Brain erythropoietin fine-tunes a counterbalance between neurodifferentiation and microglia in the adult hippocampus

In adult cornu ammonis hippocampi, erythropoietin (EPO) expression drives the differentiation of new neurons,independent of DNA synthesis, and increases dendritic spine density. This substantial brain hardwareupgrade is part of a regulatory circle: during motor-cognitive challenge, neurons experience ‘‘functional’’hypoxia, triggering neuronal EPO production, which in turn promotes improved performance. Here, weshow an unexpected involvement of resident microglia. During EPO upregulation and stimulated neurodifferentiation,either by functional or inspiratory hypoxia, microglia numbers decrease. Treating mice with recombinanthuman (rh)EPO or exposure to hypoxia recapitulates these changes and reveals the involvement ofneuronally expressed IL-34 and microglial CSF1R. Surprisingly, EPO affects microglia in phases, initiallyby inducing apoptosis, later by reducing proliferation, and overall dampens microglia activity and metabolism,as verified by selective genetic targeting of either the microglial or pyramidal neuronal EPO receptor.We suggest that during accelerating neuronal differentiation, EPO acts as regulator of the CSF1R-dependentmicroglia.