title: Deficiency of FK506-binding protein (FKBP) 51 alters sleep architecture and recovery sleep responses to stress in mice.
abstract: FK506-binding protein 51 (FKBP51) is a co-chaperone of the glucocorticoid receptor, functionally linked to its activity via an ultra-short negative feedback loop. Thus, FKBP51 plays an important regulatory role in the hypothalamic-pituitary-adrenocortical (HPA) axis necessary for stress adaptation and recovery. Previous investigations illustrated that HPA functionality is influenced by polymorphisms in the gene encoding FKBP51, which are associated with both increased protein levels and depressive episodes. Because FKBP51 is a key molecule in stress responses, we hypothesized that its deletion impacts sleep. To study FKBP51-involved changes in sleep, polysomnograms of FKBP51 knockout (KO) mice and wild-type (WT) littermates were compared at baseline and in the recovery phase after 6-h sleep deprivation (SD) and 1-h restraint stress (RS). Using another set of animals, the 24-h profiles of hippocampal free corticosterone levels were also determined. The most dominant effect of FKBP51 deletion appeared as increased nocturnal wake, where the bout length was significantly extended while non-rapid eye movement sleep (NREMS) and rapid eye movement sleep were rather suppressed. After both SD and RS, FKBP51KO mice exhibited less recovery or rebound sleep than WTs, although slow-wave activity during NREMS was higher in KOs, particularly after SD. Sleep compositions of KOs were nearly opposite to sleep profiles observed in human depression. This might result from lower levels of free corticosterone in FKBP51KO mice, confirming reduced HPA reactivity. The results indicate that an FKBP51 deletion yields a pro-resilience sleep phenotype. FKBP51 could therefore be a therapeutic target for stress-induced mood and sleep disorders.
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Stefana
authors.initials: S
authors.lastname: Albu
authors.forename: Christoph P N
authors.initials: CP
authors.lastname: Romanowski
authors.forename: M
authors.initials: M
authors.lastname: Letizia Curzi
authors.forename: Vladimira
authors.initials: V
authors.lastname: Jakubcakova
authors.forename: Cornelia
authors.initials: C
authors.lastname: Flachskamm
authors.forename: Nils C
authors.initials: NC
authors.lastname: Gassen
authors.forename: Jakob
authors.initials: J
authors.lastname: Hartmann
authors.forename: Mathias V
authors.initials: MV
authors.lastname: Schmidt
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schmidt
authors.forename: Theo
authors.initials: T
authors.lastname: Rein
authors.forename: Florian
authors.initials: F
authors.lastname: Holsboer
authors.forename: Felix
authors.initials: F
authors.lastname: Hausch
authors.forename: Marcelo
authors.initials: M
authors.lastname: Paez-Pereda
authors.forename: Mayumi
authors.initials: M
authors.lastname: Kimura
mesh_terms: D000818:Animals; D003345:Corticosterone / Q000097:blood; D003866:Depressive Disorder / Q000378:metabolism; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010913:Pituitary-Adrenal System / Q000378:metabolism; D011110:Polymorphism, Genetic; D017286:Polysomnography; D012890:Sleep; D012892:Sleep Deprivation / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology*; D012893:Sleep Wake Disorders / Q000378:metabolism / Q000503:physiopathology; D012895:Sleep, REM; D022021:Tacrolimus Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000099159:Tacrolimus Binding Protein 5
chemical_list: D003345:Corticosterone; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5
keywords: FKBP51; depression; free corticosterone; rapid eye movement sleep; restraint stress; slow-wave activity