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    The HDAC inhibitor SAHA improves depressive-like behavior of CRTC1-deficient mice: possible relevance for treatment-resistant depression

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    Type
    Article
    Authors
    Meylan, Elsa M.
    Halfon, Olivier
    Magistretti, Pierre J. cc
    Cardinaux, Jean-René cc
    KAUST Department
    Biological and Environmental Sciences and Engineering (BESE) Division
    Bioscience Program
    Date
    2016-03-09
    Online Publication Date
    2016-03-09
    Print Publication Date
    2016-08
    Permanent link to this record
    http://hdl.handle.net/10754/601123
    
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    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.
    Citation
    The HDAC inhibitor SAHA improves depressive-like behavior of CRTC1-deficient mice: possible relevance for treatment-resistant depression 2016 Neuropharmacology
    Sponsors
    This 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.
    Publisher
    Elsevier BV
    Journal
    Neuropharmacology
    DOI
    10.1016/j.neuropharm.2016.03.012
    PubMed ID
    26970016
    Additional Links
    http://linkinghub.elsevier.com/retrieve/pii/S0028390816300843
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.neuropharm.2016.03.012
    Scopus Count
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    Articles; Biological and Environmental Sciences and Engineering (BESE) Division; Bioscience Program

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