Regulation of Memory Formation by the Transcription Factor XBP1

Publication date: Available online 4 February 2016
Source:Cell Reports
Author(s): Gabriela Martínez, René L. Vidal, Pablo Mardones, Felipe G. Serrano, Alvaro O. Ardiles, Craig Wirth, Pamela Valdés, Peter Thielen, Bernard L. Schneider, Bredford Kerr, Jose L. Valdés, Adrian G. Palacios, Nibaldo C. Inestrosa, Laurie H. Glimcher, Claudio Hetz
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.

Graphical abstract

Teaser

Using gain- and loss-of-function approaches, Martinez et al. demonstrate that XBP1, a master regulator of the unfolded protein response (UPR), regulates learning and memory-related processes. This function of XBP1 in the nervous system involves the control of BDNF expression in the hippocampus.


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