Neuronal activity‐dependent local activation of dendritic unfolded protein response promotes expression of brain‐derived neurotrophic factor in cell soma

摘要

Abstract Unfolded protein response ( UPR ) has roles not only in resolving the accumulation of unfolded proteins owing to endoplasmic reticulum ( ER ) stress, but also in regulation of cellular physiological functions. ER stress transducers providing the branches of UPR signaling are known to localize in distal dendritic ER of neurons. These reports suggest that local activation of UPR branches may produce integrated outputs for distant communication, and allow regulation of local events in highly polarized neurons. Here, we demonstrated that synaptic activity‐ and brain‐derived neurotrophic factor ( BDNF )‐dependent local activation of UPR signaling could be associated with dendritic functions through retrograde signal propagation by using murine neuroblastoma cell line, Neuro‐2A and primary cultured hippocampal neurons derived from postnatal day 0 litter C57 BL /6 mice. ER stress transducer, inositol‐requiring kinase 1 ( IRE 1), was activated at postsynapses in response to excitatory synaptic activation. Activated dendritic IRE 1 accelerated accumulation of the downstream transcription factor, x‐box‐binding protein 1 ( XBP 1), in the nucleus. Interestingly, excitatory synaptic activation‐dependent up‐regulation of XBP 1 directly facilitated transcriptional activation of BDNF . BDNF in turn drove its own expression via IRE 1‐ XBP 1 pathway in a protein kinase A‐dependent manner. Exogenous treatment with BDNF promoted extension and branching of dendrites through the protein kinase A‐ IRE 1‐ XBP 1 cascade. Taken together, our findings indicate novel mechanisms for communication between soma and distal sites of polarized neurons that are coordinated by local activation of IRE 1‐ XBP 1 signaling. Synaptic activity‐ and BDNF ‐dependent distinct activation of dendritic IRE 1‐ XBP 1 cascade drives BDNF expression in cell soma and may be involved in dendritic extension. Cover Image for this issue: doi. 10.1111/jnc.14159 .