Sandra Kumar

Introduction: Major Depressive Disorder (MDD) is a mood disorder involving persistent feelings of anhedonia that affects approximately 350 million people around the world.¹ While the etiology of depression can be traced back to the hypersecretion of cortisol and faulty hypothalamic-pituitary-adrenal (HPA) axis, studies look at the role of FKBP prolyl isomerase 5 (FKBP5) on stress regulation.² During stress events glucocorticoids bind to glucocorticoid receptors (GR) which upregulate expression of the FKBP5 gene releasing a binding protein which creates a short negative feedback loop to dampen the stress response.^2,3 Mutations of this gene can cause a prolonged stress response leading to an increase in MDD development.^2,3 Methods: Rats were exposed to unpredictable stress and their brains were analyzed to investigate the effect of GRa isoforms on the pathogenesis of depression as well as the dysregulation of GR-responsive genes.⁴ Mice were bred to knock out the FKBP5 gene while other mice overexpressed the gene and were put under acute stress to measure levels of GR phosphorylation.⁵ Mice were bred to be deficient on FKBP5 and the areas of the brain containing the excitatory and inhibitory postsynaptic currents were measured.⁶ Mice were treated with different compounds that inhibited FKBP5 and GR expression was measured.² Patients with depression were recruited and received antidepressant treatment and were analyzed to see who had a risk allele and what effect that had on their treatment.⁷ Results: The results showed an increase in FKBP5 in the prefrontal cortex of females displaying how high levels of these genes contribute to depressive-like behavior through GR dysregulation.⁴ Overexpressed FKBP5 groups had reduced thymus and increased blood cortisone levels while knockout mice had higher levels of transcriptionally active GR.⁵ FKBP5 deletion showed GR activation was not altered during stress events displaying stress resilience in the mice.⁶ Benztropine mesylate was found as a novel FKBP51-specific inhibitor as it directly bound to FKBP5 thus disrupting the FKBP51/GR complex.² Patients who did not respond well to antidepressant treatment had high gene expression of the FKBP5 SNP rs1360780.⁷ Conclusion: FKBP5 is a gene that plays a central role in stress regulation response.  However by inhibiting FKBP5 expression subjects can experience stress resilience and can even restore normal GR activity. These findings can be used in the diagnosis, individualized treatment and potential therapeutic relief of those diagnosed with MDD.

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3. Han KM, Won E, Sim Y, et al. Influence of FKBP5 polymorphism and DNA methylation on structural changes of the brain in major depressive disorder. Sci Rep. 2017;7:42621. Published 2017 Feb 15. doi:10.1038/srep42621
4. Aleksic M, Brkic Z, Petrovic Z, Francija E, Lukic I, Adzic M. Sex-specific contribution of glucocorticoid receptor alpha isoforms to anxiety and depressive-like behavior in mice [published online ahead of print, 2022 Feb 20]. J Neurosci Res. 2022;10.1002/jnr.25032. doi:10.1002/jnr.25032
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