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Cited by 975Neuroscience and Neuropharmacology ResearchNeuroinflammation and Neurodegeneration MechanismsNeurogenesis and neuroplasticity mechanisms

Emerging roles of astrocytes in neural circuit development

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Clarke, Laura E., Barres, Ben A.·2013·Nature Reviews Neuroscience
DOI 10.1038/nrn3484PMC PMC4431630
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Abstract

Astrocytes are now emerging as key participants in many aspects of brain development, function and disease. In particular, new evidence shows that astrocytes powerfully control the formation, maturation, function and elimination of synapses through various secreted and contact-mediated signals. Astrocytes are also increasingly being implicated in the pathophysiology of many psychiatric and neurological disorders that result from synaptic defects. A better understanding of how astrocytes regulate neural circuit development and function in the healthy and diseased brain might lead to the development of therapeutic agents to treat these diseases.

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  • Astrocytes support neurite outgrowth, neuronal survival, synapse formation and synaptic pruning, all vital during brain development.

    “As the most numerous cell type in the mammalian brain, astrocytes support neurite outgrowth, neuronal survival, synapse formation and synaptic pruning, all of which are vital during brain development (Chung et al., 2013; Clarke and Barres, 2013).”

    From Sterol dysregulation in Smith–Lemli–Opitz syndrome causes astrocyte immune reactivity through microglia crosstalk (2022) · cites this paper as Clarke and Barres, 2013

    The Conclusions and future perspectives section says astrocytes control synapse formation and elimination, and the Astrocyte control of synapse pruning section places elimination during brain development. The passages found do not establish that astrocytes are the most numerous mammalian brain cell type or directly support the attributed roles in neurite outgrowth and neuronal survival; those terms appear chiefly in reference titles. Page numbers are unavailable in our copy. (LLM, conf=0.86)

