Cell Reports (Feb 2016)

Regulation of Memory Formation by the Transcription Factor XBP1

  • 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

DOI
https://doi.org/10.1016/j.celrep.2016.01.028
Journal volume & issue
Vol. 14, no. 6
pp. 1382 – 1394

Abstract

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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.