Differential modulation of GR signaling and HDACs in the development of resilient/vulnerable phenotype and antidepressant-like response of vorinostat. (February 2021)

• Record Type: Journal Article
• Authors: K V, Athira; Wahul, Abhipradnya Bipin; Soren, Kalyani; Das, Tapatee; Dey, Sandeep; Samudrala, Pavan Kumar; Kumar, Arvind; Lahkar, Mangala; Chakravarty, Sumana
• Is Part Of: Psychoneuroendocrinology. Volume 124(2021)
• Publication Date: 2021-02
• Subjects: Chronic social defeat stress -- Depression -- Epigenetics -- Glucocorticoid receptor -- Histone deacetylases -- Resilience; Psychoneuroendocrinology -- Periodicals; Endocrinology -- Periodicals; Neurology -- Periodicals; Psychiatry -- Periodicals; Neuropsychoendocrinologie -- Périodiques; 616.8
• DOI: 10.1016/j.psyneuen.2020.105083
• Languages: English
• ISSNs: 0306-4530

Abstract

Abstract: The present study explored the antidepressant potential of vorinostat (VOR) against chronic social defeat stress (CSDS) in mice. Since this model has the remarkable capacity to delineate the resilient and the defeated mice, we also looked for their molecular deviations. Defeated mice showed classical phenotypic alterations such as anhedonia, social avoidance, anxiety and despair. Whereas, resilient mice were immune to the development of those. Both defeated and resilient mice demonstrated marked CORT elevation in blood. Development of resilience vs. defeat to CSDS was found to be associated with the differential nuclear levels of GR, HDAC3 and HDAC6 in the hippocampus. Activation of a stress responsive adaptive mechanism involving these mediators at the nuclear level might be offering resilience while maladaptive mechanisms leading to defeat. Interestingly, an elevated hippocampal HDAC6 level in defeated mice was also observed, which was restored by VOR treatment. Further studies will be necessary to delineate the HDAC6 associated antidepressant mechanisms. As HDAC3 and HDAC6 are crucial mediators of GR signaling, further molecular studies may aid in understanding the basis of development of resilience to target MDD with new prospective. Graphical Abstract: ga1 Highlights: Vorinostat attenuated chronic social defeat stress-induced neurobehavioral alterations in defeated mice. Vorinostat showed antidepressant-like responses via modulation of cytoplasmic HDAC6 level. Resilience vs. defeat to chronic social defeat stress was based on differential nuclear levels of GR, HDAC3 and HDAC6. Resilience may involve activation of a stress responsive adaptive mechanism. Maladaptive mechanisms to stress might be leading to defeat.