Molecular mechanisms of BDNF signalling in central nervous system myelination

© 2016 Dr. Haley Moss PeckhamMyelination within the CNS allows the fast and efficient transmission of action potentials along axons. Both myelin and the oligodendrocytes that generate myelin and wrap the axons are crucial for the development and maintenance of an adaptive and healthy nervous system. Interestingly, the process of myelination is responsive to neural activity so myelination also contributes to a form of neuroplasticity called white matter plasticity. Disorders as varied as multiple sclerosis and schizophrenia result when myelination is compromised, and experiences in the world, from childhood neglect and maltreatment to learning a second language, leave their trace in the white matter of our brains. Much remains to be discovered about the factors that regulate myelination and the signalling networks these factors utilise. Our laboratory has taken an interest in a growth factor that has a recognised role in synaptic plasticity and is epigenetically regulated. This molecule is brain-derived neurotrophic factor (BDNF). Our studies reveal that BDNF exerts a pro-myelinating effect in vitro and utilises Erk1/2 to mediate this effect. Specifically, BDNF acts on oligodendroglial TrkB receptors to myelinate the axons of DRG neurons in co-culture with oligodendrocytes. Studies in vivo confirm a role for BDNF, TrkB and Erk1/2 in myelination. Previous work from our laboratory indicates that loss of TrkB from myelinating oligodendrocytes leads to a phenotype of thinner myelin in the CNS, and my results reveal that when TrkB is deleted from the time of oligodendrocyte specification, this phenotype is restricted to thinner myelin only around large diameter axons. This suggests that there compensation occurs for the loss of TrkB but the factors that contribute to this putative mechanism of compensation are not yet known. Surprisingly, despite TrkB null oligodendrocytes only yielding a relatively mild hypomyelinating phenotype in vivo, I discovered that in the context of a myelinating co-culture, TrkB null oligodendrocytes exhibit a severely reduced capacity to myelinate. This led me to pose the question: how were oligodendrocytes that had a very limited capacity to myelinate in vitro able to myelinate the majority of axons normally in vivo? The result suggested that a cell or factor that was present in vivo but absent in the myelinating co-culture system was enhancing the oligodendrocytes capacity to myelinate. Interestingly, in vitro studies demonstrate that Fyn kinase associates with and is activated by TrkB, and that Fyn translocates neuronal TrkB receptors to lipid rafts in response to BDNF treatment. Similarly to BDNF, in vivo studies on Fyn kinase reveal that it too has a role in synaptic plasticity and myelination and this potentially suggests they utilise a common signalling pathway. In this work I interrogated BDNF signalling in oligodendrocytes and identified that BDNF and Fyn kinase do share a common signalling pathway: Fyn kinase is a downstream mediator of the pro-myelinating effect of BDNF. I then hypothesised that Fyn kinase could form part of a mechanism that compensates for the loss of oligodendroglial TrkB in myelination in vivo. I demonstrated that forced over-expression of Fyn kinase by TrkB null oligodendrocytes enhanced myelination in vitro. However, I also found that in isolated, cultured TrkB null oligodendrocytes the expression of Fyn kinase protein was lower than control oligodendrocytes although proportionally more of it was active. Taken together, these results suggest that Fyn kinase could, in principle, contribute towards redundancy in myelination but requires factors or cells, absent from the in vitro myelination assay, but present in vivo that increase its activation or expression level. Further studies are required to identify these factors and to determine if this putative compensation mechanism occurs in vivo. BDNF and Fyn kinase both have roles in neural plasticity and it is consistent with a maxim of biological economy that they would have complementary roles in white matter plasticity. BDNF switches oligodendrocytes into an activity dependent mode of myelination, and the findings of this study indicate that Fyn kinase mediates BDNF driven myelination, suggesting a role for Fyn kinase in white matter plasticity as well. Due to the burgeoning burden of neurodegeneration and the recognition that white matter plasticity is affected in mental illness and by experiences of trauma, it is imperative that we interrogate the molecular mechanisms of white matter plasticity to better target treatments to alleviate the distress caused by these challenges