Brain derived neurotrophic factor is involved in the regulation of glycogen synthase kinase 3ß (GSK3ß) signalling.

Glycogen synthase kinase 3ß (GSK3ß) is involved in several biochemical processes in neurons regulating cellular survival, gene expression, cell fate determination, metabolism and proliferation. GSK3ß activity is inhibited through the phosphorylation of its Ser-9 residue. In this study we sought to investigate the role of BDNF/TrkB signalling in the modulation of GSK3ß activity. BDNF/TrkB signalling regulates the GSK3ß activity both in vivo in the retinal tissue as well as in the neuronal cells under culture conditions. We report here for the first time that BDNF can also regulate GSK3ß activity independent of its effects through the TrkB receptor signalling. Knockdown of BDNF lead to a decline in GSK3ß phosphorylation without having a detectable effect on the TrkB activity or its downstream effectors Akt and Erk1/2. Treatment with TrkB receptor agonist had a stimulating effect on the GSK3ß phosphorylation, but the effect was significantly less pronounced in the cells in which BDNF was knocked down. The use of TrkB receptor antagonist similarly, manifested itself in the form of downregulation of GSK3ß phosphorylation, but a combined TrkB inhibition and BDNF knockdown exhibited a much stronger negative effect. In vivo, we observed reduced levels of GSK3ß phosphorylation in the retinal tissues of the BDNF(+/-) animals implicating critical role of BDNF in the regulation of the GSK3ß activity. Concluding, BDNF/TrkB axis strongly regulates the GSK3ß activity and BDNF also exhibits GSK3ß regulatory effect independent of its actions through the TrkB receptor signalling.