Functional hypoxia drives neuroplasticity and neurogenesis via brain erythropoietin

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, Hannelore Ehrenreich. - (Nature Communications 11 (2020) 1313 (9 March); p. 1-12)

  • PMID: 32152318
  • PMCID: PMC7062779
  • DOI: 10.1038/s41467-020-15041-1


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.

Original document


Research / Study
9 March 2020
Arinrad, Sahab
Bansal, Vikas
Bonn, Stefan
Butt, Umer Javed
Curto, Yasmina
Ehrenreich, Hannelore
Hassouna, Imam
Martens, Hendrik
Miskowiak, Kamilla
Nacher, Juan
Nave, Klaus-Armin
Qadir Ibrahim, Abdul
Rajput, Ashish
Scharkowski, Franziska
Schneider, Katharina
Seelbach, Anna
Steixner-Kumar, Agnes A.
Wakhloo, Debia
Werner, Hauke B.
Wojcik, Sonja M.
Wüstefeld, Liane
Zillmann, Matthias R.
Other organisations
Centre for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB)
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) - Spanish Network Centre for Biomedical Research in Mental Health
Hospital Clínico Universitario de València - University Hospital of Valencia
Københavns Universitetshospital - Copenhagen University Hospital
Max-Planck-Institut für Experimentelle Medizin - Max Planck Institute of Experimental Medicine
Universitat de València (UV) - University of Valencia
Universitätsklinikum Hamburg-Eppendorf (UKE) - University Medical Center Hamburg-Eppendorf
Doping classes
S2. Peptide Hormones, Growth Factors
Erythropoietin (EPO)
Document category
Scientific article
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Pdf file
Date generated
14 January 2021
Date of last modification
3 February 2021
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