Neurotrophins have long been viewed as key players in neuronal survival and differentiation during development. Recently, one of the neurotrophins, brain-derived neurotrophic factor (BDNF), has emerged as a potent factor for synaptic modulation. Actions of BDNF are mediated by activation of receptor tyrosine kinase TrkB. Our laboratory has previously reported that Cdk5 (cyclin-dependent kinase 5), a serine/threonine kinase, phosphorylates TrkB at Ser478. Given the abundant expression of Cdk5 and TrkB in neurons throughout development, and their respective concentration at the synapse, we are interested in explicating the crosstalk between Cdk5 and BDNF signaling and functions. To examine the involvement of Cdk5 in BDNF-mediated neuronal survival, we adopted starvation-induced apoptosis...[ Read more ]

Neurotrophins have long been viewed as key players in neuronal survival and differentiation during development. Recently, one of the neurotrophins, brain-derived neurotrophic factor (BDNF), has emerged as a potent factor for synaptic modulation. Actions of BDNF are mediated by activation of receptor tyrosine kinase TrkB. Our laboratory has previously reported that Cdk5 (cyclin-dependent kinase 5), a serine/threonine kinase, phosphorylates TrkB at Ser478. Given the abundant expression of Cdk5 and TrkB in neurons throughout development, and their respective concentration at the synapse, we are interested in explicating the crosstalk between Cdk5 and BDNF signaling and functions. To examine the involvement of Cdk5 in BDNF-mediated neuronal survival, we adopted starvation-induced apoptosis in cortical neurons as a model. Based on the studies using pharmacological inhibitor of Cdk5 as well as Cdk5 knockout neurons, we found that Cdk5 activity was required for BDNF-mediated protection against apoptosis. However, over-expression of a TrkB mutant lacking the Cdk5 phosphorylation site had no effect on BDNF-stimulated neuronal survival, indicating that the effect of Cdk5 was not directly mediated by phosphorylation of TrkB by Cdk5. We next examined the effect of Cdk5 on BDNF-mediated synaptic plasticity. Dendritic spine analysis assay was performed in hippocampal neurons to study the role of Cdk5 and BDNF in spine morphogenesis. Interestingly, we found that Cdk5-mediated phosphorylation of TrkB is required for BDNF-stimulated increase in spine density and spine area. In addition, we also found that Cdk5 activity is required for BDNF-facilitated long-term potentiation in hippocampal slices. In summary, these observations suggest that Cdk5 activity is required for BDNF-stimulated neuronal survival and synaptic plasticity, but distinctive mechanisms may underlie different functions.