A new anti-depressive strategy for the elderly: ablation of FKBP5/FKBP51.

O'Leary JC, Dharia S, Blair LJ, Brady S, Johnson AG, Peters M, Cheung-Flynn J, Cox MB, de Erausquin G, Weeber EJ, Jinwal UK, Dickey CA
PLoS One. 2011 6 (9): e24840

PMID: 21935478 · PMCID: PMC3174203 · DOI:10.1371/journal.pone.0024840

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.

MeSH Terms (13)

Aged, 80 and over Animals Blotting, Western Corticosterone Depressive Disorder Humans Immunohistochemistry Maze Learning Mice Mice, Knockout Polymerase Chain Reaction Polymorphism, Single Nucleotide Tacrolimus Binding Proteins

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