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dc.contributor.authorMeylan, Elsa M.
dc.contributor.authorHalfon, Olivier
dc.contributor.authorMagistretti, Pierre J.
dc.contributor.authorCardinaux, Jean-René
dc.date.accessioned2016-03-10T13:15:22Z
dc.date.available2016-03-10T13:15:22Z
dc.date.issued2016-03-09
dc.identifier.citationThe HDAC inhibitor SAHA improves depressive-like behavior of CRTC1-deficient mice: possible relevance for treatment-resistant depression 2016 Neuropharmacology
dc.identifier.issn00283908
dc.identifier.pmid26970016
dc.identifier.doi10.1016/j.neuropharm.2016.03.012
dc.identifier.urihttp://hdl.handle.net/10754/601123
dc.description.abstractMajor depression is a highly complex disabling psychiatric disorder affecting millions of people worldwide. Despite the availability of several classes of antidepressants, a substantial percentage of patients are unresponsive to these medications. A better understanding of the neurobiology of depression and the mechanisms underlying antidepressant response is thus critically needed. We previously reported that mice lacking CREB-regulated transcription coactivator 1 (CRTC1) exhibit a depressive-like phenotype and a blunted antidepressant response to the selective serotonin reuptake inhibitor fluoxetine. In this study, we similarly show that Crtc1‒/‒ mice are resistant to the antidepressant effect of chronic desipramine in a behavioral despair paradigm. Supporting the blunted response to this tricyclic antidepressant, we found that desipramine does not significantly increase the expression of Bdnf and Nr4a1-3 in the hippocampus and prefrontal cortex of Crtc1‒/‒ mice. Epigenetic regulation of neuroplasticity gene expression has been associated with depression and antidepressant response, and histone deacetylase (HDAC) inhibitors have been shown to have antidepressant-like properties. Here, we show that unlike conventional antidepressants, chronic systemic administration of the HDAC inhibitor SAHA partially rescues the depressive-like behavior of Crtc1‒/‒ mice. This behavioral effect is accompanied by an increased expression of Bdnf, but not Nr4a1-3, in the prefrontal cortex of these mice, suggesting that this epigenetic intervention restores the expression of a subset of genes by acting downstream of CRTC1. These findings suggest that CRTC1 alterations may be associated with treatment-resistant depression, and support the interesting possibility that targeting HDACs may be a useful therapeutic strategy in antidepressant development.
dc.description.sponsorshipThis work was funded by a grant from the Swiss National Science Foundation (grant number 31003A-135692), and partly supported by the National Centre of Competence in Research (NCCR) Synapsy.
dc.language.isoen
dc.publisherElsevier BV
dc.relation.urlhttp://linkinghub.elsevier.com/retrieve/pii/S0028390816300843
dc.rightsNOTICE: this is the author’s version of a work that was accepted for publication in Neuropharmacology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Neuropharmacology, 9 March 2016. DOI: 10.1016/j.neuropharm.2016.03.012
dc.subjectmood disorders
dc.subjectantidepressants
dc.subjectanimal model of depression
dc.subjectCREB coactivator
dc.subjectBDNF
dc.subjectHDAC inhibitor
dc.subjectSAHA
dc.subjectepigenetics
dc.titleThe HDAC inhibitor SAHA improves depressive-like behavior of CRTC1-deficient mice: possible relevance for treatment-resistant depression
dc.typeArticle
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Division
dc.contributor.departmentBioscience Program
dc.identifier.journalNeuropharmacology
dc.eprint.versionPost-print
dc.contributor.institutionCenter for Psychiatric Neuroscience, Department of Psychiatry, University Medical Center, University of Lausanne, Prilly, Switzerland
dc.contributor.institutionService of Child and Adolescent Psychiatry, Department of Psychiatry, University Medical Center, University of Lausanne, Lausanne, Switzerland
dc.contributor.institutionLaboratory of Neuroenergetics and Cellular Dynamics, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
dc.contributor.affiliationKing Abdullah University of Science and Technology (KAUST)
kaust.personMagistretti, Pierre J.
refterms.dateFOA2017-03-09T00:00:00Z
dc.date.published-online2016-03-09
dc.date.published-print2016-08


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