Revisiting adult neurogenesis and the role of erythropoietin for neuronal and oligodendroglial differentiation in the hippocampus

Recombinant human erythropoietin (EPO) improves cognitive performance in neuropsychiatric diseases ranging from schizophrenia and multiple sclerosis to major depression and bipolar disease. This consistent EPO effect on cognition is independent of its role in hematopoiesis. The cellular mechanisms of action in brain, however, have remained unclear. Here we studied healthy young mice and observed that 3-week EPO administration was associated with an increased number of pyramidal neurons and oligodendrocytes in the hippocampus of ∼20%. Under constant cognitive challenge, neuron numbers remained elevated until >6 months of age. Surprisingly, this increase occurred in absence of altered cell proliferation or apoptosis. After feeding a 15 N-leucine diet, we used nanoscopic secondary ion mass spectrometry, and found that in EPO-treated mice, an equivalent number of neurons was defined by elevated 15 N-leucine incorporation. In EPO-treated NG2-Cre-ERT2 mice, we confirmed enhanced differentiation of preexisting oligodendrocyte precursors in the absence of elevated DNA synthesis. A corresponding analysis of the neuronal lineage awaits the identification of suitable neuronal markers. In cultured neurospheres, EPO reduced Sox9 and stimulated miR124, associated with advanced neuronal differentiation. We are discussing a resulting working model in which EPO drives the differentiation of non-dividing precursors in both (NG2+) oligodendroglial and neuronal lineages. As endogenous EPO expression is induced by brain injury, such a mechanism of adult neurogenesis may be relevant for central nervous system regeneration. Fil: Hassouna, I.. Minufiya University; . Max Planck Institut Fur Experimentelle Medizin; Fil: Ott, C.. Max Planck Institut Fur Experimentelle Medizin; Fil: Wüstefeld, L.. Max Planck Institut Fur Experimentelle Medizin; Fil: Offen, N.. Universität Würzburg; Alemania Fil: Neher, R.A.. Max Planck Institute For Developmental Biology; Fil: Mitkovski, M.. Max Planck Institut Fur Experimentelle Medizin; Fil: Winkler, D.. Max Planck Institut Fur Experimentelle Medizin; Fil: Sperling, S.. Max Planck Institut Fur Experimentelle Medizin; Fil: Fries, L.. Universität Würzburg; Alemania Fil: Goebbels, S.. Max Planck Institut Fur Experimentelle Medizin; Fil: Vreja, I.C.. International Max Planck Research School Molecular Biology; . Universitatsmedizin Gottingen; Fil: Hagemeyer, N.. Max Planck Institut Fur Experimentelle Medizin; Fil: Dittrich, M.. Universität Würzburg; Alemania Fil: Rossetti, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Salud y Ambiente del Litoral. Universidad Nacional del Litoral. Instituto de Salud y Ambiente del Litoral; Argentina Fil: Kröhnert, K.. Universitatsmedizin Gottingen; Fil: Hannke, K.. Max Planck Institut Fur Experimentelle Medizin; Fil: Boretius, S.. Christian-albrechts-universitat Zu Kiel; Fil: Zeug, A.. Medizinische Hochschule Hannover (mhh); Fil: Höschen, C.. Universitat Technical Zu Munich; Alemania Fil: Dandekar, T.. Universität Würzburg; Alemania Fil: Dere, E.. Max Planck Institut Fur Experimentelle Medizin; Fil: Neher, E.. Max Planck Institute For Biophysical Chemistry (karl Friedrich Bonhoeffer Institute); . Deutsche Forschungsgemeinschaft (dfg); Fil: Rizzoli, S.O.. Universitatsmedizin Gottingen; . Deutsche Forschungsgemeinschaft (dfg); Fil: Nave, K.-A.. Deutsche Forschungsgemeinschaft (dfg); . Max Planck Institut Fur Experimentelle Medizin; Fil: Sirén, A.-L.. Universität Würzburg; Alemania Fil: Ehrenreich, H.. Max Planck Institut Fur Experimentelle Medizin; . Deutsche Forschungsgemeinschaft (dfg)