Neurotrophic Glucocorticoid Signalling

Glucocorticoids are stress hormones released into circulation that play central roles in the immediate and slower adaptive responses of the brain and body to environmental and internal stimuli, whether perceived or imagined. Receptors for glucocorticoids translocate from the cytosol to the nucleus and mitochondria to regulate the expression of numerous genes involved in neuroplasticity, metabolism, inflammation, immunity, and the cytoskeleton. Rapid effects of glucocorticoids are mediated by distinct receptor-associated mechanisms to facilitate or suppress neurotransmitter release. Feedforward and feedback mechanisms in neurotransmission thus depend on glucocorticoid receptor localization and functional states across synapses. Post-translational modifications of glucocorticoid receptors generate specific docking sites for signalling effectors which vary between active and inactive neurons. Diversity of glucocorticoid reactivity produces heterogeneous cellular responses that integrate prior experience. The activity-dependent trans-synaptic neurotrophic messenger BDNF emerges as a key modulator of glucocorticoid receptor signalling diversity. These mechanisms have been investigated with deletion mutants in a variety of preclinical models, pointing not only at possible causes of human diseases but also at potential strategies for mitigating them. This review specifically focuses on neurotrophic glucocorticoid signalling as a coincidence detection mechanism between BDNF and glucocorticoids, extending beyond classical genomic and non-genomic frameworks.