Signaling pathways controlling activity-dependent local translation of BDNF and their localization in dendritic arbors

Brain-derived neurotrophic factor (BDNF) is encoded by multiple mRNA variants whose differential subcellular distribution constitutes a "spatial code" for local translation of BDNF and selective morphological remodeling of dendrites. Here, we investigated where BDNF translation takes place and what are the signaling pathways involved. Cultured hippocampal neurons, treated with KCl showed increased BDNF in the soma, proximal and distal dendrites even in quaternary branches. Activity-dependent increase of BDNF is abolished by cycloheximide, suggesting local translation, and requires activation of glutamate and Trk receptors. Our data show that BDNF translation is regulated by multiple signaling cascades including RAS/Erk and mTOR pathways, CaMKII/CPEB1, Aurora-A/CPEB1 and Src/ZBP1 pathways. Aurora-A, CPEB1, ZBP1, eiF4E, S6 are present throughout the dendritic arbor. Neuronal activity increases Aurora-A, CPEB1, ZBP1 levels in distal dendrites while eiF4E, S6 are unaffected. BDNF-6, the main dendritic BDNF transcript, is translated in the same subcellular domains and in response to the same pathways as total BDNF. In conclusion, we identified the signaling cascades controlling BDNF translation and we describe how their localization is modulated in response to electrical activity.