TY - JOUR
T1 - A new anti-depressive strategy for the elderly
T2 - Ablation of FKBP5/FKBP51
AU - O'Leary, John C.
AU - Dharia, Sheetal
AU - Blair, Laura J.
AU - Brady, Sarah
AU - Johnson, Amelia G.
AU - Peters, Melinda
AU - Cheung-Flynn, Joyce
AU - Cox, Marc B.
AU - de Erausquin, Gabriel
AU - Weeber, Edwin J.
AU - Jinwal, Umesh K.
AU - Dickey, Chad A.
PY - 2011/9/15
Y1 - 2011/9/15
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pone.0024840
DO - 10.1371/journal.pone.0024840
M3 - Article
C2 - 21935478
AN - SCOPUS:80052833400
SN - 1932-6203
VL - 6
JO - PloS one
JF - PloS one
IS - 9
M1 - e24840
ER -