Heterogeneity of Astrocytes in Grey and White Matter

  • Susanne Köhler
  • Ulrike Winkler
  • Johannes HirrlingerEmail author
Original Paper


Astrocytes are a diverse and heterogeneous type of glial cells. The major task of grey and white matter areas in the brain are computation of information at neuronal synapses and propagation of action potentials along axons, respectively, resulting in diverse demands for astrocytes. Adapting their function to the requirements in the local environment, astrocytes differ in morphology, gene expression, metabolism, and many other properties. Here we review the differential properties of protoplasmic astrocytes of grey matter and fibrous astrocytes located in white matter in respect to glutamate and energy metabolism, to their function at the blood–brain interface and to coupling via gap junctions. Finally, we discuss how this astrocytic heterogeneity might contribute to the different susceptibility of grey and white matter to ischemic insults.


Astrocytes Heterogeneity Grey matter White matter Oligodendrocytes 



JH would like to thank Klaus-Armin Nave, Göttingen, for longstanding collaboration and ongoing support.


This work was supported by the Deutsche Forschungsgemeinschaft (DFG; priority program 1757; Grant Number HI 1414/6-1). The funding sources were not involved in study design, data collection and interpretation, or the decision to submit the work for publication.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Somjen GG (1988) Nervenkitt: notes on the history of the concept of neuroglia. Glia 1(1):2–9PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Matyash V, Kettenmann H (2010) Heterogeneity in astrocyte morphology and physiology. Brain Res Rev 63(1–2):2–10PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Oberheim NA, Wang X, Goldman S et al (2006) Astrocytic complexity distinguishes the human brain. Trends Neurosci 29(10):547–553. CrossRefGoogle Scholar
  4. 4.
    Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119(1):7–35. CrossRefGoogle Scholar
  5. 5.
    Miller RH, Raff MC (1984) Fibrous and protoplasmic astrocytes are biochemically and developmentally distinct. J Neurosci 4(2):585–592PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Chaboub LS, Deneen B (2012) Developmental origins of astrocyte heterogeneity: the final frontier of CNS development. Dev Neurosci 34(5):379–388. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Bignami A, Eng LF, Dahl D et al (1972) Localization of the glial fibrillary acidic protein in astrocytes by immunofluorescence. Brain Res 43(2):429–435. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Aberg F, Kozlova EN (2000) Metastasis-associated mts1 (S100A4) protein in the developing and adult central nervous system. J Comp Neurol 424(2):269–282PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Wang DD, Bordey A (2008) The astrocyte odyssey. Prog Neurobiol 86(4):342–367. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Emsley JG, Macklis JD (2006) Astroglial heterogeneity closely reflects the neuronal-defined anatomy of the adult murine CNS. Neuron Glia Biol 2(3):175–186. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Yang Y, Vidensky S, Jin L et al (2011) Molecular comparison of GLT1+ and ALDH1L1+ astrocytes in vivo in astroglial reporter mice. Glia 59(2):200–207. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Cahoy JD, Emery B, Kaushal A et al (2008) A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci 28(1):264–278. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Bachoo RM, Kim RS, Ligon KL et al (2004) Molecular diversity of astrocytes with implications for neurological disorders. Proc Natl Acad Sci USA 101(22):8384–8389PubMedCrossRefGoogle Scholar
  14. 14.
