Neuroinflammatory inhibition of synaptic long‐term potentiation requires immunometabolic reprogramming of microglia

Immunometabolism refers to the rearrangement of metabolic pathways in response to immune stimulation, and the ability of these metabolic pathways themselves to control immune functions. Many aspects of immunometabolism have been revealed through studies of peripheral immune cells. However, immunometabolic reprogramming of microglia, the resident immune cell of the central nervous system, and the consequential outcome on neuronal activity have remained difficult to unravel. Microglia are highly sensitive to subtle changes in their environment, limiting the techniques available to study their metabolic and inflammatory profiles. Here, using fluorescence lifetime imaging of endogenous NAD(P)H, we measure the metabolic activity of individual microglia within acute hippocampal slices. We observed an LPS‐induced increase in aerobic glycolysis, which was blocked by the addition of 5 mM 2‐deoxyglucose (2DG). This LPS‐induced glycolysis in microglia was necessary for the stabilization of hypoxia inducible factor‐1α (HIF‐1α) and production of the proinflammatory cytokine, interleukin‐1β (IL‐1β). Upon release, IL‐1β acted via the neuronal interleukin‐1 receptor to inhibit the formation of synaptic long‐term potentiation (LTP) following high frequency stimulation. Remarkably, the addition of 2DG to blunt the microglial glycolytic increase also inhibited HIF‐1α accumulation and IL‐1β production, and therefore rescued LTP in LPS‐stimulated slices. Overall, these data reveal the importance of metabolic reprogramming in regulating microglial immune functions, with appreciable outcomes on cytokine release and neuronal activity. Main Points LPS‐stimulated microglia increase aerobic glycolysis, promoting HIF‐1α accumulation and IL‐1β production. IL‐1β acts on neuronal IL‐1R, inhibiting long‐term potentiation. 2DG blocks metabolic reprogramming and IL‐1β release, and rescues long‐term potentiation.