Anatomy and Neuroscience - Theses
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ItemInvestigating the role of neuronal TrkB in remyelination(2023-02)Demyelinating diseases, such as multiple sclerosis (MS), involve damage to the fatty, proteinaceous myelin sheaths surrounding nerve fibres and subsequent development of neurological symptoms related to the damaged area. Repair of the damaged myelin can completely or partially reverse the neurological deficits, however, over time with repetitive demyelinating events and incomplete remyelination this ultimately results in the degeneration of neurons and development of permanent disabilities. Currently, there is a lack of therapies effective in promoting myelin repair. A complete understanding of the factors that promote remyelination is critical for developing therapeutic strategies for myelin repair to prevent permanent neurological disability. Many studies have focused on the potential of oligodendrocytes (the myelin-generating cells in the central nervous system) to enhance the generation of myelin. However, neurons certainly have an intimate relationship with oligodendrocytes and are well-positioned to influence the process of myelination. Previously, neuronal expression of the tyrosine kinase receptor TrkB has been shown to promote myelination in early development and during ageing. However, whether neuronally expressed TrkB receptors also influences the extent of oligodendroglial and myelin damage post a demyelinating injury, and the subsequent process of remyelination has not been elucidated. In this thesis, I generated an inducible, neuron-specific TrkB receptor knockout mouse line to investigate the role of neuronal TrkB receptors in the extent of both demyelination and remyelination following the induction of a demyelinating insult with cuprizone administration. I found that following deletion of TrkB, these mice exhibit a normally myelinated nervous system, but do however develop a motor phenotype consistent with a decrease in precise motor control. Following administration with cuprizone, I revealed that neuronal expression of TrkB is important for the differentiation of OPCs (oligodendrocyte progenitor cells) that are generated in response to the demyelinating insult. Finally, although reduced expression of neuronal TrkB did not influence the overall extent of remyelination, I found that axons with small diameter required expression of neuronal TrkB to be efficiently remyelinated. This work is the first to identify that neuronally expressed TrkB receptors have a role in OPC differentiation following demyelination. This thesis suggests there is therapeutic potential in targeting neuronal TrkB signalling to promote myelin repair, albeit this may only be specific to smaller diameter neurons.