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Eur Neuropsychopharmacol. 2015 Nov;25(11):2036-48. doi: 10.1016/j.euroneuro.2015.08.016. Epub 2015 Sep 16.

Chronic stress and antidepressant induced changes in Hdac5 and Sirt2 affect synaptic plasticity.

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Dept. Pharmacology and Toxicology (University of Navarra), Pamplona, Spain.
Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Dept. Drug Chemistry and Technologies, "Sapienza" University of Rome, Rome, Italy.
Dept. Pharmacology and Toxicology (University of Navarra), Pamplona, Spain. Electronic address:


Changes in histone acetylation could contribute to the pathogenesis of depression and antidepressant therapy. Using the chronic social defeat stress (CSDS) model of depression and different antidepressant treatments we studied the regulation of histone deacetylases (Hdac׳s) and synaptic plasticity markers in the prefrontal cortex (PFC). Further, functional implication of identified Hdac׳s in brain plasticity was explored. Mice were exposed to CSDS (10 days) followed by saline or imipramine (4 weeks). PFC Hdac׳s mRNA abundance was studied and compared to human׳s. Further, protein expression of acetylated histones (AcH3 and AcH4), neuroplasticity markers (CREB and pro-BDNF) and selected Hdac׳s were analyzed. Moreover, other antidepressants (fluoxetine and reboxetine) and selective HDAC inhibitors were studied. CSDS increased Hdac5 and Sirt2 mRNA whereas repeated imipramine did the opposite. Accordingly, stress and imipramine induced opposite changes on AcH3, AcH4 and CREB expression. At protein level, CSDS upregulated nuclear fraction of Hdac5 and repeated imipramine and reboxetine increased its phosphorylated form (p-Hdac5), mainly located in the cytoplasm. Moreover, Sirt2 was downregulated by all monoaminergic antidepressants. Further, repeated treatment with the class IIa Hdac inhibitor MC1568 and the Sirt2 inhibitor 33i for three weeks increased synaptic plasticity in the prefrontal cortex. Our results suggest that Hdac5 and Sirt2 upregulation could constitute stable stress-induced neuronal adaptations. Noteworthy, the SIRT2 upregulation in depressed patients supports the interest of this target for therapeutic intervention. On the other hand, cytoplasmic Hdac5 export and Sirt2 downregulation induced by monoaminergic antidepressants could contribute to the well-known beneficial effects of antidepressants on brain plasticity.


Chronic social defeat stress (CSDS); Histone deacetylase 5 (HDAC5); Imipramine; Major depression; Prefrontal cortex (PFC); Sirt2

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