Altered metabotropic glutamate receptor 5 markers in PTSD: In vivo and postmortem evidence.

Abstract

Posttraumatic stress disorder (PTSD) is a prevalent and highly disabling disorder, but there is currently no targeted pharmacological treatment for it. Dysfunction of the glutamate system has been implicated in trauma and stress psychopathology, resulting in a growing interest in modulation of the glutamate system for the treatment of PTSD. Specifically, the metabotropic glutamate receptor 5 (mGluR5) represents a promising treatment target. We used [18F]FPEB, a radioligand that binds to the mGluR5, and positron emission tomography (PET) to quantify in vivo mGluR5 availability in human PTSD vs. healthy control (HCs) subjects. In an independent sample of human postmortem tissue, we investigated expression of proteins that have a functional relationship with mGluR5 and glucocorticoids in PTSD. We observed significantly higher cortical mGluR5 availability in PTSD in vivo and positive correlations between mGluR5 availability and avoidance symptoms. In the postmortem sample, we observed up-regulation of SHANK1, a protein that anchors mGluR5 to the cell surface, as well as decreased expression of FKBP5, implicating aberrant glucocorticoid functioning in PTSD. Results of this study provide insight into molecular mechanisms underlying PTSD and suggest that mGluR5 may be a promising target for mechanism-based treatments aimed at mitigating this disorder.

• Authors: Sophie E Holmes, Matthew J Girgenti, Margaret T Davis, Robert H Pietrzak, Nicole DellaGioia, Nabeel Nabulsi, David Matuskey, Steven Southwick, Ronald S Duman, Richard E Carson, John H Krystal, Irina Esterlis, Traumatic Stress Brain Study Group
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 114 Issue 31 Pg. 8390-8395 (08 01 2017) ISSN: 1091-6490 [Electronic] United States
• PMID: 28716937 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Glucocorticoids
• Nerve Tissue Proteins
• Radiopharmaceuticals
• Receptor, Metabotropic Glutamate 5
• SHANK1 protein, human
• Glutamic Acid
• Tacrolimus Binding Proteins
• tacrolimus binding protein 5

Topics

• Adult
• Base Sequence
• Female
• Gene Expression (physiology)
• Glucocorticoids (metabolism)
• Glutamic Acid (metabolism)
• Humans
• Male
• Nerve Tissue Proteins (biosynthesis)
• Positron-Emission Tomography (methods)
• Radiopharmaceuticals (pharmacology)
• Receptor, Metabotropic Glutamate 5 (metabolism)
• Sequence Analysis, RNA
• Stress Disorders, Post-Traumatic (drug therapy, pathology)
• Tacrolimus Binding Proteins (biosynthesis)