Anatomy and Neuroscience - Theses
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ItemInvestigation of the role of TrkB on oligodendroglial development and central nervous system myelination( 2012)Understanding the extracellular factors and the mechanisms they utilize to regulate CNS myelination will provide better insight into potential therapeutic strategies for demyelinating diseases. The neurotrophin brain-derived neurotrophic factor (BDNF) has been shown to promote myelination via the activation of oligodendrocyte expressed TrkB receptors in vitro. To investigate the precise role of BDNF in regulating CNS myelination in vivo, I generated conditional knockout mice in which TrkB was deleted specifically in post-mitotic oligodendrocytes. In this study, I found that deletion of oligodendrocyte expressed TrkB disrupted normal CNS myelination. It significantly delayed myelin protein expression and myelination of CNS white matter tracts. Further ultrastructural analyses at P12 showed the decreased myelination was not due to a change in oligodendrocyte density but reduced myelin thickness in the TrkB conditional knockout mice. Curiously, the TrkB conditional knockout mice also exhibited an increased density of oligodendrocyte precursor cells (OPCs) in CNS white matter tracts. In vitro myelination assays, co-culturing dorsal root ganglion neurons with OPCs subjected to TrkB knockdown, revealed increased OPC proliferation, indicating TrkB receptor expression exerts a cell autonomous effect upon OPC proliferation. Thus, my data demonstrates that deletion of TrkB exerts distinct influences on cells in the oligodendroglial lineage in vivo, exerting a proliferative effect upon OPCs and obstructing normal myelination by oligodendrocytes. While BDNF exerts a promyelinating influence during development, it is not required for the maintenance of a myelinated CNS in the adult mice, as normal myelin protein expression and myelination of CNS white matter tracts was observed in the TrkB conditional knockout mice. Interestingly, TrkB expression was undetectable in oligodendrocytes from adult mice. However, oligodendrocyte expressed TrkB receptors were substantially re-expressed in adult wildtype mice undergoing remyelination following a cuprizone induced demyelinating challenge, suggesting that oligodendrocyte TrkB receptor is essential for remyelination. In summary, this study establishes that TrkB expression in oligodendroglia exerts an important influence on oligodendrocytes to promote myelination during development. Further studies are required to investigate if BDNF-TrkB exerts a potential role in remyelination.