title: 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.
authors: 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.
authors: Gabriela
authors: G
authors: Martínez
authors: 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.
authors: René L
authors: RL
authors: Vidal
authors: 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.
authors: Pablo
authors: P
authors: Mardones
authors: Center of Aging and Regeneration (CARE), Department of Cell and Molecular Biology, Faculty of Biological Sciences, Pontifical Catholic University of Chile, Santiago, Chile.
authors: Felipe G
authors: FG
authors: Serrano
authors: Centro Interdisciplinario de Neurociencia de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaiso, Chile.
authors: Alvaro O
authors: AO
authors: Ardiles
authors: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
authors: Craig
authors: C
authors: Wirth
authors: 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.
authors: Pamela
authors: P
authors: Valdés
authors: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
authors: Peter
authors: P
authors: Thielen
authors: Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors: Bernard L
authors: BL
authors: Schneider
authors: Centro de Estudios Científicos, Valdivia, Chile.
authors: Bredford
authors: B
authors: Kerr
authors: 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.
authors: Jose L
authors: JL
authors: Valdés
authors: Centro Interdisciplinario de Neurociencia de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaiso, Chile.
authors: Adrian G
authors: AG
authors: Palacios
authors: Center of Aging and Regeneration (CARE), Department of Cell and Molecular Biology, Faculty of Biological Sciences, Pontifical Catholic University of Chile, Santiago, Chile.
authors: Nibaldo C
authors: NC
authors: Inestrosa
authors: Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: lglimche@med.cornell.edu.
authors: Laurie H
authors: LH
authors: Glimcher
authors: 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.
authors: Claudio
authors: C
authors: Hetz
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D051048:Diacylglycerol O-Acyltransferase / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000235:genetics; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D005071:Evoked Potentials / Q000502:physiology; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D008568:Memory / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D058977:Molecular Sequence Annotation; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D056811:Unfolded Protein Response / Q000235:genetics; D000071717:X-Box Binding Protein 1 / Q000172:deficiency / Q000235:genetics*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C516957:DGAT2 protein, mouse; D051048:Diacylglycerol O-Acyltransferase