RESULTS
FKBP5 mRNA expression in the non-human primate (NHP) and human brains was analyzed over a range of prenatal and postnatal ages. Figure 1A summarizes the data analysis workflow. Microarray data from NHP brain development showed an interesting pattern at postnatal ages. FKBP5 mRNA was detected in regions of interest (ROIs) relevant to MDD (prefrontal cortex, hippocampus, amygdala, and striatum) at 0, 3, and 12 months. During this range of time, FKBP5 had a much stronger expression in the ROIs than in other brain regions. By 48 months, FKBP5 expression was detected in all brain regions. Moreover, within the ROIs, there was a sharp contrast between time points before birth and after birth: FKBP5 expression was only apparent after birth (Fig. 1B).
Similarly, the study of FKBP5 mRNA transcriptome expression in the human prefrontal cortex, hippocampal formation, amygdaloid complex, and striatum at early postnatal ages confirmed what was already observed in NHPs (Fig. 1B). In particular, FKBP5 expression at 2, 3, 8, 11, and 13 years was strongly upregulated for ROIs in comparison to other brain regions. Again, it is clear that FKBP5 mRNA expression increases strongly after birth. The evidence that the gene turns on soon after birth would suggest that FKBP5 is vulnerable to being altered by the animal’s interaction with the environment, and thereby ELS. Further, this effect is observed specifically in regions involved with MDD. FKBP5 mRNA expression were not available from the developing mouse brain Allen atlas (http://developingmouse.brain-map.org). However, in situhybridization data from the adult C57BL/6 mouse Allen atlas confirmed that FKBP5 mRNA is highly expressed in MDD-relevant regions such as the prefrontal cortex and hippocampus (Fig. 2).
These observations led us to verify whether FKBP5 mRNA expression was deregulated in the brain of a mouse model of MDD as well as human MDD. To this end, we analyzed RNAseq data from the medial prefrontal cortex (mPFC) and ventral hippocampus (vHPC) of C57BL/6 control mice and C57BL/6 mice subjected to chronic social defeat stress (CSDS) (Laine et al., 2018), a widely used model of MDD. In the mPFC, we detected an up-regulation of FKBP5 mRNA in CSDS mice compared to age-matched controls (Fig. 3A, left; CSDS vs. control, t-test p<0.01; rank-sum test, p<0.01). A trend to an up-regulation of FKBP5 mRNA was also detected in the vHPC of CSDS mice (Fig. 3A, right; CSDS vs. control, t-test p<0.05; rank-sum test, p=0.08333). A significant up-regulation of FKBP5 mRNA in the prefrontal cortex was also detected in human MDD patients compared to control subjects (Fig. 3B; MDD vs. control, p<0.001, Mann Whitney test; data re-analyzed Cohort 1 / Figure 1a of Matosin et. al., 2023). Thus, the up-regulation of FKBP5 mRNA observed in the PFC of human MDD patients and socially-defeated mice confirms our idea of a prominent role of FKBP5 in MDD.