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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 .

journal of neurochemistry

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