Brain erythropoietin fine-tunes a counterbalance between neurodifferentiation and microglia in the adult hippocampus
Laura Fernandez Garcia-Agudo,
Agnes A. Steixner-Kumar,
Yasmina Curto,
Nadine Barnkothe,
Imam Hassouna,
Sebastian Jähne,
Umer Javed Butt,
Katharina Grewe,
Martin S. Weber,
Kim Green,
Silvio Rizzoli,
Juan Nacher,
Klaus-Armin Nave,
Hannelore Ehrenreich
Affiliations
Laura Fernandez Garcia-Agudo
Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany
Agnes A. Steixner-Kumar
Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany
Yasmina Curto
Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany
Nadine Barnkothe
Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany
Imam Hassouna
Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany
Sebastian Jähne
Department of Neuro- and Sensory Physiology, University Medical Center Göttingen, Göttingen, Germany
Umer Javed Butt
Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany
Katharina Grewe
Department of Neuro- and Sensory Physiology, University Medical Center Göttingen, Göttingen, Germany
Martin S. Weber
Institute of Neuropathology and Department of Neurology, UMG, Göttingen, Germany
Kim Green
Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, USA
Silvio Rizzoli
Department of Neuro- and Sensory Physiology, University Medical Center Göttingen, Göttingen, Germany
Juan Nacher
Neurobiology Unit, Program in Neurosciences and Interdisciplinary Research Structure for Biotechnology and Biomedicine (BIOTECMED), Universitat de València, Burjassot, Spain
Klaus-Armin Nave
Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany
Hannelore Ehrenreich
Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany; Corresponding author
Summary: 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.
