The HDAC inhibitor SAHA improves depressive-like behavior of CRTC1-deficient mice: possible relevance for treatment-resistant depression
MetadataShow full item record
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.
CitationThe HDAC inhibitor SAHA improves depressive-like behavior of CRTC1-deficient mice: possible relevance for treatment-resistant depression 2016 Neuropharmacology
SponsorsThis 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.
- Deletion of CREB-regulated transcription coactivator 1 induces pathological aggression, depression-related behaviors, and neuroplasticity genes dysregulation in mice.
- Authors: Breuillaud L, Rossetti C, Meylan EM, Mérinat C, Halfon O, Magistretti PJ, Cardinaux JR
- Issue date: 2012 Oct 1
- Involvement of the agmatinergic system in the depressive-like phenotype of the Crtc1 knockout mouse model of depression.
- Authors: Meylan EM, Breuillaud L, Seredenina T, Magistretti PJ, Halfon O, Luthi-Carter R, Cardinaux JR
- Issue date: 2016 Jul 12
- Leptin receptor deficiency confers resistance to behavioral effects of fluoxetine and desipramine via separable substrates.
- Authors: Guo M, Lu XY
- Issue date: 2014 Dec 2
- Prelimbic Stimulation Ameliorates Depressive-Like Behaviors and Increases Regional BDNF Expression in a Novel Drug-Resistant Animal Model of Depression.
- Authors: Moshe H, Gal R, Barnea-Ygael N, Gulevsky T, Alyagon U, Zangen A
- Issue date: 2016 Mar-Apr
- Antidepressant-like effect of sodium butyrate is associated with an increase in TET1 and in 5-hydroxymethylation levels in the Bdnf gene.
- Authors: Wei Y, Melas PA, Wegener G, Mathé AA, Lavebratt C
- Issue date: 2014 Oct 31