More-over, it has been observed that depletion of theFKBP5 gene in mice results in reduced HPA axisactivity, increase in active coping style strategyand diminished response to acute stress, mak-ing FKBP5-knockout mice more resilient to acuteand chronic stress
This conclusion makes me wonder if DNA methylation of the FKBP5 gene could be a beneficial solution for schizophrenic individuals? Or would this gene regulation be too permanent and hinder the body's healthy stress response?
. Several studies reported the dysreg-ulation in diurnal cortisol levels, showing ele-vated diurnal and afternoon levels of cortisolin schizophrenia patients [39]. The literature onstress responsivity in schizophrenia is fairly con-sistent showing a pattern of blunted cortisol lev-els in response to stressors [40]
Seemed contradictory that the stress response is blunted, but the diurnal (baseline) cortisol is elevated! Perhaps this is because baseline HPA axis activity is higher due to chronic stress, but when additional stressors arrive (cortisol), stress response is "numb" to it. Doesn't rise as much as in healthy individuals.
KBP5 SNPs it has been shown that twoFKBP5 variants (rs9470080 and rs9394309) af-fect threat-related amygdala reactivity in the in-dividuals exposed to childhood emotional ne-glect
The amygdala is critical for our emotional processing, especially pertaining to fear. So when someone with these SNPs experiences childhood trauma --> heightened amygdala activity --> increased stress response (cortisol and FKBP5) --> prolonged stress response
prenatal maternal infec-tions
This epigenetic cause stood out because it is particularly time-sensitive. I wonder if signaling molecules from the mother's immune system activation interfere with signaling molecules in the fetus's development, therefore impacting gene expression or even brain development
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As the article mentioned previously, GR activation should decrease production of cortisol from the HPA axis. However, the figure also reveals that the complex formed from GR, cortisol, and FKBP5 will stimulate more FKBP5 production too. Therefore, it seems FKBP5 is part of a positive feedback loop that occurs simultaneously with the negative feedback of cortisol. FKBP5 activity must overpower the negative feedback in Schizophrenic patients.
Higher lev-els of FKBP5 protein lead eventually to reducedsensitivity of the GR to cortisol, causing dimin-ished negative feedback regulation of the HPAaxis.
When cortisol levels are elevated, FKBP5 protein will bind to GR, making it less sensitive to cortisol, decreasing the negative feedback inhibition. Interestingly, FKBP5 is also regulated by cortisol. So, I wonder what amount of cortisol defines the boundary between healthy and dysfunctional?