Dexamethasone resets the circadian clock in hippocampus via multiple mechanisms involving lithium‐independent GSK3β signalling

BACKGROUND AND PURPOSE: Circadian clock in hippocampus (HPC) temporally controls memory processing. Here we have tested the hypothesis that glucocorticoids (GC) play a major role in HPC clock synchronization and therapy with Dexamethasone (DEX) may reset the HPC clock. EXPERIMENTAL APPROACH: The effect of DEX on the HPC clock was studied via its injections to Wistar rats in vivo and treatments to HPC organotypic explants of mPer2luc mice in vitro. KEY RESULTS: Daily injections of DEX reinstated adrenalectomy-abolished rhythms in clock gene expression profiles (Per1, Per2, Nr1d1, Bmal1) in the rat CA1, CA3 and dentate gyrus (DG). The largest DEX effect was detected in the DG. DEX treatments of ex vivo HPC and DG organotypic explants from mPer2luc mice reset the PER2-driven rhythm of bioluminescence with the largest responses at the time of the bioluminescence peak. DEX injections acutely induced Gilz expression in the HPC in vivo; and the DEX-induced shifts in vitro were significantly reduced by inhibitors of downstream pathways, such as PKA (H89), MEK (U0126), and of GSK3β activity (CHIR99021, but not LiCl). DEX produced phase advances of the HPC clock via acceleration of PER2 protein decay from its peak levels, and phase delays via acceleration of PER2 protein accumulation from its trough levels. CONCLUSION AND IMPLICATIONS: Our results demonstrate for the first time that DEX treatment resets the HPC clock via a non-canonical mechanism. DEX treatment may thus plausibly modulate cognitive functions and this novel effect needs to be considered in the broad spectrum of GC medications.