Glucocorticoids can strengthen or impair memory consolidation via glucocorticoid receptor (GR) transcriptional mechanisms. GR-mediated transcription is highly context-dependent and relies on the downstream interactome of transcription factors and coregulators which govern the diversity of transcriptional outcomes. Selective GR modulators (SGRMs) are ligands that can be used to activate a subset of GR-coregulator interactions to induce agonistic effects on some, and antagonistic effects on other processes. Integrating behavioral assessment, genome transcriptomics and SGRM interactome analysis allows the identification of specific signaling routes that are responsible for particular GR-mediated effects on brain function.

In this study, we set out to identify downstream GR coregulator recruitment, by comparison of the coregulator profiles of two SGRMs (CORT108297 and CORT118335) with opposite effects on memory consolidation, benchmarked against those of cortisol and the antagonist mifepristone. We also dissect CORT108297-induced GR interactome to better understand its beneficial properties in an Alzheimer’s disease (AD) rat model.

Coregulatory factors recruitment profiles were obtained using the Microarray Assay for Realtime Coregulator-Nuclear receptor Interaction (MARCoNI) technology.

Agonistic properties of SGRMs are expected to underlie memory consolidation enhancement. 7 coregulators expressed in the hippocampus interact with GR preferentially after CORT108297 compared to CORT118335 treatment, including Nuclear Receptor Coactivators (NCOA) 1 and 2.

Beneficial effects observed in rat AD model (particularly the restoration of hippocampal integrity) seemed to rely on CORT108297 antagonistic properties. 8 co-regulators significantly expressed in the hippocampus induced antagonistic-like interactions with GR, including CREB binding protein (CBP) and Nuclear Corepressor 1 (NCOR1).

We hypothesize that these identified co-regulators form a shortlist of the interactions that underlie the differential effects of the SGRMs on hippocampal physiology and memory consolidation.