Functional hypoxia drives neuroplasticity and neurogenesis via brain erythropoietin

Debia Wakhloo, Franziska Scharkowski, Yasmina Curto, Umer Javed Butt, Vikas Bansal, Agnes A. Steixner-Kumar, Liane Wüstefeld, Ashish Rajput, Sahab Arinrad, Matthias R. Zillmann, Anna Seelbach, Imam Hassouna, Katharina Schneider, Abdul Qadir Ibrahim, Hauke B. Werner, Henrik Martens, Kamilla Miskowiak, Sonja M. Wojcik, Stefan Bonn, Juan Nacher, Klaus-Armin Nave () and Hannelore Ehrenreich ()
Additional contact information
Debia Wakhloo: Max Planck Institute of Experimental Medicine
Franziska Scharkowski: Max Planck Institute of Experimental Medicine
Yasmina Curto: Max Planck Institute of Experimental Medicine
Umer Javed Butt: Max Planck Institute of Experimental Medicine
Vikas Bansal: Max Planck Institute of Experimental Medicine
Agnes A. Steixner-Kumar: Max Planck Institute of Experimental Medicine
Liane Wüstefeld: Max Planck Institute of Experimental Medicine
Ashish Rajput: University Clinic Hamburg-Eppendorf
Sahab Arinrad: Max Planck Institute of Experimental Medicine
Matthias R. Zillmann: Max Planck Institute of Experimental Medicine
Anna Seelbach: Max Planck Institute of Experimental Medicine
Imam Hassouna: Max Planck Institute of Experimental Medicine
Katharina Schneider: Max Planck Institute of Experimental Medicine
Abdul Qadir Ibrahim: University Clinic Hamburg-Eppendorf
Hauke B. Werner: Max Planck Institute of Experimental Medicine
Henrik Martens: Synaptic Systems GmbH
Kamilla Miskowiak: Copenhagen University Hospital, Rigshospitalet
Sonja M. Wojcik: Max Planck Institute of Experimental Medicine
Stefan Bonn: University Clinic Hamburg-Eppendorf
Juan Nacher: Universitat de València
Klaus-Armin Nave: Max Planck Institute of Experimental Medicine
Hannelore Ehrenreich: Max Planck Institute of Experimental Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract Erythropoietin (EPO), named after its role in hematopoiesis, is also expressed in mammalian brain. In clinical settings, recombinant EPO treatment has revealed a remarkable improvement of cognition, but underlying mechanisms have remained obscure. Here, we show with a novel line of reporter mice that cognitive challenge induces local/endogenous hypoxia in hippocampal pyramidal neurons, hence enhancing expression of EPO and EPO receptor (EPOR). High-dose EPO administration, amplifying auto/paracrine EPO/EPOR signaling, prompts the emergence of new CA1 neurons and enhanced dendritic spine densities. Single-cell sequencing reveals rapid increase in newly differentiating neurons. Importantly, improved performance on complex running wheels after EPO is imitated by exposure to mild exogenous/inspiratory hypoxia. All these effects depend on neuronal expression of the Epor gene. This suggests a model of neuroplasticity in form of a fundamental regulatory circle, in which neuronal networks—challenged by cognitive tasks—drift into transient hypoxia, thereby triggering neuronal EPO/EPOR expression.

Date: 2020
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DOI: 10.1038/s41467-020-15041-1

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