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  1. [2]Christopherson KS Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis Cell 120 421 433 2005 This study identifies a novel family of astrocyte-secreted proteins that promotes the formation of excitatory synapses. 15707899
  2. [3]Hughes EG Elmariah SB Balice-Gordon RJ Astrocyte secreted proteins selectively increase hippocampal GABAergic axon length, branching, and synaptogenesis Mol Cell Neurosci 43 136 145 2010 This study demonstrates that in addition to releasing molecules that regulate excitatory synaptogenesis, astrocytes release different molecules to control inhibitory synaptogenesis. 19850128 PMC2818511
  3. [5]Pfrieger FW Barres BA Synaptic efficacy enhanced by glial cells in vitro Science 277 1684 1687 1997 References 5 and 6 were the first studies to show that astrocytes can induce and control the number of excitatory synapses by secreting soluble signals. 9287225
  4. [6]Ullian EM Sapperstein SK Christopherson KS Barres BA Control of synapse number by glia Science 291 657 661 2001 11158678
  5. [8]Stellwagen D Malenka RC Synaptic scaling mediated by glial TNF-α Nature 440 1054 1059 2006 16547515
  6. [9]Yang Y Contribution of astrocytes to hippocampal long-term potentiation through release of D-serine Proc Natl Acad Sci USA 100 15194 15199 2003 14638938 PMC299953
  7. [10]Mauch DH CNS synaptogenesis promoted by glia-derived cholesterol Science 294 1354 1357 2001 11701931
  8. [11]Craig AM Graf ER Linhoff MW How to build a central synapse: clues from cell culture Trends Neurosci 29 8 20 2006 16337695 PMC2820512
  9. [12]Auerbach BD Osterweil EK Bear MF Mutations causing syndromic autism define an axis of synaptic pathophysiology Nature 480 63 68 2011 22113615 PMC3228874
  10. [13]Bennett MR Synapse formation and regression in the cortex during adolescence and in schizophrenia Med J Aust 190 S14 S16 2009 19220167
  11. [15]Glantz LA Lewis DA Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia Arch Gen Psychiatry 57 65 73 2000 10632234
  12. [16]Hutsler JJ Zhang H Increased dendritic spine densities on cortical projection neurons in autism spectrum disorders Brain Res 1309 83 94 2010 19896929
  13. [17]Irwin SA Abnormal dendritic spine characteristics in the temporal and visual cortices of patients with fragile-X syndrome: a quantitative examination Am J Med Genet 98 161 167 2001 11223852
  14. [18]Penzes P Cahill ME Jones KA Vanleeuwen JE Woolfrey KM Dendritic spine pathology in neuropsychiatric disorders Nature Neurosci 14 285 293 2011 21346746 PMC3530413
  15. [19]Sweet RA Henteleff RA Zhang W Sampson AR Lewis DA Reduced dendritic spine density in auditory cortex of subjects with schizophrenia Neuropsychopharmacology 34 374 389 2009 18463626 PMC2775717
  16. [20]Jacobs S Doering LC Astrocytes prevent abnormal neuronal development in the fragile X mouse J Neurosci 30 4508 4514 2010 20335488 PMC6634485
  17. [21]Lioy DT A role for glia in the progression of Rett’s syndrome Nature 475 497 500 2011 This study shows that astrocytes are integral components of Rett’s syndrome and that the restoration of MECP2 in astrocytes can rescue abnormal dendrite morphology and function in vivo, supporting the idea that targeting of glia might be a new strategy for treating neurodevelopmental diseases. 21716289 PMC3268776
  18. [22]Freeman MR Specification and morphogenesis of astrocytes Science 330 774 778 2010 21051628 PMC5201129
  19. [23]Bushong EA Martone ME Jones YZ Ellisman MH Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains J Neurosci 22 183 192 2002 11756501 PMC6757596
  20. [24]Halassa MM Fellin T Takano H Dong JH Haydon PG Synaptic islands defined by the territory of a single astrocyte J Neurosci 27 6473 6477 2007 17567808 PMC6672436
  21. [25]Fiacco TA McCarthy KD Astrocyte calcium elevations: properties, propagation, and effects on brain signaling Glia 54 676 690 2006 17006896
  22. [26]Barres BA Silverstein BE Corey DP Chun LL Immunological, morphological, and electrophysiological variation among retinal ganglion cells purified by panning Neuron 1 791 803 1988 2908449
  23. [27]Meyer-Franke A Kaplan MR Pfrieger FW Barres BA Characterization of the signaling interactions that promote the survival and growth of developing retinal ganglion cells in culture Neuron 15 805 819 1995 7576630
  24. [28]Xu J Xiao N Xia J Thrombospondin 1 accelerates synaptogenesis in hippocampal neurons through neuroligin 1 Nature Neurosci 13 22 24 2010 19915562
  25. [29]Diniz LP Astrocyte-induced synaptogenesis is mediated by transforming growth factor β signaling through modulation of D-serine levels in cerebral cortex neurons J Biol Chem 287 41432 41445 2012 23055518 PMC3510841
