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PMID: 20887954 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis.

Cell stem cell ·Vol. 7 ·No. 4 ·2010-10-08 ·Pages 483-95

Sierra A, Encinas JM, Deudero JJ, Chancey JH, Enikolopov G, Overstreet-Wadiche LS, Tsirka SE, Maletic-Savatic M

Abstract

In the adult hippocampus, neuroprogenitor cells in the subgranular zone (SGZ) of the dentate gyrus give rise to newborn neuroblasts. However, only a small subset of these cells integrates into the hippocampal circuitry as mature neurons at the end of a 4 week period. Here, we show that the majority of the newborn cells undergo death by apoptosis in the first 1 to 4 days of their life, during the transition from amplifying neuroprogenitors to neuroblasts. These apoptotic newborn cells are rapidly cleared out through phagocytosis by unchallenged microglia present in the adult SGZ niche. Phagocytosis by the microglia is efficient and undeterred by increased age or inflammatory challenge. Our results suggest that the main critical period of newborn cell survival occurs within a few days of birth and reveal a new role for microglia in maintaining the homeostasis of the baseline neurogenic cascade.

MeSH Terms
Animals Apoptosis Hippocampus/cytology Mice Mice, Transgenic Neural Stem Cells/cytology Neurogenesis Phagocytosis
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Sierra Amanda
Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. amanda.sierrasaavedra@gmail.com
Encinas Juan M
Deudero Juan J P
Chancey Jessica H
Enikolopov Grigori
Overstreet-Wadiche Linda S
Tsirka Stella E
Maletic-Savatic Mirjana
References (50)
50 references, click to expand
  1. Cell death in early neural development: beyond the neurotrophic theory.
    Trends Neurosci. 2000 Oct;23(10):454-8 PMID: 11006461
  2. Fluoxetine targets early progenitor cells in the adult brain.
    Proc Natl Acad Sci U S A. 2006 May 23;103(21):8233-8 PMID: 16702546
  3. Identifying and quantitating neural stem and progenitor cells in the adult brain.
    Methods Cell Biol. 2008;85:243-72 PMID: 18155466
  4. Increased generation of granule cells in adult Bcl-2-overexpressing mice: a role for cell death during continued hippocampal neurogenesis.
    Eur J Neurosci. 2005 Oct;22(8):1907-15 PMID: 16262630
  5. Subpopulations of proliferating cells of the adult hippocampus respond differently to physiologic neurogenic stimuli.
    J Comp Neurol. 2003 Dec 22;467(4):455-63 PMID: 14624480
  6. Neural stem and progenitor cells in nestin-GFP transgenic mice.
    J Comp Neurol. 2004 Feb 9;469(3):311-24 PMID: 14730584
  7. Glutamate and astrocytes--key players in human mesial temporal lobe epilepsy?
    Epilepsia. 2008;49 Suppl 2:42-52 PMID: 18226171
  8. Neuroscience: the brain's garbage men.
    Nature. 2007 Apr 26;446(7139):987-9 PMID: 17410127
  9. Activity-dependent extrinsic regulation of adult olfactory bulb and hippocampal neurogenesis.
    Ann N Y Acad Sci. 2009 Jul;1170:664-73 PMID: 19686209
  10. Caspase inhibitors increase short-term survival of progenitor-cell progeny in the adult rat dentate gyrus following status epilepticus.
    Eur J Neurosci. 2001 Sep;14(6):937-45 PMID: 11595032
  11. A macrophage colony-stimulating factor receptor-green fluorescent protein transgene is expressed throughout the mononuclear phagocyte system of the mouse.
    Blood. 2003 Feb 1;101(3):1155-63 PMID: 12393599
  12. Live astrocytes visualized by green fluorescent protein in transgenic mice.
    Dev Biol. 1997 Jul 1;187(1):36-42 PMID: 9224672
  13. Programmed cell death of adult-generated hippocampal neurons is mediated by the proapoptotic gene Bax.
    J Neurosci. 2004 Dec 8;24(49):11205-13 PMID: 15590937
  14. Diverse microglial motility behaviors during clearance of dead cells in hippocampal slices.
    Glia. 2004 Apr 15;46(2):195-206 PMID: 15042586
  15. Enhanced hippocampal neurogenesis in the absence of microglia T cell interaction and microglia activation in the murine running wheel model.
    Glia. 2009 Aug 1;57(10):1046-61 PMID: 19115394
  16. Dynamic contribution of nestin-expressing stem cells to adult neurogenesis.
    J Neurosci. 2007 Nov 14;27(46):12623-9 PMID: 18003841
  17. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood.
    Nat Neurosci. 2006 Feb;9(2):268-75 PMID: 16415867
  18. NMDA-receptor-mediated, cell-specific integration of new neurons in adult dentate gyrus.
    Nature. 2006 Aug 24;442(7105):929-33 PMID: 16906136
  19. Analysis of neurogenesis and programmed cell death reveals a self-renewing capacity in the adult rat brain.
    Neurosci Lett. 2000 Sep 8;291(1):17-20 PMID: 10962143
  20. Short-term and long-term survival of new neurons in the rat dentate gyrus.
    J Comp Neurol. 2003 Jun 9;460(4):563-72 PMID: 12717714
  21. The role of N-methyl-D-asparate receptors in neurogenesis.
    Hippocampus. 2006;16(3):267-70 PMID: 16425227
  22. Dynamics of cell proliferation in the adult dentate gyrus of two inbred strains of mice.
    Brain Res Dev Brain Res. 2002 Mar 31;134(1-2):77-85 PMID: 11947938
