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Functional hypoxia drives neuroplasticity and neurogenesis via brain erythropoietin

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  3. Effect of Early Recombinant Human Erythropoietin on Neurodevelopmental Outcomes at Age 5 Years

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  • 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
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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 languageEnglish
Article number1313
JournalNature Communications
Volume11
Issue number1
Pages (from-to)1313
ISSN2041-1723
DOIs
Publication statusPublished - 1 Dec 2020

ID: 59921826