  26. [30]Ullian EM Harris BT Wu A Chan JR Barres BA Schwann cells and astrocytes induce synapse formation by spinal motor neurons in culture Mol Cell Neurosci 25 241 251 2004 15019941
  27. [31]Buard I Steinmetz CC Claudepierre T Pfrieger FW Glial cells promote dendrite formation and the reception of synaptic input in Purkinje cells from postnatal mice Glia 58 538 545 2010 19908290
  28. [32]Krencik R Weick JP Liu Y Zhang ZJ Zhang SC Specification of transplantable astroglial subtypes from human pluripotent stem cells Nature Biotech 29 528 534 2011 PMC3111840 21602806
  29. [33]Goritz C Mauch DH Pfrieger FW Multiple mechanisms mediate cholesterol-induced synaptogenesis in a CNS neuron Mol Cell Neurosci 29 190 201 2005 15911344
  30. [36]Sigrist SJ Plested AJ How to button a bouton with α2δs Nature Neurosci 12 1357 1358 2009 19861946
  31. [37]DeFreitas MF Identification of integrin α3β1 as a neuronal thrombospondin receptor mediating neurite outgrowth Neuron 15 333 343 1995 7544141
  32. [38]Crawford DC Jiang X Taylor A Mennerick S Astrocyte-derived thrombospondins mediate the development of hippocampal presynaptic plasticity in vitro J Neurosci 32 13100 13110 2012 22993427 PMC3475988
  33. [39]Jones EV Astrocytes control glutamate receptor levels at developing synapses through SPARC-β-integrin interactions J Neurosci 31 4154 4165 2011 21411656 PMC6623508
  34. [40]Ben-Ari Y Gaiarsa JL Tyzio R Khazipov R GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations Physiol Rev 87 1215 1284 2007 17928584
  35. [41]Liu QY Schaffner AE Li YX Dunlap V Barker JL Upregulation of GABAA current by astrocytes in cultured embryonic rat hippocampal neurons J Neurosci 16 2912 2923 1996 8622122 PMC6579057
  36. [42]Elmariah SB Oh EJ Hughes EG Balice-Gordon RJ Astrocytes regulate inhibitory synapse formation via Trk-mediated modulation of postsynaptic GABAA receptors J Neurosci 25 3638 3650 2005 15814795 PMC6725365
  37. [43]Tsai HH Regional astrocyte allocation regulates CNS synaptogenesis and repair Science 337 358 362 2012 The authors use genetic approaches to demonstrate that astrocytes are allocated to distinct spatial domains and that the ablation of specific astrocyte populations results in abnormal synaptogenesis. 22745251 PMC4059181
  38. [44]Hama H Hara C Yamaguchi K Miyawaki A PKC signaling mediates global enhancement of excitatory synaptogenesis in neurons triggered by local contact with astrocytes Neuron 41 405 415 2004 14766179
  39. [45]Barker AJ Koch SM Reed J Barres BA Ullian EM Developmental control of synaptic receptivity J Neurosci 28 8150 8160 2008 18701677 PMC2566963
  40. [46]Ybot-Gonzalez P Copp AJ Greene ND Expression pattern of glypican-4 suggests multiple roles during mouse development Dev Dyn 233 1013 1017 2005 15830372
  41. [47]Johnson KG The HSPGs Syndecan and Dallylike bind the receptor phosphatase LAR and exert distinct effects on synaptic development Neuron 49 517 531 2006 16476662
  42. [48]Dunah AW LAR receptor protein tyrosine phosphatases in the development and maintenance of excitatory synapses Nature Neurosci 8 458 467 2005 15750591
  43. [49]Alvarez VA Sabatini BL Anatomical and physiological plasticity of dendritic spines Annu Rev Neurosci 30 79 97 2007 17280523
  44. [52]Dunaevsky A Blazeski R Yuste R Mason C Spine motility with synaptic contact Nature Neurosci 4 685 686 2001 11426220
  45. [53]Lendvai B Stern EA Chen B Svoboda K Experience-dependent plasticity of dendritic spines in the developing rat barrel cortex in vivo Nature 404 876 881 2000 10786794
  46. [54]Dailey ME Smith SJ The dynamics of dendritic structure in developing hippocampal slices J Neurosci 16 2983 2994 1996 8622128 PMC6579052
  47. [55]Portera-Cailliau C Pan DT Yuste R Activity-regulated dynamic behavior of early dendritic protrusions: evidence for different types of dendritic filopodia J Neurosci 23 7129 7142 2003 12904473 PMC6740658
  48. [56]Ziv NE Smith SJ Evidence for a role of dendritic filopodia in synaptogenesis and spine formation Neuron 17 91 102 1996 8755481
  49. [57]Campbell G Shatz CJ Synapses formed by identified retinogeniculate axons during the segregation of eye input J Neurosci 12 1847 1858 1992 1578274 PMC6575897
  50. [58]Lehre KP Rusakov DA Asymmetry of glia near central synapses favors presynaptically directed glutamate escape Biophys J 83 125 134 2002 12080105 PMC1302132
  51. [59]Ventura R Harris KM Three-dimensional relationships between hippocampal synapses and astrocytes J Neurosci 19 6897 6906 1999 10436047 PMC6782870
