Corticosteroid‐regulated gene transcription in <scp>SH</scp> ‐ <scp>SY5Y</scp> ‐derived neurons: Insights into the mineralocorticoid and glucocorticoid receptor‐mediated response

Post-traumatic stress disorder (PTSD) and major depressive disorder (MDD) are debilitating stress-related psychiatric disorders that can develop following exposure to traumatic events or chronic stress in some individuals. The neurobiological processes leading to disease remain largely unknown. Among others, these disorders are characterized by a dysregulated hypothalamic-pituitary-adrenal axis, which is regulated by the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). This leads to altered downstream corticosteroid-induced gene expression. In vitro models are promising tools to investigate specific neurobiological underpinnings of the stress response in the brain. Here, we investigated the suitability of SH-SY5Y-derived neurons as a cost-efficient system to study the role of GR and MR in the neuronal stress response. SH-SY5Y-derived neurons were characterized, exposed to corticosteroids, and analyzed on transcriptomic and proteomic levels. We show that (i) these neurons express sufficient and seemingly functional GR and MR to allow the study of corticosteroid-induced transcription, (ii) three corticosteroids cortisol, dexamethasone, and aldosterone, induced similar transcriptomic effects, (iii) the antagonist spironolactone mildly attenuated the effects of dexamethasone in FKBP5, DUSP1, and SUPV3L1. Mifepristone did not significantly alter the effect of aldosterone. (iv) Integrating transcriptomic alterations of these corticosteroid-exposed neurons with those of iPSC-derived neurons exposed to dexamethasone showed concordant corticosteroid-induced effects in the two in vitro systems. To determine translational validity, we compared the gene expression in these neurons with the transcriptome of postmortem brain samples from individuals with PTSD and MDD, yielding stronger negative correlations of corticosteroid effects in SH-SY5Y-derived neurons with PTSD signatures than with MDD signatures. Upon further refinement and validation, SH-SY5Y-derived neurons may serve as a simplistic tool to study neuronal corticosteroid-induced gene expression and the implicated molecular networks around GR and MR. Strengthening our insight into these receptors' functions improves our understanding of the hypothalamic-pituitary-adrenal axis, which is commonly altered in stress-related psychiatric disorders such as PTSD and MDD.