Regulation of Memory Formation by the Transcription Factor XBP1

• Published in: Cell reports (Cambridge) Vol. 14; no. 6; pp. 1382 - 1394
• Main Authors: Martínez, Gabriela, Vidal, René L., Mardones, Pablo, Serrano, Felipe G., Ardiles, Alvaro O., Wirth, Craig, Valdés, Pamela, Thielen, Peter, Schneider, Bernard L., Kerr, Bredford, Valdés, Jose L., Palacios, Adrian G., Inestrosa, Nibaldo C., Glimcher, Laurie H., Hetz, Claudio
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.02.2016; Elsevier
• Subjects: Animals; Brain-Derived Neurotrophic Factor - genetics; Brain-Derived Neurotrophic Factor - metabolism; Diacylglycerol O-Acyltransferase - genetics; Diacylglycerol O-Acyltransferase - metabolism; Endoplasmic Reticulum - genetics; Endoplasmic Reticulum Stress - genetics; Evoked Potentials - physiology; Gene Expression Profiling; Gene Expression Regulation, Developmental; Hippocampus - cytology; Hippocampus - metabolism; Long-Term Potentiation - physiology; Male; Memory - physiology; Mice; Mice, Knockout; Molecular Sequence Annotation; Neurons - cytology; Neurons - metabolism; Promoter Regions, Genetic; Signal Transduction; Unfolded Protein Response - genetics; X-Box Binding Protein 1 - deficiency; X-Box Binding Protein 1 - genetics
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.01.028

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. [Display omitted] •Cognitive processes activate the IRE1 branch of the UPR pathway in the hippocampus•The UPR transcription factor XBP1 controls learning and memory-related processes•Enforced expression of XBP1s in the hippocampus improves spatial memory•XBP1 controls synaptic plasticity-related genes, including the expression of BDNF 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.