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 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. [Display omitted] • Microglia transiently respond to EPO by apoptosis, followed by abridged proliferation • Reduction of microglia allows undisturbed fast differentiation of immature neurons • Microglial and pyramidal EPOR are critical for neurodifferentiation in CA1 on EPO • EPO acts as regulator of neuronally expressed IL-34 and CSF1R-dependent microglia Fernandez Garcia-Agudo et al. report prominent EPO effects on neurodifferentiation that depend on a counterbalance between microglia and neurons. Microglia respond to EPO by transient apoptosis followed by dampened activity and reduced proliferation, allowing undisturbed differentiation of immature neuronal subpopulations. This ultimately results in increased numbers of mature hippocampal neurons. [ABSTRACT FROM AUTHOR]