Functional Hypoxia Drives Neuroplasticity and Neurogenesis Via Brain Erythropoietin

Overview

Journal Nat Commun

Specialty Biology

Date 2020 Mar 11

PMID 32152318

Citations 64

Authors

Debia Wakhloo

Franziska Scharkowski

Yasmina Curto

Umer Javed Butt

Vikas Bansal

Agnes A Steixner-Kumar

Liane Wustefeld

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

Affiliations

Soon will be listed here.

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.

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