4.42 Molecular Dysregulation of Glucocorticoid Receptor Pathways in Teenage Suicide Completers

Document Type

Conference Proceeding

Publication Date

10-1-2025

Publication Title

J Am Acad Child Adolesc Psychiatry

Abstract

Objectives: Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, a stress-response system regulated by the glucocorticoid receptor (GR), has been linked to suicide, yet few molecular studies focus on adolescents. This study compared: 1) messenger-ribonucleic acid (RNA) expression of GR chaperones (FKBP4, FKBP5, HSP90, p23, BAG1); and 2) GR-regulated genes (P11, GPR158, SKA2) in the prefrontal cortex (Brodmann Area 9; BA9) and hippocampus of teenage suicide deaths (TSD) vs matched controls (C), predicting region-specific up-regulation of chaperones, down-regulation of BAG1 and P11, and overall evidence of impaired GR transcription. Methods: First, brain tissue was obtained postmortem from 24 TSD and 24 C subjects matched for age, sex, postmortem interval, pH, and RNA integrity. Second, quantitative real-time polymerase chain reaction (PCR) measured target-gene expression, normalized to the geometric mean of 3 housekeeping genes (ΔCt). Third, multivariate ANCOVA (MANCOVA) followed by individual ANCOVAs tested group effects; the covariates were age, sex, pH, postmortem interval, RNA integrity, and antidepressant exposure. Finally, fold-change (FC = 2∧–ΔΔCt) and Benjamini-Hochberg–adjusted p < .05 defined significance. Results: In BA9, FKBP4 and HSP90 were up-regulated (FC ≈ 1.4), BAG1 was down-regulated (FC ≈ 0.8), and P11 was reduced (FC ≈ .8); GPR158 was elevated (FC ≈ 1.5). In the hippocampus, FKBP4 and p23 were increased (FC ≈ 1.4), while BAG1 and P11 were unchanged; GPR158 remained elevated (FC ≈ 1.6). SKA2 showed a nonsignificant upward trend in BA9. Conclusions: Teenage suicide completers exhibit region-specific GR dysregulation: increased FKBP4/HSP90 and decreased BAG1/P11 in BA9, plus increased FKBP4/p23 in the hippocampus. Up-regulation of GPR158 across regions suggests prolonged cortisol exposure or faulty feedback. These molecular alterations may weaken stress-response control, amplifying suicide risk in adolescence, and identify FKBP5, BAG1, and P11 as potential biomarkers for early detection and intervention. S, R, DAM

Volume

64

Issue

10S

First Page

S262

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