Chondroitin sulphate proteoglycans (CSPGs) from the glial scar inhibit axonal regeneration following spinal cord injury. CSPG expression can be induced by transforming growth factor β (TGFβ), which suggests that inhibition of TGFβ may reduce CSPG levels. Astrocytes were treated with cyclic AMP (cAMP), which reduced TGFβ signaling protein Smad2 in astrocytes. However, cAMP-treated astrocytes showed strong neurocan expression following TGFβ treatment, which suggests that TGFβ may mediate CSPG expression through non-Smad pathways. Smad2 or Smad4 were knocked down in astrocytes using siRNA and TGFβ-induced neurocan, brevican and aggrecan expression were still observed, indicating that Smad signaling is not required for CSPG expression. Administration of a PI3K/Akt inhibitor produced significant reductions in neurocan, brevican and aggrecan expression in astrocytes, which suggests that PI3K/Akt pathway mediates CSPG expression. Erk1/2 inhibitor treatment did not reduce CSPG expression significantly. Targeting non-Smad signaling pathways may therefore be effective strategies to reduce CSPG expression following injury.

Acquiring knowledge of the morphological, molecular, and functional changes that occur to neurons following axotomy is a key step for a comprehensive understanding of the nervous system and how it reacts to injury. Propriospinal commissural interneurons (PCIs or CINs) are a class of neuron with axons that project through the ventral commissure to the contralateral spinal cord. My goal was to examine the morphological, molecular, and functional changes that occur to adult feline PCIs following a proximal axotomy. We first determined whether proximally axotomized PCIs develop de novo axons from their dendrites. C3 PCIs were proximally axotomized and several weeks later we stained PCIs and prepared the tissue for histological evaluation. Two primary classes of axotomized PCI were identified: those with a very short axon (called permanently axotomized) and those with an axon that projected across the injury site. Permanently axotomized PCIs had processes with morphological features typical of axons that emerged from their distal dendrites. These axonal processes of the distal dendrites also had GAP-43 (an axonal marker) and lacked MAP2a/b (a dendritic marker). We concluded that permanently axotomized PCIs develop de novo axons from distal dendrites. We then determined whether the axons that crossed the lesion site were representative of spontaneous functional regeneration. First, we showed that PCI axons regenerate through an environment that is typically highly inhibitory to regenerating axons. Second, we established that the regenerated axons conduct action potentials. Finally, we found that regenerated PCI axons form functional synaptic connections with neurons in the contralateral spinal cord. Collectively, these data indicated that spinal interneurons are capable of spontaneous functional regeneration through an injured spinal cord. PCI growth cones are complex and unlike growth cones previously described in the literature. The final study of the thesis examines the morphologies of PCI growth cones within spinal cord injury sites. We found that PCI growth cones have a wide range of morphologies that is independent of their location within the lesion site. Taken together, these data indicate that PCIs have a remarkable capacity for axonal elongation and contribute to remodelling of spinal circuitry following spinal injury. / Thesis (Ph.D, Physiology) -- Queen's University, 2009-12-07 11:21:47.036

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Lam Shi Ying Joyce. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (leaves 107-114). / Abstract in English and Chinese. / Chapter CHAPTER 1 --- GENERAL INTRODUCTION --- p.1-19 / Chapter CHAPTER 2 --- EXPRESSION OF PROTEIN KINASE C (PKC) ISOFORMS IN THE VENTRAL TEMPORAL (VT) AND DORSAL NASAL (DN) RETINAL GROWTH CONES OF MOUSE EMBRYOS / INTRODUCTION --- p.20-22 / MATERIALS AND METHODS --- p.22-24 / RESULTS --- p.24-31 / DISCUSSION --- p.31-37 / FIGURES --- p.38-46 / Chapter CHAPTER 3 --- EFFECTS ON MOUSE NASAL AND TEMPORAL RETINAL NEURITES TO CHONDROITIN SULPHATES (CS) AFTER ALTERATION OF PKC ACTIVITY / INTRODUCTION --- p.47-48 / MATERIALS AND METHODS --- p.49-51 / RESULTS --- p.51-59 / DISCUSSION --- p.60-67 / FIGURES --- p.68-74 / Chapter CHAPTER 4 --- EFFECTS ON AXON ROUTING AFTER ALTERATION OF PKC ACTIVITY ON GUIDANCE OF RETINAL GANGLION CELL AXONS AT THE OPTIC CHIASM OF MOUSE EMBRYOS / INTRODUCTION --- p.75-76 / MATERIALS AND METHODS --- p.77-80 / RESULTS --- p.80-89 / DISCUSSION --- p.89-95 / FIGURES --- p.96-103 / Chapter CHAPTER 5 --- GENERAL CONCLUSION --- p.104-106 / REFERENCES --- p.107-114

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