Adversity-Related Changes to the Spatial Localisation of Hippocampal Cortisol Receptors in Psychiatric Disorders

Abstract Background Dysfunction of the stress response is a major risk factor for psychopathology, however, molecular evidence of the mechanism in humans is limited. Hippocampal cortisol receptors NR3C1 and NR3C2 and their modulators (e.g. FKBP5) are key coordinators of this stress response. Aims adulthood: n=5; no stress: n=3; controls: n=3). Spatial transcriptomics (Visium, 10x Genomics) was performed to measure spatial gene expression. Hippocampal subregions were manually annotated using subregion specific markers, and the expression of cortisol receptors and FKBP5 was compared across groups for all hippocampal subregions and layers. Results Psychiatric cases with childhood stress exposure exhibited significantly lower FKBP5 expression in the CA4 subregion compared to controls (-35%, PFDR = 0.046) and no stress cases (-53.2%, PFDR = 9.150e-15). FKBP5 was lower in the polymorphic layer of the dentate gyrus compared to controls (-19.7%, PFDR = 0.016) and no stress cases (-29.5%, PFDR = 0.0034). Adulthood stress cases displayed higher FKBP5 expression in the molecular layer of the dentate gyrus compared to controls (+4.54%, PFDR = 0.01242) and no stress cases (+4.75%, PFDR = 0.000573). Cortisol receptor expression was uniform throughout the hippocampus with no difference in expression between stress groups. Discussion & Conclusions The lasting FKBP5 expression changes indicate a potential target for future therapeutic development for psychiatric disorders associated with childhood stress exposure.