Abstract

BDNF, a major neurotrophin of the central nervous system (CNS), initiates signaling events that are essential for neuronal survival, regeneration, and plasticity. The activity‐dependent transcription of BDNF is a hallmark of neuronal activation associated with synaptic plasticity in several brain regions, including the hippocampus. We recently discovered that mice with a CNS‐specific deletion of the UPR transcription factor Xbp1 develop impaired memory flexibility and contextual fear conditioning responses. These behavioral alterations correlate with lower expression of Bdnf in the hippocampus, but not in the amygdala, compared with control littermates. Conversely, transgenic mice overexpressing XBP1s in the CNS display improved performance in these behavioral tasks, with a concomitant increase in hippocampal BDNF mRNA and protein levels as well as enhanced long‐term potentiation (LTP) in the hippocampus. The activity‐dependent promoters of BDNF contain highly similar CRE sites, which are transactivated by CREB binding associated with canonical cAMP/MAPK signaling. These regions are homologous to one of the consensus XBP1s binding sites, containing an ACGT core. Using a luciferase reporter construct, we show that Xbp1s is capable of transactivating this BDNF promoter region, albeit with lower efficiency than CREB. Based on these results, we further explored the connection between general UPR activation and BDNF expression/signaling using mouse primary cortical neurons as a model system. We corroborated that BDNF signaling induces splicing of the immature form of Xbp1 RNA to produce the transcriptionally active form Xbp1s. This event requires the activity of the UPR sensor and Xbp1 endoribonuclease Ire1‐ alpha as well as signaling through the BDNF receptor TrkB. Interestingly, chronic depolarization with extracellular KCl also activates Xbp1 splicing, suggesting that this UPR module is engaged by neuronal activity and/or intracellular calcium transients. Lastly, we show that inducing the UPR with tunicamycin synergizes with BDNF signaling in primary neurons, increasing its autoactivation amplitude and duration together with its signaling outputs measured as Arc and Fos mRNA levels. These results unveil a novel role of the UPR in modulating BDNF expression and signaling, opening a new area of research for neuroregeneration and neuroenhancing strategies.