  52. [60]Benediktsson AM Schachtele SJ Green SH Dailey ME Ballistic labeling and dynamic imaging of astrocytes in organotypic hippocampal slice cultures J Neurosci Methods 141 41 53 2005 15585287
  53. [61]Haber M Zhou L Murai KK Cooperative astrocyte and dendritic spine dynamics at hippocampal excitatory synapses J Neurosci 26 8881 8891 2006 16943543 PMC6675342
  54. [62]Hirrlinger J Hulsmann S Kirchhoff F Astroglial processes show spontaneous motility at active synaptic terminals in situ Eur J Neurosci 20 2235 2239 2004 15450103
  55. [63]Nett WJ Oloff SH McCarthy KD Hippocampal astrocytes in situ exhibit calcium oscillations that occur independent of neuronal activity J Neurophysiol 87 528 537 2002 11784768
  56. [64]Perea G Araque A Properties of synaptically evoked astrocyte calcium signal reveal synaptic information processing by astrocytes J Neurosci 25 2192 2203 2005 15745945 PMC6726085
  57. [65]Wang X Astrocytic Ca2+ signaling evoked by sensory stimulation in vivo Nature Neurosci 9 816 823 2006 16699507
  58. [66]Panatier A Astrocytes are endogenous regulators of basal transmission at central synapses Cell 146 785 798 2011 This study uses elegant imaging techniques to demonstrate that astrocytes can detect and respond to physiological synaptic stimuli. 21855979
  59. [67]Danbolt NC Glutamate uptake Prog Neurobiol 65 1 105 2001 11369436
  60. [68]Verbich D Prenosil GA Chang PK Murai KK McKinney RA Glial glutamate transport modulates dendritic spine head protrusions in the hippocampus Glia 60 1067 1077 2012 22488940
  61. [70]Carmona MA Murai KK Wang L Roberts AJ Pasquale EB Glial ephrin-A3 regulates hippocampal dendritic spine morphology and glutamate transport Proc Natl Acad Sci USA 106 12524 12529 2009 19592509 PMC2718351
  62. [71]Goda Y Davis GW Mechanisms of synapse assembly and disassembly Neuron 40 243 264 2003 14556707
  63. [72]Kano M Hashimoto K Synapse elimination in the central nervous system Curr Opin Neurobiol 19 154 161 2009 19481442
  64. [73]Katz LC Shatz CJ Synaptic activity and the construction of cortical circuits Science 274 1133 1138 1996 8895456
  65. [75]Trachtenberg JT Long-term in vivo imaging of experience-dependent synaptic plasticity in adult cortex Nature 420 788 794 2002 12490942
  66. [76]Fuentes-Medel Y Glia and muscle sculpt neuromuscular arbors by engulfing destabilized synaptic boutons and shed presynaptic debris PLoS Biol 7 e1000184 2009 19707574 PMC2724735
  67. [77]Stevens B The classical complement cascade mediates CNS synapse elimination Cell 131 1164 1178 2007 18083105
  68. [78]Hong YK Chen C Wiring and rewiring of the retinogeniculate synapse Curr Opin Neurobiol 21 228 237 2011 21558027 PMC3099477
  69. [79]Perry VH O’Connor V C1q: the perfect complement for a synaptic feast? Nature Rev Neurosci 9 807 811 2008 18827829
  70. [80]Gasque P The receptor for complement anaphylatoxin C3a is expressed by myeloid cells and nonmyeloid cells in inflamed human central nervous system: analysis in multiple sclerosis and bacterial meningitis J Immunol 160 3543 3554 1998 9531317
  71. [81]Schiefer J Kampe K Dodt HU Zieglgansberger W Kreutzberg GW Microglial motility in the rat facial nucleus following peripheral axotomy J Neurocytol 28 439 453 1999 10767097
  72. [83]al-Ali SY al-Hussain SM An ultrastructural study of the phagocytic activity of astrocytes in adult rat brain J Anat 188 257 262 1996 8621323 PMC1167560
  73. [84]Bechmann I Nitsch R Astrocytes and microglial cells incorporate degenerating fibers following entorhinal lesion: a light, confocal, and electron microscopical study using a phagocytosis-dependent labeling technique Glia 20 145 154 1997 9179599
  74. [85]Lantos PL An electron microscope study of reacting astrocytes in gliomas induced by n-ethyl-n-nitrosourea in rats Acta Neuropathol 30 175 181 1974 4446962
  75. [86]Berbel P Innocenti GM The development of the corpus callosum in cats: a light- and electron-microscopic study J Comp Neurol 276 132 156 1988 3192762
  76. [87]Loov C Hillered L Ebendal T Erlandsson A Engulfing astrocytes protect neurons from contact-induced apoptosis following injury PLoS ONE 7 e33090 2012 22461890 PMC3312890
  77. [88]Nguyen JV Myelination transition zone astrocytes are constitutively phagocytic and have synuclein dependent reactivity in glaucoma Proc Natl Acad Sci USA 108 1176 1181 2011 21199938 PMC3024691
  78. [91]Lovatt D The transcriptome and metabolic gene signature of protoplasmic astrocytes in the adult murine cortex J Neurosci 27 12255 12266 2007 17989291 PMC6673251
  79. [92]Mallat M Marin-Teva JL Cheret C Phagocytosis in the developing CNS: more than clearing the corpses Curr Opin Neurobiol 15 101 107 2005 15721751
