Single nucleotide polymorphisms (SNPs) in FK506-binding protein 5 (FKBP5) have been shown to combine with environmental factors increases risk for psychiatric diseases, like post-traumatic stress disorder (PTSD). While mechanisms of FKBP5 contribution to this increased risk are still under investigation, it has been shown that many of these SNPs increase FKBP5 expression through decreased FKBP5 DNA methylation. To evaluate the consequences of this enhanced expression, we generated a novel mouse model using targeted insertion of a single copy of the FKBP5 gene at the Hipp11 locus. The inserted FKBP5 contained a tetracycline operator, which allowed for high expression throughout the forebrain when crossed with an activator line. Evaluation of this model was done using behavioral, electrophysiological, and biochemical analysis. Overall, we have found that high expression of FKBP5 alters memory as tested by both Morris water maze and long-term depression. Importantly, this alteration was detectable in the absence of stress and other environmental factors. Further studies in this model may help reveal additional mechanisms by which FKBP5 alters learning and memory.
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