Transcriptional signature of a hypersensitive glucocorticoid receptor variant in the neuroendocrine system suggests enhanced vulnerability to brain disorders.

The natural substitution Ala610Val in the porcine glucocorticoid receptor (GRAla610Val) leads to a profound compensatory downregulation of the hypothalamic-pituitary-adrenal (HPA) axis in early ontogeny. In this study, we leveraged this unique animal model to explore mechanisms of HPA axis regulation and consequences of its genetically-based persistent hypoactivity. To this end, we examined transcriptional signature of GRAla610Val in the hypothalamus, hippocampus, amygdala and adrenal gland in resting conditions (i.e. baseline glucocorticoid level) using mRNA sequencing. In addition, we studied transcriptome responses to two different doses of dexamethasone in the hypothalamus and hippocampus, depending on GRAla610Val. Across tissues, GRAla610Val consistently influenced the expression of several clustered protocadherins, particularly PCDHB7. Clustered protocadherins play an important role in neuronal connectivity and are implicated in different neurobiological disorders. Moreover, in line with our previous findings in blood immune cells, we found higher expression of pro-inflammatory genes, including canonical members of the TLR4 signaling pathway, in the brain of Val carriers. While the pro-inflammatory priming occurs already at resting conditions in the amygdala, in hypothalamus and hippocampus this seems to be associated with a stronger downregulation of several marker genes of homeostatic microglia, such as SALL1, by dexamethasone in Val carriers. Regarding the regulation of the HPA axis, GRAla610Val showed a dose-dependent effect on the central regulator of the axis, CRH, suggesting a dynamic adaptation to the glucocorticoid hypersensitivity of the Val variant. In the adrenal gland, GRAla610Val appears to downregulate cortisol production by impairing mitochondrial function. Overall, the transcriptional signature of GRAla610Val provides strong evidence that GR hypersensitivity leads to increased susceptibility to brain disorders.