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.