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

Abstract

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.

Ribosome-associated vesicles: A dynamic subcompartment of the endoplasmic reticulum in secretory cells

“…In developing neurons, our visualization of RAVs localized to dendrites may be relevant to the emerging understanding of local translation. Local translation is increasingly recognized as an essential contributor to activity-dependent synaptic plasticity and neuron remodeling (57,58). Despite thousands of mRNAs trafficked to dendrites presumably for site-specific translation, the machinery for local translation of the protein products remains poorly defined (59).…”

Expression of BDNF and trkB in the hippocampus of a rat genetic model of vulnerability (Roman low‐avoidance) and resistance (Roman high‐avoidance) to stress‐induced depression

“…Studies on the BDNF targeting on hippocampal CA3 dendrites (Baj, Pinhero, Vaghi, & Tongiorgi, 2016;Baj et al, 2012;Righi, Tongiorgi, & Cattaneo, 2000) further suggest the possibility of concurrent mechanisms of BDNF-mediated trophic support. Thus, upon the anterograde transport along the mossy fibers (Altar & DiStefano, 1998;Altar et al, 1997), the endogenous BDNF secreted along the neuronal activity may contribute to local mechanisms of trophic support that drive the accumulation of BDNF and trkB mRNAs in specific subcellular compartments of the CA3 pyramidal neurons (Righi et al, 2000).…”

Distinct effects on the dendritic arbor occur by microbead versus bath administration of brain-derived neurotrophic factor

“…Additionally, trafficking of the BDNF 5′ UTR splice variant resulting from exon 6 is impaired in mice expressing the BDNF human variant Val66Met [81], having implications for BDNF action on the dendritic arbor. Finally, as the Val66Met mutation results in decreased transport of BDNF mRNA in the dendrites (as reviewed in [82]), and thus a disruption of the BDNF mRNA spatial code [83], it is possible that local stimulation of the dendritic arbor by BDNF-coated beads may alleviate some of the issues caused by this dysregulation in BDNF mRNA transport. Thus, expression of specific BDNF mRNAs is crucial for the proper regulation of dendritogenesis and other cellular processes.…”