Glycogen synthase kinase 3 beta (GSK3 beta) is involved in several biochemical processes in neurons regulating cellular survival, gene expression, cell fate determination, metabolism and proliferation. GSK3 beta 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 GSK3 beta activity. BDNF/TrkB signalling regulates the GSK3 beta 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 GSK3 beta activity independent of its effects through the TrkB receptor signalling. Knockdown of BDNF lead to a decline in GSK3 beta 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 GSK3 beta 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 GSK3 beta phosphorylation, but a combined TrkB inhibition and BDNF knockdown exhibited a much stronger negative effect. In vivo, we observed reduced levels of GSK3 beta phosphorylation in the retinal tissues of the BDNF+/- animals implicating critical role of BDNF in the regulation of the GSK3 beta activity. Concluding, BDNF/TrkB axis strongly regulates the GSK3 beta activity and BDNF also exhibits GSK3 beta regulatory effect independent of its actions through the TrkB receptor signalling. (C) 2014 Elsevier Inc. All rights reserved.