Abstract

The brain‐derived neurotrophic factor (BDNF) is a major signaling peptide in the central nervous system (CNS), where it mediates neuronal survival, differentiation, and plasticity. Upon binding to the tropomyosin receptor kinase B (TrkB), BDNF triggers intracellular phosphorylation cascades that converge in the phosphoactivation of the transcription factor CREB, initiating the expression of canonical targets. Phospho‐CREB, in turn, can drive BDNF transcriptional auto‐induction through CRE sequences in BDNF activity‐dependent promoters I and IV. We recently showed that, in addition to the classic CREB pathway, BDNF expression is regulated by the phylogenetically‐related UPR transcription factor XBP1, whose expression modulates cognitive performance in mice. Here, we further investigate the relationship between BDNF signaling and the UPR by treating primary mouse neurons in culture with recombinant BDNF and UPR agonists (tunicamycin, thapsigargin and brefeldin A). General UPR activation was associated with a 5‐ to 20‐fold increase in the mRNA levels of BDNF isoform I and a similar 5‐ to 10‐fold induction of BDNF IV. These treatments also resulted in a concomitant increase of Fos but not Arc mRNA levels. Using a luciferase reporter assay, we show that the transcription factor ATF6 is also capable of transactivating the BDNF promoter, indicating that multiple UPR effectors may be connected to the regulation of BDNF expression and signaling. Strikingly, simultaneous stimulation of the UPR and BDNF pathways resulted in a dose‐dependent potentiation (up to 10‐fold) of BDNF auto‐induction and signaling in primary neurons, measured as the expression of BdnfI mRNA and the downstream genes Arc and Fos. This effect was specific for Bdnf isoform I and was partially blunted by chemical UPR inhibitors, suggesting that a fully functional UPR pathway is necessary to achieve a maximum response to BDNF in this model system. We propose that the activation of both XBP1 and ATF6 UPR pathways provide gain amplification to BDNF signaling, possibly combining direct promoter transactivation with a more general stimulation of the secretory pathway. This novel mechanism might be relevant for the onset of long‐term neuronal plasticity and BDNF‐mediated neuroregeneration.