title: Revisiting adult neurogenesis and the role of erythropoietin for neuronal and oligodendroglial differentiation in the hippocampus.
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 a15N-leucine diet, we used nanoscopic secondary ion mass spectrometry, and found that in EPO-treated mice, an equivalent number of neurons was defined by elevated15N-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.
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.|On leave of absence from Physiology Unit, Zoology Department, Faculty of Science, Menoufia University, Al Minufya, Egypt.
authors.forename: I
authors.initials: I
authors.lastname: Hassouna
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Ott
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Wüstefeld
authors.affiliation: Department of Neurosurgery, University of Würzburg, Würzburg, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Offen
authors.affiliation: Evolutionary Dynamics and Biophysics, Max Planck Institute for Developmental Biology, Tübingen, Germany.
authors.forename: R A
authors.initials: RA
authors.lastname: Neher
authors.affiliation: Light Microscopy Facility, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Mitkovski
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Winkler
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Sperling
authors.affiliation: Department of Neurosurgery, University of Würzburg, Würzburg, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Fries
authors.affiliation: Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Goebbels
authors.affiliation: Department of Neuro- and Sensory Physiology, University Medical Center Göttingen, Germany.|International Max Planck Research School Molecular Biology, Göttingen, Germany.
authors.forename: I C
authors.initials: IC
authors.lastname: Vreja
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Hagemeyer
authors.affiliation: Department of Bioinformatics, Biocenter, University of Würzburg, Würzburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Dittrich
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: M F
authors.initials: MF
authors.lastname: Rossetti
authors.affiliation: Department of Neuro- and Sensory Physiology, University Medical Center Göttingen, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Kröhnert
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Hannke
authors.affiliation: Department of Diagnostic Radiology, Christian-Albrechts-Universität, Kiel, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Boretius
authors.affiliation: Cellular Neurophysiology, Hannover Medical School, Hannover, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Zeug
authors.affiliation: Department of Ecology and Ecosystem Management, Lehrstuhl für Bodenkunde, Technische Universität München, Freising-Weihenstephan, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Höschen
authors.affiliation: Department of Bioinformatics, Biocenter, University of Würzburg, Würzburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Dandekar
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Dere
authors.affiliation: Department of Membrane Biophysics, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.|DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Göttingen, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Neher
authors.affiliation: Department of Neuro- and Sensory Physiology, University Medical Center Göttingen, Germany.|DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Göttingen, Germany.
authors.forename: S O
authors.initials: SO
authors.lastname: Rizzoli
authors.affiliation: Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.|DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Göttingen, Germany.
authors.forename: K-A
authors.initials: KA
authors.lastname: Nave
authors.affiliation: Department of Neurosurgery, University of Würzburg, Würzburg, Germany.
authors.forename: A-L
authors.initials: AL
authors.lastname: Sirén
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.|DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Göttingen, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Ehrenreich
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002490:Central Nervous System / Q000378:metabolism; D003071:Cognition / Q000187:drug effects; D004921:Erythropoietin / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055495:Neurogenesis / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects* / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D011994:Recombinant Proteins; D004921:Erythropoietin
references.citation: Cell Stem Cell. 2007 Dec 13;1(6):612-27
references.pmid: 18371403
references.citation: Glia. 2009 May;57(7):693-702
references.pmid: 18985736
references.citation: Nat Commun. 2014 Apr 10;5:3664
references.pmid: 24718107
references.citation: J Neurosci. 2002 Feb 1;22(3):614-8
references.pmid: 11826088
references.citation: J Neurosci. 2007 Mar 14;27(11):2788-92
references.pmid: 17360900
references.citation: Prog Neurobiol. 2009 May;88(1):41-63
references.pmid: 19428961
references.citation: Nucleic Acids Res. 1999 Nov 15;27(22):4324-7
references.pmid: 10536138
