by Priscilla, Ka-Yee Chan. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1998. / Includes bibliographical references (leaves 77-100). / Abstract also in Chinese. / ACKNOWLEDGEMENTS --- p.4 / ABSTRACT --- p.5 / ABSTRACT (Chinese) --- p.7 / PUBLICATION --- p.8 / ABBREVIATION --- p.9 / Chapter CHAPTER 1 --- INTRODUCTION --- p.10 / Chapter 1.1 --- Overview of the study --- p.10 / Chapter 1.2. --- Substantia nigra pars reticulata (SNR) --- p.12 / Chapter 1.2.1 --- SNR and the basal ganglia / Chapter 1.2.2 --- GABA neurotransmission in SNR / Chapter 1.2.3 --- SNR and epilepsy / Chapter 1.3 --- GABAb receptors --- p.18 / Chapter 1.3.1 --- GABA receptors / Chapter 1.3.2 --- GABAb receptors and their classification / Chapter 1.3.3 --- Agonists and antagonists of GABAb receptor / Chapter 1.3.4 --- Distribution of GAB AB receptor / Chapter 1.3.5 --- GABAb receptors in epilepsy and the involvement of SNR / Chapter 1.4 --- Cannabinoid receptors --- p.24 / Chapter 1.4.1 --- Cannabinoid receptors and their classification / Chapter 1.4.2 --- Agonists and antagonists of cannabinoid receptor / Chapter 1.4.3 --- Distribution of cannabinoid receptors / Chapter 1.4.4 --- Cannabinoid receptors in epilepsy and the involvement of SNR / Chapter CHAPTER 2 --- METHODS --- p.31 / Chapter 2.1 --- Brain slice preparation and maintenance --- p.31 / Chapter 2.2 --- Experimental set-up --- p.32 / Chapter 2.2.1 --- Visualization of neurones / Chapter 2.2.2 --- Electrophysiological recordings / Chapter 2.2.3 --- Evoked stimulation / Chapter 2.2.4 --- Drug preparation and administration / Chapter 2.3 --- Identification of GAB A and dopamine neurones --- p.36 / Chapter 2.4 --- Data analysis --- p.37 / Chapter 2.4.1 --- Construction of dose-response curve / Chapter 2.4.2 --- Analysis of synaptic currents / Chapter 2.4.3 --- Statistics / Chapter CHAPTER 3 --- RESULTS --- p.39 / Chapter 3.1 --- Basic characteristics of IPSCs in SNR --- p.39 / Chapter 3.1.1 --- Spontaneous and miniature IPSCs / Chapter 3.1.2 --- Evoked IPSCs / Chapter 3.2 --- GABAb receptors in SNR --- p.42 / Chapter 3.2.1 --- Postsynaptic GABAb receptors in SNR neurones / Chapter 3.2.1.1 --- Baclofen-activated postsynaptic response / Chapter 3.2.1.2 --- Effects of GABAb receptor antagonist on IPSCs / Chapter 3.2.2 --- Presynaptic GABAb receptors / Chapter 3.2.3 --- Effects of GAB A uptake blocker / Chapter 3.3 --- Cannabinoid receptors in SNR --- p.51 / Chapter 3.3.1 --- Postsynaptic cannabinoid receptors in SNR neurones / Chapter 3.3.2 --- Presynaptic action of cannabinoids / Chapter CHAPTER 4 --- DISCUSSION and CONCLUSION --- p.55 / Chapter 4.1 --- General properties of IPSCs --- p.55 / Chapter 4.2 --- GABAb receptors in SNR neurones --- p.58 / Chapter 4.2.1 --- Postsynaptic GABAB receptors in SNR neurones / Chapter 4.2.2 --- GABAb component in spontaneous and evoked IPSCs / Chapter 4.2.3 --- Presynaptic GABAb receptors in SNR / Chapter 4.2.4 --- Role of GABA uptake / Chapter 4.3 --- Cannabinoid receptors in SNR neurones --- p.67 / Chapter 4.3.1 --- Postsynaptic cannabinoid receptors in SNR neurones / Chapter 4.3.2 --- Presynaptic cannabinoid receptors in SNR / Chapter 4.4 --- SNR GABAb and cannabinoid receptors - their role in epilepsy --- p.72 / Chapter 4.5 --- Concluding remarks and future direction --- p.75 / REFERENCES --- p.77

by Wu Cheok Wai. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1998. / Includes bibliographical references (leaves 35-39 (2nd gp.)). / Abstract also in Chinese. / Abstract in English --- p.i / Abstract in Chinese --- p.iii / Acknowledgment --- p.v / Chapter Chapter 1: --- Introduction --- p.1 / Chapter 1.1 --- GABAa Mediated Neurotransmission --- p.1 / Chapter 1.2 --- Determinants of GABAa IPSC Kinetics --- p.3 / Chapter 1.3 --- Detection of the Spontaneous IPSCs --- p.5 / Chapter 1.4 --- The C++ Programming Language --- p.7 / Chapter Chapter 2: --- The Detection Algorithm --- p.11 / Chapter 2.1 --- Overview of the Algorithm --- p.11 / Chapter 2.2 --- Detection of Events --- p.12 / Chapter 2.3 --- Measurement of Parameters --- p.20 / Chapter Chapter 3: --- Performance Evaluation --- p.22 / Chapter 3.1 --- The Automatic Detection Software --- p.22 / Chapter 3.2 --- Performance of the Software --- p.23 / Chapter 3.3 --- Discussion --- p.25 / Chapter Chapter 4: --- Application --- p.28 / Chapter 4.1 --- Introduction --- p.28 / Chapter 4.2 --- Materials and Methods --- p.29 / Chapter 4.3 --- Results --- p.32 / Chapter 4.4 --- Discussion --- p.33 / Reference --- p.35 / Appendix --- p.40

Regrowth in the lesioned central nervous system is impeded by inhibitory molecules including myelin-associated inhibitors (MAIs) and chondroitin sulfate proteoglycans (CSPGs). Inhibitory molecules engage neuronal cell surface receptors and activate the small GTPase RhoA in injured neurons to mediate neurite outgrowth inhibition through targeted modifications to the cytoskeleton. Inhibition of RhoA with the ribosyltransferase C3 attenuates neurite outgrowth inhibition in vitro and in vivo but the ubiquitous expression and multifunctionality of RhoA may limit the specificity of therapeutic RhoA antagonists. The hypothesis of the thesis is that molecules that functionally interact with RhoA to mediate myelin-dependent inhibition may represent more specific targets for therapeutic intervention. We have explored the contribution of two RhoA interacting proteins to the neurite outgrowth inhibitory effects of MAIs. In Chapter 2 we describe the contribution of the rho effector, Rho kinase (ROCK) to MAI responses in neurons. In Chapter 3 we identify the cytosolic phosphoprotein CRMP4b (Collapsin Response Mediator Protein 4b) as a novel RhoA binding partner that mediates neuronal responses to CNS inhibitors. By structure function analysis we have developed a molecular antagonist of CRMP4b-RhoA binding that promotes neurite outgrowth on inhibitory substrates in vitro and has the potential to be a potent and specific molecular therapeutic for spinal cord injury. In Chapter 4 we identify glycogen sythase kinase 3b (GSK3b) as an important kinase in the MAI pathway that regulates protein interactions with RhoA. This thesis provides insights into the signal transduction machinery that is engaged in response to CNS inhibitors and suggests several novel therapeutic targets to promote axon regeneration following CNS injury.

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