title: The HDAC inhibitor SAHA improves depressive-like behavior of CRTC1-deficient mice: Possible relevance for treatment-resistant depression.
abstract: Major 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.
authors.affiliation: Center for Psychiatric Neuroscience, Department of Psychiatry, University Medical Center, University of Lausanne, Prilly, Switzerland; Service of Child and Adolescent Psychiatry, Department of Psychiatry, University Medical Center, University of Lausanne, Lausanne, Switzerland.
authors.forename: Elsa M
authors.initials: EM
authors.lastname: Meylan
authors.affiliation: Service of Child and Adolescent Psychiatry, Department of Psychiatry, University Medical Center, University of Lausanne, Lausanne, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Halfon
authors.affiliation: Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia; Laboratory of Neuroenergetics and Cellular Dynamics, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland; Center for Psychiatric Neuroscience, Department of Psychiatry, University Medical Center, University of Lausanne, Prilly, Switzerland.
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Magistretti
authors.affiliation: Center for Psychiatric Neuroscience, Department of Psychiatry, University Medical Center, University of Lausanne, Prilly, Switzerland; Service of Child and Adolescent Psychiatry, Department of Psychiatry, University Medical Center, University of Lausanne, Lausanne, Switzerland. Electronic address: Jean-Rene.Cardinaux@chuv.ch.
authors.forename: Jean-René
authors.initials: JR
authors.lastname: Cardinaux
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism; D061218:Depressive Disorder, Treatment-Resistant / Q000188:drug therapy* / Q000378:metabolism; D003891:Desipramine / Q000494:pharmacology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008297:Male; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000378:metabolism; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics; D000077337:Vorinostat
chemical_list: D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; C519509:Crtc1 protein, mouse; D004268:DNA-Binding Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D009419:Nerve Tissue Proteins; C539818:Nr4a1 protein, mouse; C539883:Nr4a2 protein, mouse; C490411:Nr4a3 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D014157:Transcription Factors; D000077337:Vorinostat; D003891:Desipramine
keywords: Animal model of depression; Antidepressants; BDNF; CREB coactivator; Desipramine hydrochloride (PubChem CID: 65327); Epigenetics; HDAC inhibitor; Mood disorders; SAHA; Vorinostat (PubChem CID: 5311)