title: Enhancement of stress resilience through histone deacetylase 6-mediated regulation of glucocorticoid receptor chaperone dynamics.
abstract: BACKGROUND
  Acetylation of heat shock protein 90 (Hsp90) regulates downstream hormone signaling via the glucocorticoid receptor (GR), but the role of this molecular mechanism in stress homeostasis is poorly understood. We tested whether acetylation of Hsp90 in the brain predicts and modulates the behavioral sequelae of a mouse model of social stress.
  
  
  METHODS
  Mice subjected to chronic social defeat stress were stratified into resilient and vulnerable subpopulations. Hypothalamic-pituitary-adrenal axis function was probed using a dexamethasone/corticotropin-releasing factor test. Measurements of Hsp90 acetylation, Hsp90-GR interactions, and GR translocation were performed in the dorsal raphe nucleus. To manipulate Hsp90 acetylation, we pharmacologically inhibited histone deacetylase 6, a known deacetylase of Hsp90, or overexpressed a point mutant that mimics the hyperacetylated state of Hsp90 at lysine K294.
  
  
  RESULTS
  Lower acetylated Hsp90, higher GR-Hsp90 association, and enhanced GR translocation were observed in dorsal raphe nucleus of vulnerable mice after chronic social defeat stress. Administration of ACY-738, a histone deacetylase 6-selective inhibitor, led to Hsp90 hyperacetylation in brain and in neuronal culture. In cell-based assays, ACY-738 increased the relative association of Hsp90 with FK506 binding protein 51 versus FK506 binding protein 52 and inhibited hormone-induced GR translocation. This effect was replicated by overexpressing the acetylation-mimic point mutant of Hsp90. In vivo, ACY-738 promoted resilience to chronic social defeat stress, and serotonin-selective viral overexpression of the acetylation-mimic mutant of Hsp90 in raphe neurons reproduced the behavioral effect of ACY-738.
  
  
  CONCLUSIONS
  Hyperacetylation of Hsp90 is a predictor and causal molecular determinant of stress resilience in mice. Brain-penetrant histone deacetylase 6 inhibitors increase Hsp90 acetylation and modulate GR chaperone dynamics offering a promising strategy to curtail deleterious socioaffective effects of stress and glucocorticoids.
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Perelman School of Medicine, Philadelphia Pennsylvania.
authors.forename: Jeanine
authors.initials: J
authors.lastname: Jochems
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Perelman School of Medicine, Philadelphia Pennsylvania.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Teegarden
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Perelman School of Medicine, Philadelphia Pennsylvania.
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Perelman School of Medicine, Philadelphia Pennsylvania.
authors.forename: Janette
authors.initials: J
authors.lastname: Boulden
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Perelman School of Medicine, Philadelphia Pennsylvania.
authors.forename: Collin
authors.initials: C
authors.lastname: Challis
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Perelman School of Medicine, Philadelphia Pennsylvania.
authors.forename: Gabriel A
authors.initials: GA
authors.lastname: Ben-Dor
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Perelman School of Medicine, Philadelphia Pennsylvania.
authors.forename: Sangwon F
authors.initials: SF
authors.lastname: Kim
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Perelman School of Medicine, Philadelphia Pennsylvania.. Electronic address: bertonol@mail.med.upenn.edu.
authors.forename: Olivier
authors.initials: O
authors.lastname: Berton
mesh_terms: D000107:Acetylation; D000223:Adaptation, Psychological / Q000502:physiology*; D000818:Animals; D003345:Corticosterone / Q000097:blood; D065847:Dorsal Raphe Nucleus / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism*; D007031:Hypothalamus / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010913:Pituitary-Adrenal System / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D015398:Signal Transduction; D012919:Social Behavior; D013315:Stress, Psychological / Q000201:enzymology / Q000378:metabolism*
chemical_list: D018841:HSP90 Heat-Shock Proteins; D011965:Receptors, Glucocorticoid; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D003345:Corticosterone
keywords: ACY-738; Acetylation; HDAC6; Hsp90; Raphe; Resilience; Serotonin; Social defeat; Stress