The HDAC inhibitor SAHA improves depressive-like behavior of CRTC1-deficient mice: possible relevance for treatment-resistant depression
Open accessAbstract
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.
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In genetically susceptible models of treatment-resistant depression, SAHA inhibits HDAC2, restores histone acetylation and BDNF levels, and reverses antidepressant non-responsiveness.
“In genetically susceptible models of treatment-resistant depression, SAHA inhibits HDAC2, restores histone acetylation and BDNF levels, and reverses antidepressant non-responsiveness (Meylan et al., 2016; Vialou et al., 2013).”
From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Meylan et al., 2016
The Results (pages unavailable) show that SAHA increased histone acetylation and restored prefrontal-cortex Bdnf mRNA expression in Crtc1-deficient mice; the Discussion reports a partial improvement in depressive-like behavior. The paper describes inhibition of class I and II HDACs, not HDAC2-specific inhibition, and found no baseline histone-acetylation deficit to restore. It did not show restored BDNF protein levels or reversal of the mice’s non-responsiveness to conventional antidepressants. (LLM, conf=0.90)
Experimental — accuracy not yet measuredSuberoylanilide hydroxamic acid has a rapid antidepressant action and may be effective for depressive-like behaviors in mice that are resistant to conventional treatments.
“other reports have also shown that SAHA has a rapid antidepressant action 66 and that SAHA treatment may be effective for depressive-like behaviors in mice that are resistant to conventional treatments.”
From Epigenetic mechanisms of major depression: Targeting neuronal plasticity (2018) · cites this paper as [75]
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- Authors
- Meylan, E. M., Halfon, O., Magistretti, P. J., & Cardinaux, J.-R.
- Affiliations
- University of Lausanne (CH)
- École Polytechnique Fédérale de Lausanne (CH)
- Corresponding author
- Cardinaux, Jean-René
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2016-08
- Volume
- 107
- Pages
- 111-121
- ISSN
- 0028-3908 (ISSN-L)
- PMC
- PMC5939991
- OpenAlex
- W2295238601
- Cited by
- 87
- References
- 60
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 9 · 2023: 5 · 2022: 8 · 2021: 7 · 2020: 10 · 2019: 11 · 2018: 11 · 2017: 10 · 2016: 4 · 2014: 1
- FWCI
- 9.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuropharmacology (acceptedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- SERVAL (Université de Lausanne) (acceptedVersion, other-oa)
- IRIS (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- King Abdullah University of Science and Technology Repository (King Abdullah University of Science and Technology) (submittedVersion)
- Funders
- National Centre of Competence in Research Robotics
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (31003A-135692)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Keywords
- CRTC1, histone deacetylase inhibitors, vorinostat, treatment-resistant depression, depression-like behavior, desipramine, brain-derived neurotrophic factor, epigenetic regulation, neuroplasticity, antidepressant response, prefrontal cortex, hippocampus, behavioral despair
- MeSH terms
- Vorinostat, Animals, Antidepressive Agents, Major Depressive Disorder, Desipramine, Disease Models, Animal, DNA-Binding Proteins, Drug Evaluation, Preclinical, Hippocampus, Hydroxamic Acids, Male, Nerve Tissue Proteins, Receptors, Steroid, Receptors, Thyroid Hormone, Transcription Factors, Prefrontal Cortex, Mice, Knockout, Brain-Derived Neurotrophic Factor, Histone Deacetylase Inhibitors, Nuclear Receptor Subfamily 4, Group A, Member 1, Nuclear Receptor Subfamily 4, Group A, Member 2, Depressive Disorder, Treatment-Resistant
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