The brain erythropoietin cycle as driver of adaptive neuroplasticity via functional hypoxia

Introduction

Cognitive disability and decline play key roles in neuropsychiatric conditions but lack effective therapies. Erythropoietin (EPO) is a hypoxia-inducible growth factor, named after its original description in erythropoiesis.

Discovery of EPO Effects

We discovered - by 'reverse approach' (human trials first) - that recombinant human (rh) EPO has potent procognitive effects, hematopoiesis-independent.

Mechanistic Insights

Searching for mechanistic insight in mice, we saw that rhEPO markedly drives differentiation/maturation of pyramidal neurons and oligodendrocytes from non-dividing precursors in cornu ammonis, outside known neurogenesis areas.

In parallel, rhEPO dampens microglia. This suggests that endogenous, brain-expressed EPO (bEPO), acting in an auto/paracrine fashion, has fundamental, hitherto overlooked physiological significance.

Groundbreaking Hypotheses

BREPOCI will pursue the groundbreaking hypotheses that:

1. 'Functional hypoxia' is a physiological consequence of increased neuronal activity, inciting an integrated response of many brain cell types.
2. This activity-induced hypoxia stimulates bEPO expression to optimize multicellular brain plasticity, providing substantial 'hardware upgrade'.
3. BREPOCI postulates diverse EPOR in the brain and will study their nature and contribution to these pivotal processes upon normoxia, 'functional', and inspiratory hypoxia.
4. rhEPO treatment of intellectual disability/autism caused by Tbr1 or Zbtb20 loss-of-function mutations will constitute a first mechanistic approach to specific brain pathologies, translatable to humans.

Project Tools and Techniques

This ERC project can build on acquired novel genetic mouse tools, including:

• Cell-type specific EPO/EPOR mutants
• Inducible hypoxia reporters
• Multiomic mice

Additionally, sophisticated behavior tests, MRI/MRS, multiphoton imaging, NanoSIMS, sc/snRNA-seq, confocal/Lightsheet/electron microscopy, and electrophysiology will be utilized.

Objectives

BREPOCI will illuminate rhEPO/bEPO effects on physiological brain functions and explore how it limits developmental delay, intellectual disability, or neurodegeneration.