The results could lead to new treatments for post-traumatic stress disorder and other diseases

Study highlights

  • New research shows how key proteins interact to regulate the body’s response to stress
  • The targeted use of these proteins can help treat or prevent stress-related psychiatric disorders

The biological mechanisms behind stress-related psychiatric illnesses, including major depressive disorder and post-traumatic stress disorder (PTSD), are poorly understood.

New research is now describing the interplay between proteins involved in controlling the body’s response to stress and suggesting potential therapeutic targets if that response fails. The study, conducted by an international team led by researchers from McLean Hospital, appears in the journal Cell Reports.

“A dysregulated stress reaction of the body can damage the brain and increase susceptibility to mood and anxiety disorders,” says first author Jakob Hartmann, PhD. Hartmann is an assistant neuroscientist at McLean’s Neurobiology of Fear Laboratory and a lecturer in psychiatry at Harvard Medical School.

“An important brain region that is involved in the regulation of the stress response is the hippocampus,” says Hartmann. “The idea for this study came when we noticed interesting differences in the hippocampal location of three important stress-regulating proteins.”

The researchers’ experiments in non-human tissue and post-mortem brain tissue showed how these proteins – the glucocorticoid receptor (GR), the mineralocorticoid receptor (MR), and the FK506 binding protein 51 (FKBP5) – interact with each other.

In particular, MRs, rather than GRs, control the production of FKBP5 under normal conditions. FKBP5 reduces the sensitivity of GRs to the binding of stress hormones in stressful situations. FKBP5 appears to refine the stress response by acting as a mediator of the MR: GR balance in the hippocampus.

“Our results suggest that therapeutic targeting of GR, MR, and FKBP5 may be complementary in manipulating central and peripheral stress regulation,” said senior author Kerry J. Ressler, MD, PhD. Ressler is Chief Scientific Officer at McLean Hospital, Head of the McLean Division of Depression and Anxiety Disorders, and Professor of Psychiatry at Harvard Medical School.

“In addition, our data underscore the important but largely neglected role of MR signaling in stress-related psychiatric illnesses,” added Ressler. “The results of this study will open new directions for future research.”

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