Metabolic reprogramming of microglia exposed to glucocorticoids in vitro

Glial plasticity is a pathophysiological mechanism underlying stress-related diseases. Microglia cells respond to stress or stress mediators (namely glucocorticoids), undergoing a morphological remodeling process involving constant changes in number and length of cellular processes. Importantly, stress- and glucocorticoid-induced changes in microglia morphology correlate with psychiatric symptoms manifestation, and their recovery with the remission of these symptoms. Considering the energetic requirements inherent to morphological changes, we raised the question whether glucocorticoids, as crucial stress-associated hormones, could affect microglial mitochondria and the ability of these cells to monitor the surrounding microenvironment. By using a microglial cell line, we observed that the glucocorticoid dexamethasone induces transient increases in mitochondrial cellular respiration and in oxygen consumption linked to ATP production. These alterations suggest a metabolic reprogram of microglia towards a more aerobic-like state, allowing the quick production of ATP and the preservation of the surveillance ability of the surrounding microenvironment, as assessed by tracking cellular processes dynamics. The discovery that dexamethasone transiently boosts mitochondrial respiration and ATP production in microglia suggests that metabolic pathways can be central to glial adaptability. Accordingly, in acute response to dexamethasone, autophagy is promoted alongside with higher number of mitochondria, suggesting a mitochondrial network remodeling. At long-term, these adaptations are reverted, with microglia displaying lower number of mitochondria. This raises the possibility of therapeutically modulating microglial metabolism to support cellular resilience under stress or even restore homeostatic functions in disease states. These findings position microglial morphology and metabolism as promising biomarkers and therapeutic targets for stress-related brain disorders.