Regulation of Memory Formation by the Transcription Factor XBP1.

ABSTRACT

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.

Martà­nez 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