The adult mammalian central nervous system (CNS) has limited ability to regenerate and repair following injury. This is partly due to the presence of growth inhibitory molecules that are expressed during the late stages of CNS development. One of the obvious candidates that appears late during the development of the mammalian CNS is myelin. Several individual components of myelin responsible for creating a growth inhibitory environment in the CNS have been identified. One such component known as Nogo-A is widely considered to be a major growth inhibitory molecule in the mammalian CNS. Delivery of antibodies against Nogo-A in vivo can stimulate axonal regeneration and compensatory sprouting thereby enhancing functional recovery in animal models of spinal cord injury and stroke. Therefore, Nogo-A is considered to be an important target for developing therapeutic regimes to treat conditions like cerebro-vascular stroke and spinal cord injury.

Although Nogo-A was originally discovered in association with myelin, over the last few years several groups have shown the presence of Nogo-A in various neuronal subtypes in the CNS. Nogo-A mRNA is present in a wide variety of neuronal subtypes in the adult CNS. Additionally, Nogo-A protein is expressed by the neurons of developing and adult mammalian CNS. Neurons positive for Nogo-A mRNA and protein expression have also been reported in wide areas of the developing and adult human CNS. However, the physiological role of neuronal Nogo-A in the development and functioning of mammalian nervous system remains unclear.

Expression of neuronal Nogo-A is altered in various diseases in humans affecting the CNS. For example, Nogo-A expression is increased in the hippocampal pyramidal neurons of patients diagnosed with temporal lobe epilepsy and Alzheimer's disease. Also, Nogo-A mRNA levels are elevated in the frontal cortex of patients diagnosed with Schizophrenia. It is not clear if neuronal Nogo-A plays a direct role in the pathophysiology of these diseases. However, all of the above diseases are associated with significant alterations in spine density and morphology.

Whether a change in Nogo-A expression is related to the alteration of dendritic spines in these pathological states remains unknown. However, in a rodent model of stroke treated with anti-Nogo therapy an increase in spine density of layer V pyramidal neurons in the contralesional motor cortex was reported. Moreover, Nogo-A immunoreactivity has been detected in close association with the postsynaptic densities and postsynaptic dense bodies at the synapses of adult rat spinal motorneurons. These reports raise the possibility of neuronal Nogo-A playing a role in regulation of synaptic plasticity and dendritic spine morphogenesis.

This dissertation was undertaken to investigate the role of neuronal Nogo-A in dendritic spine morphogenesis. We hypothesized that neuronal Nogo-A gene knockdown would cause alteration in dendritic spine density and morphology in vivo. In pursuit of experiments to test this hypothesis we developed and used an adeno-associated virus (AAV 2/8) to induce neuron specific Nogo-A gene knockdown in vivo to study its effect on dendritic spine density and morphology of layer IV/V cortical pyramidal neurons. We found a significant reduction in the spine density of apical dendrites. The dendrites also showed significant alterations in spine morphology and an increase in the percentage of immature dendritic protrusions. These findings indicate that neuronal Nogo-A may be involved in maintaining an optimal spine density and stabilization of a mature spine morphology.