  23. Phagocytosis in the developing CNS: more than clearing the corpses.
    Curr Opin Neurobiol. 2005 Feb;15(1):101-7 PMID: 15721751
  24. Microglia promote the death of developing Purkinje cells.
    Neuron. 2004 Feb 19;41(4):535-47 PMID: 14980203
  25. Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation.
    J Neurosci. 1996 Mar 15;16(6):2027-33 PMID: 8604047
  26. Death mechanisms in status epilepticus-generated neurons and effects of additional seizures on their survival.
    Neurobiol Dis. 2003 Dec;14(3):513-23 PMID: 14678767
  27. Microglia derived from aging mice exhibit an altered inflammatory profile.
    Glia. 2007 Mar;55(4):412-24 PMID: 17203473
  28. Control of apoptosis by asymmetric cell division.
    PLoS Biol. 2008 Apr 8;6(4):e84 PMID: 18399720
  29. Expression time course and spatial distribution of activated caspase-3 after experimental status epilepticus: contribution of delayed neuronal cell death to seizure-induced neuronal injury.
    Neurobiol Dis. 2005 Apr;18(3):582-90 PMID: 15755684
  30. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life.
    Nat Neurosci. 2007 Dec;10(12):1538-43 PMID: 18026097
  31. A blast from the past: clearance of apoptotic cells regulates immune responses.
    Nat Rev Immunol. 2002 Dec;2(12):965-75 PMID: 12461569
  32. Cell death and control of cell survival in the oligodendrocyte lineage.
    Cell. 1992 Jul 10;70(1):31-46 PMID: 1623522
  33. Milestones of neuronal development in the adult hippocampus.
    Trends Neurosci. 2004 Aug;27(8):447-52 PMID: 15271491
  34. Brain inflammation and adult neurogenesis: the dual role of microglia.
    Neuroscience. 2009 Feb 6;158(3):1021-9 PMID: 18662748
  35. Glial responses to synaptic damage and plasticity.
    J Neurosci Res. 1999 Oct 1;58(1):33-41 PMID: 10491570
  36. Apoptosis and its relation to the cell cycle in the developing cerebral cortex.
    J Neurosci. 1997 Feb 1;17(3):1075-85 PMID: 8994062
  37. A transgenic marker for newly born granule cells in dentate gyrus.
    J Neurosci. 2004 Mar 31;24(13):3251-9 PMID: 15056704
  38. Inflammatory blockade restores adult hippocampal neurogenesis.
    Science. 2003 Dec 5;302(5651):1760-5 PMID: 14615545
  39. ATP mediates rapid microglial response to local brain injury in vivo.
    Nat Neurosci. 2005 Jun;8(6):752-8 PMID: 15895084
  40. Recognition and phagocytosis of cells undergoing apoptosis.
    Br Med Bull. 1997;53(3):491-508 PMID: 9374033
  41. Antibody to caspase-cleaved actin detects apoptosis in differentiated neuroblastoma and plaque-associated neurons and microglia in Alzheimer's disease.
    Am J Pathol. 1998 Feb;152(2):379-89 PMID: 9466564
  42. Determination of key aspects of precursor cell proliferation, cell cycle length and kinetics in the adult mouse subgranular zone.
    Neuroscience. 2007 Apr 25;146(1):108-22 PMID: 17307295
  43. Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus.
    J Neurosci. 2006 Jan 4;26(1):3-11 PMID: 16399667
  44. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis.
    Nature. 1995 Jul 6;376(6535):37-43 PMID: 7596430
  45. Debris clearance by microglia: an essential link between degeneration and regeneration.
    Brain. 2009 Feb;132(Pt 2):288-95 PMID: 18567623
  46. Neurogenic niche modulation by activated microglia: transforming growth factor beta increases neurogenesis in the adult dentate gyrus.
    Eur J Neurosci. 2006 Jan;23(1):83-93 PMID: 16420418
  47. Inflammation is detrimental for neurogenesis in adult brain.
    Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13632-7 PMID: 14581618
  48. Caspase-mediated death of newly formed neurons in the adult rat dentate gyrus following status epilepticus.
    Eur J Neurosci. 2002 Oct;16(8):1463-71 PMID: 12405959
  49. Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells.
    Mol Cell Neurosci. 2006 Jan;31(1):149-60 PMID: 16297637
  50. Maturation and death of adult-born olfactory bulb granule neurons: role of olfaction.
    J Neurosci. 2002 Jul 15;22(14):6106-13 PMID: 12122071
Article Info
Journal
Cell stem cell
Abbr.
Cell Stem Cell
ISSN
1875-9777
DOI
10.1016/j.stem.2010.08.014
Email
amanda.sierrasaavedra@gmail.com
Published
2010-10-08
Pages
483-95
Language
English
Region
United States
NLM ID
101311472
PMCID
PMC4008496
Subset
IM
Grants
NINDS NIH HHS · R01 NS042168 · United States
NINDS NIH HHS · K08 NS044276-05 · United States
NINDS NIH HHS · R01 NS042168-09 · United States
NINDS NIH HHS · R01 NS064025 · United States
NINDS NIH HHS · K08 NS044276 · United States
NICHD NIH HHS · P30HD024064 · United States
NINDS NIH HHS · R01 NS042168-07 · United States
NINDS NIH HHS · K08NS0044276 · United States
NICHD NIH HHS · P30 HD024064 · United States
NINDS NIH HHS · R21 NS053875 · United States
NINDS NIH HHS · R21 NS053875-02 · United States
NINDS NIH HHS · R01 NS042168-08 · United States
NINDS NIH HHS · R21NS05875-1 · United States
Corrections
CommentIn
PMID: 20887944
External Links
PubMed source DOI: 10.1016/j.stem.2010.08.014 PMC Full Text View journal details
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