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. This activity-dependent increase of BDNF was abolished by cycloheximide, suggesting local translation, and required activation of glutamate and Trk receptors. Our data showed that BDNF translation was regulated by multiple signaling cascades including RAS-Erk and mTOR pathways, and CaMKII-CPEB1, Aurora-A-CPEB1 and Src-ZBP1 pathways. Aurora-A, CPEB1, ZBP1 (also known as IGF2BP1), eiF4E, S6 (also known as rpS6) were present throughout the dendritic arbor. Neuronal activity increased the levels of Aurora-A, CPEB1 and ZBP1 in distal dendrites whereas those of eiF4E and S6 were unaffected. BDNF-6, the main dendritic BDNF transcript, was 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 the translational machinery localization is modulated in response to electrical activity.
Department of Life Sciences, B.R.A.I.N. Centre for Neuroscience, University of Trieste, Trieste 34127, Italy.
Gabriele
0000-0002-2625-9454
G
Baj
Department of Life Sciences, B.R.A.I.N. Centre for Neuroscience, University of Trieste, Trieste 34127, Italy.
Vera
0000-0003-1754-6360
V
Pinhero
Department of Life Sciences, B.R.A.I.N. Centre for Neuroscience, University of Trieste, Trieste 34127, Italy.
Valentina
V
Vaghi
Department of Life Sciences, B.R.A.I.N. Centre for Neuroscience, University of Trieste, Trieste 34127, Italy tongi@units.it.
Enrico
0000-0003-0485-0603
E
Tongiorgi
D000818:Animals; D000918:Antibody Specificity / Q000276:immunology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D056547:CA1 Region, Hippocampal / Q000378:metabolism; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism*; D005091:Exons / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D010862:Pilocarpine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects
D019208:Brain-Derived Neurotrophic Factor; D012333:RNA, Messenger; D010862:Pilocarpine; D011189:Potassium Chloride
Hippocampus; Neurotrophins; Pilocarpine; Protein synthesis