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. 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.

Impact on Microglia

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: 'Functional hypoxia' is a physiological consequence of increased neuronal activity, inciting an integrated response of many brain cell types.
2. bEPO Expression: This activity-induced hypoxia stimulates bEPO expression to optimize multicellular brain plasticity, providing substantial 'hardware upgrade'.
3. Diverse EPOR: 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. Mechanistic Approach: 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.

Methodology

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.