  80. [93]Kinchen JM Two pathways converge at CED-10 to mediate actin rearrangement and corpse removal in C. elegans Nature 434 93 99 2005 15744306
  81. [94]Ziegenfuss JS Doherty J Freeman MR Distinct molecular pathways mediate glial activation and engulfment of axonal debris after axotomy Nature Neurosci 15 979 987 2012 This study identifies new components of the glial engulfment machinery and shows that glial activation and phagocytosis after injury are mediated by distinct signalling pathways. 22706267 PMC4976689
  82. [95]Sokolowski JD Brain-specific angiogenesis inhibitor-1 expression in astrocytes and neurons: implications for its dual function as an apoptotic engulfment receptor Brain Behav Immun 25 915 921 2011 20888903 PMC3033447
  83. [96]Park D BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module Nature 450 430 434 2007 17960134
  84. [97]Wu Y Singh S Georgescu MM Birge RB A role for Mer tyrosine kinase in δvβ5 integrin-mediated phagocytosis of apoptotic cells J Cell Sci 118 539 553 2005 15673687
  85. [98]Yu X Lu N Zhou Z Phagocytic receptor CED-1 initiates a signaling pathway for degrading engulfed apoptotic cells PLoS Biol 6 e61 2008 18351800 PMC2267821
  86. [99]Chahrour M Zoghbi HY The story of Rett syndrome: from clinic to neurobiology Neuron 56 422 437 2007 17988628
  87. [101]Luikenhuis S Giacometti E Beard CF Jaenisch R Expression of MeCP2 in postmitotic neurons rescues Rett syndrome in mice Proc Natl Acad Sci USA 101 6033 6038 2004 15069197 PMC395918
  88. [102]Ballas N Lioy DT Grunseich C Mandel G Non-cell autonomous influence of MeCP2-deficient glia on neuronal dendritic morphology Nature Neurosci 12 311 317 2009 19234456 PMC3134296
  89. [103]Pfeiffer BE Huber KM The state of synapses in fragile X syndrome Neuroscientist 15 549 567 2009 19325170 PMC2762019
  90. [105]Beckel-Mitchener A Greenough WT Correlates across the structural, functional, and molecular phenotypes of fragile X syndrome Ment Retard Dev Disabil Res Rev 10 53 59 2004 14994289
  91. [106]Benavides-Piccione R On dendrites in Down syndrome and DS murine models: a spiny way to learn Prog Neurobiol 74 111 126 2004 15518956
  92. [108]Hagerman PJ Stafstrom CE Origins of epilepsy in fragile X syndrome Epilepsy Curr 9 108 112 2009 19693328 PMC2728488
  93. [109]Tabuchi K A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice Science 318 71 76 2007 17823315 PMC3235367
  94. [110]Barnby G Candidate-gene screening and association analysis at the autism-susceptibility locus on chromosome 16p: evidence of association at GRIN2A and ABAT Am J Hum Genet 76 950 966 2005 15830322 PMC1196454
  95. [111]Maekawa M Polymorphism screening of brain-expressed FABP7, 5 and 3 genes and association studies in autism and schizophrenia in Japanese subjects J Hum Genet 55 127 130 2010 20057506
  96. [112]Ming X Genetic variant of glutathione peroxidase 1 in autism Brain Dev 32 105 109 2010 19195803
  97. [113]Foo LC Development of a method for the purification and culture of rodent astrocytes Neuron 71 799 811 2011 21903074 PMC3172573
  98. [114]Rakic P Evolution of the neocortex: a perspective from developmental biology Nature Rev Neurosci 10 724 735 2009 19763105 PMC2913577
  99. [116]Gomez-Casati ME Nonneuronal cells regulate synapse formation in the vestibular sensory epithelium via erbB-dependent BDNF expression Proc Natl Acad Sci USA 107 17005 17010 2010 20837532 PMC2947909

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Authors
Clarke, L. E., & Barres, B. A.
Affiliations
Stanford Medicine (US)
Corresponding author
Clarke, Laura E.
ORCID
Barres, Ben A.
Venue
Nature Reviews Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2013-04-18
Volume
14
Issue
5
Pages
311-321
ISSN
  • 1471-003X (ISSN-L)
  • 1471-0048
DOI
10.1038/nrn3484
PMC
PMC4431630
OpenAlex
W2069498125
Cited by
975
References
17
Citations by year
2026: 41 · 2025: 74 · 2024: 62 · 2023: 67 · 2022: 76 · 2021: 77 · 2020: 89 · 2019: 71 · 2018: 71 · 2017: 86 · 2016: 87 · 2015: 76 · 2014: 68 · 2013: 27 · 2012: 1
FWCI
8.76
Type
journal article
Language
en
Update notices
erratum (2013-05-02)
Open access
Licence
Locations
  • Nature reviews. Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute on Aging (R01AG048814)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
astrocytes, neural circuit development, synaptogenesis, synapse maturation, synaptic pruning, brain development, mental illness, neurological disorders, synaptic dysfunction
MeSH terms
Animals, Astrocytes, Brain, Cell Communication, Nerve Net, Synapses, Signal Transduction

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