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

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Neher,  E.
Emeritus Group of Membrane Biophysics, MPI for Biophysical Chemistry, Max Planck Society;

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2339678.pdf
(Publisher version), 871KB

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2339678_Suppl_1.pdf
(Supplementary material), 142KB

2339678_Suppl_2.ppt
(Supplementary material), 833KB

2339678_Suppl_3.ppt
(Supplementary material), 2MB

2339678_Suppl_4.ppt
(Supplementary material), 603KB

2339678_Suppl_5.ppt
(Supplementary material), 253KB

2339678_Suppl_6.ppt
(Supplementary material), 664KB

Citation

Hassouna, I., Ott, C., Wüstefeld, L., Offen, N., Neher, R. A., Mitkovski, M., et al. (2016). Revisiting adult neurogenesis and the role of erythropoietin for neuronal and oligodendroglial differentiation in the hippocampus. Molecular Psychiatry, 21(12), 1752-1767. doi:10.1038/mp.2015.212.


Cite as: http://hdl.handle.net/11858/00-001M-0000-002B-41FB-A
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 15N-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 15N-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.