic signalling cascade .................................................................................... 6 Figure 2. The JAK/STAT, Raf/MEK/ERK, and PI3K/PTEN/Akt/mTOR pathway cascades .... 16 Figure 3. Protective effect of tPA on postnatal cortical neuron viability .................................... 45 Figure 4. Representative micrograph showing β-Tubulin staining and colocalization of DAPI in an immunostained postnatal cortical neuron ................................................................................. 46 Figure 5. tPA promotes postnatal cortical neuron survival within a 3-hour time interval ........... 46 Figure 6. tPA promotes survival of postnatal cortical neurons via activation of the mTOR pathway ........................................................................................................................................ 48 Figure 7. tPA does not significantly rely on the Raf/MEK/ERK pathway to promote
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