title: HDAC6 regulates glucocorticoid receptor signaling in serotonin pathways with critical impact on stress resilience.
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 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.
authors.affiliation: Department of Psychiatry, University of Pennsylvania Medical School, Philadelphia, PA 19104, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Espallergues
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Teegarden
authors.forename: Avin
authors.initials: A
authors.lastname: Veerakumar
authors.forename: Janette
authors.initials: J
authors.lastname: Boulden
authors.forename: Collin
authors.initials: C
authors.lastname: Challis
authors.forename: Jeanine
authors.initials: J
authors.lastname: Jochems
authors.forename: Michael
authors.initials: M
authors.lastname: Chan
authors.forename: Tess
authors.initials: T
authors.lastname: Petersen
authors.forename: Evan
authors.initials: E
authors.lastname: Deneris
authors.forename: Patrick
authors.initials: P
authors.lastname: Matthias
authors.forename: Chang-Gyu
authors.initials: CG
authors.lastname: Hahn
authors.forename: Irwin
authors.initials: I
authors.lastname: Lucki
authors.forename: Sheryl G
authors.initials: SG
authors.lastname: Beck
authors.forename: Olivier
authors.initials: O
authors.lastname: Berton
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D002478:Cells, Cultured; D003345:Corticosterone / Q000037:antagonists & inhibitors / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D017353:Gene Deletion; D005786:Gene Expression Regulation; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D007099:Imipramine / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000378:metabolism; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D011965:Receptors, Glucocorticoid / Q000378:metabolism / Q000502:physiology*; D055500:Resilience, Psychological; D059326:Serotonergic Neurons / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013315:Stress, Psychological / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D007099:Imipramine; D003345:Corticosterone