Regulation of Memory Formation by the Transcription Factor XBP1.


Contextual memory formation relies on the induction of new genes in the hippocampus. A polymorphism in the promoter of the transcription factor XBP1 was identified as a risk factor for Alzheimer’s disease and bipolar disorders. XBP1 is a major regulator of the unfolded protein response (UPR), mediating adaptation to endoplasmic reticulum (ER) stress. Using a phenotypic screen, we uncovered an unexpected function of XBP1 in cognition and behavior. Mice lacking XBP1 in the nervous system showed specific impairment of contextual memory formation and long-term potentiation (LTP), whereas neuronal XBP1s overexpression improved performance in memory tasks. Gene expression analysis revealed that XBP1 regulates a group of memory-related genes, highlighting brain-derived neurotrophic factor (BDNF), a key component in memory consolidation. Overexpression of BDNF in the hippocampus reversed the XBP1-deficient phenotype. Our study revealed an unanticipated function of XBP1 in cognitive processes that is apparently unrelated to its role in ER stress.

Martínez G, Vidal RL, Mardones P, Serrano FG, Ardiles AO, Wirth C, Valdés P, Thielen P, Schneider BL, Kerr B, Valdés JL, Palacios AG, Inestrosa NC, Glimcher LH, Hetz C

Cell Reports

febrero 04, 2016

DOI: 10.1016/j.celrep.2016.01.028

Investigador BNI: Claudio Hetz , René Vidal , José Luis Valdés