ESPE Yearbook of Paediatric Endocrinology

Brief summary: This study investigates the effect of long-acting synthetic glucocorticoids on circadian rhythmicity and hippocampal function

Glucocorticoids exert their effects by binding to glucocorticoid receptors (GRs), which regulate up to ~20% of the genome via both direct (by binding to glucocorticoid responsive elements in promoter regions) and indirect mechanisms (by interacting with bound transcription factors and epigenetic modifiers) (1, 2). GRs play a key role in the feedback regulation of the hypothalamic- pituitary-adrenal (HPA) axis. They are highly expressed in the hippocampus and their distribution is heterogeneous depending on the hippocampal subregion both at baseline and in response to stress (3, 4). Circadian oscillations of glucocorticoids are a fundamental characteristic of adrenal hormone secretion in all mammals. A major coordinator of circadian biological systems is adrenal glucocorticoid secretion, which exhibits a pronounced pre-awakening peak that regulates metabolic, immune, and cardiovascular processes, as well as mood and cognitive function. Loss of this circadian rhythm by chronic stress or synthetic glucocorticoid therapy results in adverse effects, such as impaired memory, mood, and sleep. Surprisingly, the mechanisms that underlie this deficit have not been delineated.

In this ‘reverse translational’ study, the authors demonstrate that 5-day treatment with methylprednisolone induces prolonged activation of GRs, disrupts the rhythmic activity of hippocampal function through GRs, induces N-methyl-D-aspartate receptor (NMDAR)-dependent synaptic dysfunction, and subsequently impairs memory. This model is supported by several lines of evidence: 1) Corticosteroids do not influence the master clock (SCN) or light/dark entraining behaviors due to a lack of GR expression in the SCN; 2) the hippocampus is rich in GRs, which in the presence of corticosteroids, bind to GREs on the essential clock gene Per1 to mediate hippocampal activity in competition with central clock-mediated control; 3) synthetic corticosteroid treatment eliminates the circadian variation in circulating corticosteroids, and consequently the circadian variation in the activity of hippocampal GRs to influence clock gene expression and destabilize clock-entrained NMDAR/CamkII complexes; and 4) synthetic corticosteroid treatment blocks long-term potentiation (LTP), a cellular correlate of long-term memory, by disrupting NMDAR-dependent processes to impair long-term, but not short-term, hippocampal-dependent memory.

These findings provide mechanistic insights into how the transcriptional clock machinery within the hippocampus is influenced by corticosteroid exposure, leading to adverse effects on critical hippocampal functions. They also identify a molecular basis for memory deficits in patients treated with long-acting synthetic corticosteroids. Given that a large proportion of patients treated with corticosteroids report cognitive decline and memory impairment (5), these data further support the importance of devising improved regimens of glucocorticoid therapy that recapitulate endogenous glucocorticoid rhythmicity.

References: 1. Nicolaides NC, Galata Z, Kino T, Chrousos GP, Charmandari E. The human glucocorticoid receptor: molecular basis of biologic function. Steroids. 2010; 75(1):1–12. 2. Gray JD, Kogan JF, Marrocco J, McEwen BS. Genomic and epigenomic mechanisms of glucocorticoids in the brain. Nat Rev Endocrinol. 2017; 13: 661–73. 3. Chao HM, Choo PH, McEwen BS. Glucocorticoid and mineralocorticoid receptor mRNA expression in rat brain. Neuroendocrinology. 1989; 50: 365–71. 4. Guidotti G, Calabrese F, Anacker C, Racagni G, Pariante CM, Riva MA. Glucocorticoid receptor and FKBP5 expression is altered following exposure to chronic stress: modulation by antidepressant treatment. Neuropsychopharmacology. 2013; 38: 616–27. 5. Keenan P, Jacobson M, Soleymani R, Stress M, Yaldoo D. The effect on memory of chronic prednisone treatment in patients with systemic disease. Am. Acad. Neurol. 1996; 47, 1396–1402.