Martin V1, Allaïli N2, Euvrard M1, Marday T1, Riffaud A1, Franc B1, Mocaër E3, Gabriel C3, Fossati P4, Lehericy S2, Lanfumey L1.
1 Centre de Psychiatrie et Neurosciences, INSERM UMR 894, Université Paris Descartes, Paris, France.
2 Centre de NeuroImagerie de Recherche - CENIR- Inserm UMR1127- CNRS 7225, Institut Cerveau Moelle - ICM, Sorbonne Universités, UPMC UMR S 1127, Paris, France.
3 Institut de Recherches Internationales Servier, IRIS, Suresnes, France.
4 Social and Affective Neuroscience - SAN Laboratory - Inserm U 1127- CNRS UMR 7225- Institut du Cerveau et de la Moelle- ICM - Sorbonne Universités, UPMC UMR S 1127, Paris, France.
Chronic stress is known to induce not only anxiety and depressive-like phenotypes in mice but also cognitive impairments, for which the action of classical antidepressant compounds remains unsatisfactory. In this context, we investigated the effects of chronic social defeat stress (CSDS) on anxiety-, social- and cognitive-related behaviors, as well as hippocampal Bdnf, synaptic plasticity markers (PSD-95, Synaptophysin, Spinophilin, Synapsin I and MAP-2), and epigenetic modifying enzymes (MYST2, HDAC2, HDAC6, MLL3, KDM5B, DNMT3B, GADD45B) gene expression in C57BL/6J mice. CSDS for 10 days provoked long-lasting anxious-like phenotype in the open field and episodic memory deficits in the novel object recognition test. While total Bdnf mRNA level was unchanged, Bdnf exon IV, MAP-2, HDAC2, HDAC6 and MLL3 gene expression was significantly decreased in the CSDS mouse hippocampus. In CSDS mice treated 3 weeks with 50 mg/kg/d agomelatine, an antidepressant with melatonergic receptor agonist and 5-HT2C receptor antagonist properties, the anxious-like phenotype was not reversed, but the treatment successfully prevented the cognitive impairments and hippocampal gene expression modifications. Altogether, these data evidenced that, in mice, agomelatine was effective in alleviating stress-induced altered cognitive functions, possibly through a mechanism involving BDNF signaling, synaptic plasticity and epigenetic remodeling.
Sci Rep. 2017 Apr 4;8:45907. doi: 10.1038/srep45907.
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