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Olivier Berton"HDAC6, a new regulator of stress resilience and potential novel target for antidepressant interventions"

Abstract :


Genetic variations in certain components of the glucocorticoid receptor (GR) chaperone complex have been associated with the development of stress-related affective disorders and individual variability in therapeutic responses to antidepressants.
Mechanisms that link GR chaperoning and stress susceptibility are not well understood. Here, we take advantage of a murine model of social defeat to examine how regulation of the GR chaperone complex may influence vulnerability and resilience to the long lasting behavioral impact of aversive social experiences. We find that socioaffective effects of glucocorticoid hormones are critically regulated via reversible acetylation of Hsp90, a key component of the GR chaperone complex. We provide pharmacological and genetic evidence indicating that the cytoplasmic lysine deacetylase HDAC6 controls Hsp90 acetylation in the brain, and thereby modulates Hsp90-GR protein-protein interactions, as well as hormone- and stress- induced GR translocation, with a critical impact on GR downstream signaling and behavior. Pet1-Cre driven deletion of HDAC6 in serotonin neurons, the densest HDAC6-expressing cell group in the mouse brain, dramatically reduced acute anxiogenic effects of the glucocorticoid hormone corticosterone in the open field, elevated plus maze, and social interaction tests. Serotonin-selective depletion of HDAC6 also blocked the expression of social avoidance in mice exposed to chronic social defeat and concurrently prevented the electrophysiological and morphological changes induced, in serotonin neurons, by this murine model of traumatic stress. Together, these results identify HDAC6 inhibition as a potential new strategy for pro-resilience and antidepressant interventions through regulation of the Hsp90-GR heterocomplex and focal prevention of GR signaling in serotonin pathways. Our data thus uncover an alternate mechanism by which pan-HDAC inhibitors may regulate stress-related behaviors independently of their action on histones.

 

Education

PhD (Neuroscience)
U Bordeaux II, Victor Segalen, France, 1998.
Post-Graduate Training
Postdoctoral Fellow, Artigas Lab, CSIC Dept Neurochem. Barcelona Spain , 1999-2000.
Group Leader, UCB Pharma, Psychopharmacology Unit, Brussels, Belgium, 2000-2002.
Postdoctoral Fellow, Nestler Lab, UT Southwestern Med Ctr Dallas, Tx USA, 2002-2004.
Instructor, Nestler Lab, UT Southwestern Med Ctr Dallas, Tx USA, 2004-2008.

Selected publications

Espallergues J, Teegarden S, Veerakumar A, Boulden J , Chan M, Petersen T, Deneris E, Matthias P, Lucki I, Beck SG and Berton O. HDAC6 regulates GR signaling in serotonin pathways with critical impact on stress resilience. J. Neurosci. In Press

Golden SA, Covington HE, Berton O and Russo SG. A standardized protocol for repeated social defeat stress in mice. Nat Protoc. 2011 Jul 21;6(8):1183-91.

Antidepressant actions of histone deacetylase inhibitors. Covington HE 3rd, Maze I, LaPlant QC, Vialou VF, Ohnishi YN, Berton O, Fass DM, Renthal W, Rush AJ 3rd, Wu EY, Ghose S, Krishnan V, Russo SJ, Tamminga C, Haggarty SJ, Nestler EJ. J Neurosci. 2009 Sep 16;29(37):11451-60.

Berton O, McClung CA, Dileone RJ, Krishnan V, Renthal W, Russo SJ, Graham D, Tsankova NM, Bolanos CA, Rios M, Monteggia LM, Self DW, Nestler EJ. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science.2006 Feb 10;311(5762):864-8.