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Cell Rep. 2016 Feb 16;14(6):1382-1394. doi: 10.1016/j.celrep.2016.01.028. Epub 2016 Feb 4.

Regulation of Memory Formation by the Transcription Factor XBP1.

Author information

1
Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile; Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Center for Molecular Studies of the Cell, University of Chile, Santiago, Chile; Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.
2
Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile; Center for Geroscience, Brain Health and Metabolism, Santiago, Chile; Neurounion Biomedical Foundation, CENPAR, Santiago, Chile.
3
Center of Aging and Regeneration (CARE), Department of Cell and Molecular Biology, Faculty of Biological Sciences, Pontifical Catholic University of Chile, Santiago, Chile.
4
Centro Interdisciplinario de Neurociencia de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaiso, Chile.
5
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
6
Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
7
Centro de Estudios Científicos, Valdivia, Chile.
8
Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile; Programa Disciplinario de Fisiología y Biofísica, I.C.B.M., Facultad de Medicina, Universidad de Chile, Santiago, Chile.
9
Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: lglimche@med.cornell.edu.
10
Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile; Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Center for Molecular Studies of the Cell, University of Chile, Santiago, Chile; Center for Geroscience, Brain Health and Metabolism, Santiago, Chile; Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA. Electronic address: chetz@med.uchile.cl.

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.

PMID:
26854229
DOI:
10.1016/j.celrep.2016.01.028
[Indexed for MEDLINE]
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