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Abstract

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 hardware
upgrade 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, we
show an unexpected involvement of resident microglia. During EPO upregulation and stimulated neurodifferentiation,
either by functional or inspiratory hypoxia, microglia numbers decrease. Treating mice with recombinant
human (rh)EPO or exposure to hypoxia recapitulates these changes and reveals the involvement of
neuronally expressed IL-34 and microglial CSF1R. Surprisingly, EPO affects microglia in phases, initially
by 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-dependent
microglia.