references.citation: Behav Brain Res. 2006 Aug 10;171(2):181-8
references.pmid: 16713639
references.citation: J Comp Neurol. 1965 Jun;124(3):319-35
references.pmid: 5861717
references.citation: Eur J Neurosci. 1996 Apr;8(4):666-76
references.pmid: 9081618
references.citation: Nat Rev Neurosci. 2006 Jan;7(1):30-40
references.pmid: 16371948
references.citation: Front Hum Neurosci. 2012 Apr 17;6:91
references.pmid: 22529794
references.citation: Mol Psychiatry. 2011 Jan;16(1):26-36, 1
references.pmid: 20479759
references.citation: Biol Psychiatry. 2015 Aug 15;78(4):270-7
references.pmid: 25641635
references.citation: J Cell Biol. 1992 May;117(4):849-61
references.pmid: 1577861
references.citation: Nat Neurosci. 2005 Sep;8(9):1132-3
references.pmid: 16127444
references.citation: BMC Biol. 2008 Sep 09;6:37
references.pmid: 18782446
references.citation: Nat Rev Neurosci. 2005 Jun;6(6):484-94
references.pmid: 15928718
references.citation: Nat Neurosci. 2013 Jun;16(6):668-76
references.pmid: 23624515
references.citation: Genesis. 2007 Sep;45(9):593-605
references.pmid: 17868096
references.citation: Science. 2004 Jul 9;305(5681):239-42
references.pmid: 15247477
references.citation: Hippocampus. 2006;16(3):216-24
references.pmid: 16421862
references.citation: J Neurosci Res. 2012 Mar;90(3):715-20
references.pmid: 22012685
references.citation: Neuron. 2010 Nov 18;68(4):668-81
references.pmid: 21092857
references.citation: EMBO J. 2014 Aug 1;33(15):1667-80
references.pmid: 25001178
references.citation: Mol Med. 2015 Sep 01;:null
references.pmid: 26349059
references.citation: Glia. 2014 Jun;62(6):896-913
references.pmid: 24578301
references.citation: BMC Biol. 2011 Apr 28;9:27
references.pmid: 21527022
references.citation: Cell. 2002 Aug 23;110(4):429-41
references.pmid: 12202033
references.citation: Nat Rev Neurosci. 2009 Jan;10(1):9-22
references.pmid: 19096367
references.citation: Methods Mol Biol. 2010;633:241-52
references.pmid: 20204633
references.citation: J Comp Neurol. 1990 Jun 1;296(1):1-22
references.pmid: 2358525
references.citation: Nat Neurosci. 2005 Sep;8(9):1179-87
references.pmid: 16116450
references.citation: Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):862-7
references.pmid: 15642952
references.citation: Brain Res Brain Res Protoc. 2001 Jul;7(3):211-21
references.pmid: 11431122
references.citation: Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):3717-20
references.pmid: 7731971
references.citation: Nat Methods. 2005 May;2(5):333-6
references.pmid: 15846359
references.citation: Nat Methods. 2015 Jul;12(7):671-8
references.pmid: 26005811
references.citation: Neurosci Lett. 2002 Dec 16;334(3):153-6
references.pmid: 12453618
references.citation: Physiol Rev. 2014 Oct;94(4):991-1026
references.pmid: 25287858
references.citation: Glia. 2012 Feb;60(2):159-74
references.pmid: 22076934
references.citation: Biophys J. 2009 May 6;96(9):3791-800
references.pmid: 19413985
references.citation: J Neurosci. 2002 Mar 1;22(5):1784-93
references.pmid: 11880507
references.citation: Gene Expr Patterns. 2004 Oct;4(6):733-9
references.pmid: 15465497
references.citation: PLoS Biol. 2005 Sep;3(9):e283
references.pmid: 16086633
references.citation: J Neurosci. 2001 Dec 15;21(24):9733-43
references.pmid: 11739582
references.citation: Neuron. 2011 May 26;70(4):661-73
references.pmid: 21609823
references.citation: Cell Stem Cell. 2011 May 6;8(5):566-79
references.pmid: 21549330
references.citation: Nat Neurosci. 2010 Oct;13(10):1181-9
references.pmid: 20871603
references.citation: Neuropharmacology. 2011 Feb-Mar;60(2-3):354-64
references.pmid: 20932982
references.citation: Nat Rev Neurosci. 2007 Jun;8(6):481-8
references.pmid: 17514200
references.citation: Nat Neurosci. 2009 Apr;12(4):399-408
references.pmid: 19287386
references.citation: EMBO J. 2011 Sep 23;30(20):4299-308
references.pmid: 21946562
references.citation: J Neurochem. 2007 Sep;102(6):1953-65
references.pmid: 17555554
references.citation: Cell Stem Cell. 2009 May 8;4(5):375-6
references.pmid: 19427286
references.citation: Brain. 2007 Oct;130(Pt 10):2577-88
references.pmid: 17728357
references.citation: J Neurosci. 2006 Jan 25;26(4):1269-74
references.pmid: 16436614
references.citation: Blood. 2011 Dec 8;118(24):6258-68
references.pmid: 21998215
references.citation: Mol Psychiatry. 2007 Feb;12(2):206-20
references.pmid: 17033631
references.citation: Cell Tissue Res. 2009 Dec;338(3):333-41
references.pmid: 19885679
references.citation: Neurotherapeutics. 2009 Jan;6(1):108-27
references.pmid: 19110203
references.citation: J Biol Chem. 2007 Aug 31;282(35):25875-83
references.pmid: 17604282
references.citation: Science. 1977 Sep 9;197(4308):1092-4
references.pmid: 887941
references.citation: Nat Rev Neurosci. 2010 May;11(5):339-50
references.pmid: 20354534
references.citation: Brain Struct Funct. 2007 Jul;212(1):19-35
references.pmid: 17717696
references.citation: Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10526-31
references.pmid: 10984541
references.citation: Mol Psychiatry. 2004 Jan;9(1):42-54
references.pmid: 14581931
references.citation: Mol Med. 2012 May 09;18:628-35
references.pmid: 22396019