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.
Highlights
Genes regulating the hypothalamus-pituitary-adrenal (HPA) axis are associated with susceptibility to depression as well as antidepressant efficacy [1,2,3]
An age-dependent increase in b-gal expression was observed in the upper cortical layers of the forebrain (Figure 1A). This was consistent with the age-dependent increase in FKBP51 expression that had been previously reported in normal mice [17]
Research in the last decade has shown that variation in the FKBP5 gene is associated with depression and several other mood and anxiety disorders
Summary
Genes regulating the hypothalamus-pituitary-adrenal (HPA) axis are associated with susceptibility to depression as well as antidepressant efficacy [1,2,3]. While most studies have focused on the variants in GR because of its role as a transcriptional regulator [6], the involvement of FKBP5 and its gene product, FKBP51, have received little attention. This is largely due to uncertainty about how to approach this relatively unknown protein. It remains to be proven whether FKBP51 is a valid therapeutic target for treating depression, despite its clear genetic link
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