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FKBP51, FKBP5 knockout mice, Synapsin, HPA Axis, Stress reactivity, Schizophrenia, Bipolar disorder, PTSD, Prefrontal Cortex, Akt kinase
Abstract:
Both the molecular co-chaperone FKBP51 and the presynaptic vesicle
protein synapsin (alternatively spliced from SYN1-3) are intensively
discussed players in the still insufficiently explored pathobiology of
psychiatric disorders such as major depression, schizophrenia and
posttraumatic stress disorder (PTSD). To address their still unknown
interaction, we compared the expression levels of synapsin and five
other neurostructural and HPA axis related marker proteins in the
prefrontal cortex (PFC) and the hippocampus of restrained-stressed and
unstressed Fkbp5 knockout mice and corresponding wild-type littermates.
In addition, we compared and correlated the gene expression levels of
SYN1, SYN2 and FKBP5 in three different online datasets comprising
expression data of human healthy subjects as well as of predominantly
medicated patients with different psychiatric disorders. In summary, we
found that Fkbp5 deletion, which we previously demonstrated to improve
stress-coping behavior in mice, prevents the stress-induced decline in
prefrontal cortical (pc), but not in hippocampal synapsin expression.
Accordingly, pc, but not hippocampal, synapsin protein levels correlated
positively with a more active mouse stress coping behavior. Searching
for an underlying mechanism, we found evidence that deletion of Fkbp5
might prevent stress-induced pc synapsin loss, at least in part, through
improvement of pc Akt kinase activity. These results, together with our
finding that FKBP5 and SYN1 mRNA levels were regulated in opposite
directions in the PFC of schizophrenic patients, who are known for
exhibiting an altered stress-coping behavior, provide the first evidence
of a role for pc synapsin in FKBP51 modulation of stress responsiveness.
This role might extend to other tissues, as we found FKBP5 and SYN1
levels to correlate inversely not only in human PFC samples but also in
other expression sites. The main limitation of this study is the small
number of individuals included in the correlation analyses. Future
studies will have to verify the here-postulated role of the FKBP51 Akt
kinase synapsin pathway in stress responsiveness. (C) 2014 Elsevier Ltd.
All rights reserved.
