title: A new anti-depressive strategy for the elderly: ablation of FKBP5/FKBP51.
abstract: The gene FKBP5 codes for FKBP51, a co-chaperone protein of the Hsp90 complex that increases with age. Through its association with Hsp90, FKBP51 regulates the glucocorticoid receptor (GR). Single nucleotide polymorphisms (SNPs) in the FKBP5 gene associate with increased recurrence of depressive episodes, increased susceptibility to post-traumatic stress disorder, bipolar disorder, attempt of suicide, and major depressive disorder in HIV patients. Variation in one of these SNPs correlates with increased levels of FKBP51. FKBP51 is also increased in HIV patients. Moreover, increases in FKBP51 in the amygdala produce an anxiety phenotype in mice. Therefore, we tested the behavioral consequences of FKBP5 deletion in aged mice. Similar to that of naïve animals treated with classical antidepressants FKBP5-/- mice showed antidepressant behavior without affecting cognition and other basic motor functions. Reduced corticosterone levels following stress accompanied these observed effects on depression. Age-dependent anxiety was also modulated by FKBP5 deletion. Therefore, drug discovery efforts focused on depleting FKBP51 levels may yield novel antidepressant therapies.
authors.affiliation: Department of Molecular Medicine, Byrd Alzheimer's Research Institute, University of South Florida, Tampa, Florida, United States of America.
authors.forename: John C
authors.initials: JC
authors.lastname: O'Leary
authors.forename: Sheetal
authors.initials: S
authors.lastname: Dharia
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Blair
authors.forename: Sarah
authors.initials: S
authors.lastname: Brady
authors.forename: Amelia G
authors.initials: AG
authors.lastname: Johnson
authors.forename: Melinda
authors.initials: M
authors.lastname: Peters
authors.forename: Joyce
authors.initials: J
authors.lastname: Cheung-Flynn
authors.forename: Marc B
authors.initials: MB
authors.lastname: Cox
authors.forename: Gabriel
authors.initials: G
authors.lastname: de Erausquin
authors.forename: Edwin J
authors.initials: EJ
authors.lastname: Weeber
authors.forename: Umesh K
authors.initials: UK
authors.lastname: Jinwal
authors.forename: Chad A
authors.initials: CA
authors.lastname: Dickey
mesh_terms: D000369:Aged, 80 and over; D000818:Animals; D015153:Blotting, Western; D003345:Corticosterone / Q000097:blood; D003866:Depressive Disorder / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D006801:Humans; D007150:Immunohistochemistry; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000099159:Tacrolimus Binding Protein 5
chemical_list: D003345:Corticosterone; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5