RT Journal Article SR Electronic T1 HDAC6 Regulates Glucocorticoid Receptor Signaling in Serotonin Pathways with Critical Impact on Stress Resilience JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 4400 OP 4416 DO 10.1523/JNEUROSCI.5634-11.2012 VO 32 IS 13 A1 Julie Espallergues A1 Sarah L. Teegarden A1 Avin Veerakumar A1 Janette Boulden A1 Collin Challis A1 Jeanine Jochems A1 Michael Chan A1 Tess Petersen A1 Evan Deneris A1 Patrick Matthias A1 Chang-Gyu Hahn A1 Irwin Lucki A1 Sheryl G. Beck A1 Olivier Berton YR 2012 UL http://www.jneurosci.org/content/32/13/4400.abstract AB 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 show that the effects of glucocorticoid hormones on socioaffective behaviors 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 proresilience 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.