Teleost retinal ganglion cells can regenerate severed axons following injury, something their mammalian counterparts cannot do. In the teleost, successful regeneration has been attributed in part to microglial cell activities including the phagocytosis of myelin. Although the regulation of microglial phagocytosis has been studied in mammals, in the teleost it is largely unexamined. The present study was designed to identify mediators of microglial phagocytosis released by injured goldfish optic nerve during the course of regeneration. We found that microglial phagocytosis was significantly enhanced in the presence of a 7 day regenerating nerve or medium conditioned by the nerve (CM). When either nerve or CM was incubated with microglia along with an antibody against tumour necrosis factor alpha (TNFalpha), this effect was neutralized. The L929 cell cytotoxicity assay further demonstrated TNFalpha activity in the CM. However, Western blot analysis did not confirm this result. Therefore, further work is necessary to clearly establish the presence of TNFalpha.

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Su Huan Xing. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2002. / Includes bibliographical references (leaves 79-89). / Abstracts in English and Chinese. / Abstract --- p.i / 中文摘要 --- p.iii / Acknowledgements --- p.iv / Abbreviations Frequently Used --- p.v / Table of contents --- p.vi / Chapter Chapter1 --- General Introduction --- p.1 / Chapter Chapter2 --- Effects of an intravitreal optic nerve graft on the sprouting and regeneration of axotomized retinal ganglion cells --- p.17 / Chapter Chapter3 --- Effects of an intravitreal pre-injured optic nerve graft on the sprouting and regeneration of axotomized retinal ganglion cells --- p.44 / Chapter Chapter4 --- Effects of co-transplantation of an optic nerve graft and a peripheral nerve graft into the vitreous body on the sprouting and regeneration of axotomized retinal ganglion cells --- p.60 / Chapter Chapter5 --- General discussion --- p.74 / References --- p.79 / Tables --- p.90

by Ling Lin. / "November 2002." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2002. / Includes bibliographical references (p. 149-168). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

During development of the nervous system, formation of specific connections between nerve cells depends on the stability of growing axons to reach appropriate target cells and form synapses. In culture, hippocampal neurons form numerous synapses by developing axonal and dendritic extensions. To elucidate principles of neuronal signaling and network establishment, creation of neuronal networks in which connectivity and pathways can be experimentally controlled is of great interest. In the present study we used a microcontact printing technique to control and study neurite outgrowth of hippocampal neurons in vitro. My preliminary results show that hippocampal neurons follow the microcontact printed pattern of poly-D-lysine (PDL). In doing so, neurons retain their morphology with normal subcellular distribution of various cell adhesion and synaptic molecules. However, the distribution of various axonal or dendrite components is altered. Hence we have developed a system in which isolated axons and dendrites align with inputs from very few neurons. With this technique we intend to study axon-dendrite communications on a spatially restricted and defined substrate.

Glial cells represent the most abundant cell population in the central nervous system (CNS), and yet, have historically been thought of as merely support cells for neurons. Over the past few decades, however, the number of identified roles that glial cells play in the CNS has expanded at an exponential rate, revealing new and exciting functions in neuron-glial communication. At synapses, astrocytes are now recognized as part of a "tripartite" complex with pre- and postsynaptic structures and can modulate synaptic transmission and plasticity. Accumulating evidence has also revealed new roles for oligodendrocytes in regulating axon diameter and integrity, and ion channel clustering. Despite our knowledge of the physiological connections between neurons and glia, relatively little is known about the morphological interplay of these cells during development and in the mature brain. The results presented in this thesis reveal the extent and time-course of rapid remodelling of astrocytes and oligodendrocytes in close proximity to dendritic spines and axons respectively. These findings provide further evidence that glia play an important role in regulating the structural plasticity of the brain. The methodology developed also provides a powerful system for the study of neuron-glial structural dynamics and may contribute to the development of novel therapeutic strategies for diseases affecting the central nervous system.

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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