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

Hassouna, I. and Ott, C. and Wüstefeld, L. and Offen, N. and Neher, R. A. and Mitkovski, M. and Winkler, D. and Sperling, S. and Fries, L. and Goebbels, S. and Vreja, I. C. and Hagemeyer, N. and Dittrich, M. and Rossetti, M. F. and Kröhnert, K. and Hannke, K. and Boretius, S. and Zeug, A. and Höschen, C. and Dandekar, T. and Dere, E. and Neher, E. and Rizzoli, S. O. and Nave, K.-A. and Sirén, A.-L. and Ehrenreich, H.. (2016) Revisiting adult neurogenesis and the role of erythropoietin for neuronal and oligodendroglial differentiation in the hippocampus. Molecular Psychiatry, 21 (12). pp. 1752-1767.

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Abstract

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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Computational & Systems Biology > Computational Modeling of Biological Processes (Neher)
UniBasel Contributors:Neher, Richard
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Nature Publishing Group
ISSN:1359-4184
e-ISSN:1476-5578
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:16 Sep 2019 10:19
Deposited On:25 Oct 2017 15:12

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