    Yeh TH, Lee DY, Gianino SM et al (2009) Microarray analyses reveal regional astrocyte heterogeneity with implications for neurofibromatosis type 1 (NF1)-regulated glial proliferation. Glia 57(11):1239–1249. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Hawrylycz MJ, Lein ES, Guillozet-Bongaarts AL et al (2012) An anatomically comprehensive atlas of the adult human brain transcriptome. Nature 489(7416):391–399. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Schitine C, Nogaroli L, Costa MR et al (2015) Astrocyte heterogeneity in the brain: from development to disease. Front Cell Neurosci 9:76. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Luskin MB, McDermott K (1994) Divergent lineages for oligodendrocytes and astrocytes originating in the neonatal forebrain subventricular zone. Glia 11(3):211–226CrossRefGoogle Scholar
  18. 18.
    Bribián A, Figueres-Oñate M, Martín-López E et al (2016) Decoding astrocyte heterogeneity: new tools for clonal analysis. Neuroscience 323:10–19PubMedCrossRefGoogle Scholar
  19. 19.
    García-Marqués J, López-Mascaraque L (2013) Clonal identity determines astrocyte cortical heterogeneity. Cereb Cortex 23(6):1463–1472. CrossRefPubMedGoogle Scholar
  20. 20.
    Cai J, Chen Y, Cai W-H et al (2007) A crucial role for Olig2 in white matter astrocyte development. Development 134(10):1887–1899. CrossRefPubMedGoogle Scholar
  21. 21.
    Vue TY, Kim EJ, Parras CM et al (2014) Ascl1 controls the number and distribution of astrocytes and oligodendrocytes in the gray matter and white matter of the spinal cord. Development 141(19):3721–3731. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Freeman MR (2010) Specification and morphogenesis of astrocytes. Science 330(6005):774–778PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Morel L, Higashimori H, Tolman M et al (2014) VGluT1+ neuronal glutamatergic signaling regulates postnatal developmental maturation of cortical protoplasmic astroglia. J Neurosci 34(33):10950–10962. CrossRefPubMedCentralPubMedGoogle Scholar
  24. 24.
    Molofsky AV, Deneen B (2015) Astrocyte development: a guide for the perplexed. Glia 63(8):1320–1329. CrossRefPubMedGoogle Scholar
  25. 25.
    Han X, Chen M, Wang F et al (2013) Forebrain engraftment by human glial progenitor cells enhances synaptic plasticity and learning in adult mice. Cell Stem Cell 12(3):342–353. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Dimou L, Götz M (2014) Glial cells as progenitors and stem cells: new roles in the healthy and diseased brain. Physiol Rev 94(3):709–737. CrossRefGoogle Scholar
  27. 27.
    Falk S, Götz M (2017) Glial control of neurogenesis. Curr Opin Neurobiol 47:188–195. CrossRefPubMedGoogle Scholar
  28. 28.
    Miller SJ (2018) Astrocyte heterogeneity in the adult central nervous system. Front Cell Neurosci 12:401. CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Theis M, Giaume C (2012) Connexin-based intercellular communication and astrocyte heterogeneity. Brain Res 1487:88–98. CrossRefPubMedGoogle Scholar
  30. 30.
    Degen J, Dublin P, Zhang J et al (2012) Dual reporter approaches for identification of Cre efficacy and astrocyte heterogeneity. FASEB J 26(11):4576–4583. CrossRefPubMedGoogle Scholar
  31. 31.
    Farmer WT, Murai K (2017) Resolving astrocyte heterogeneity in the CNS. Front Cell Neurosci 11:300. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Lee Y, Su M, Messing A et al (2006) Astrocyte heterogeneity revealed by expression of a GFAP-LacZ transgene. Glia 53(7):677–687PubMedCrossRefGoogle Scholar
  33. 33.
    Zhang Y, Barres BA (2010) Astrocyte heterogeneity: an underappreciated topic in neurobiology. Curr Opin Neurobiol 20(5):588–594. CrossRefPubMedGoogle Scholar
  34. 34.
    Oberheim NA, Goldman SA, Nedergaard M (2012) Heterogeneity of astrocytic form and function. Methods Mol Biol 814:23–45. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Bayraktar OA, Fuentealba LC, Alvarez-Buylla A et al (2015) Astrocyte development and heterogeneity. Cold Spring Harb Perspect Biol 7(1):a020362. CrossRefPubMedCentralPubMedGoogle Scholar
  36. 36.
    Molders A, Koch A, Menke R et al (2018) Heterogeneity of the astrocytic AMPA-receptor transcriptome. Glia 66(12):2604–2616. CrossRefPubMedGoogle Scholar
  37. 37.
    Morel L, Men Y, Chiang MSR et al (2018) Intracortical astrocyte subpopulations defined by astrocyte reporter mice in the adult brain. Glia 67:171–181. CrossRefPubMedGoogle Scholar
  38. 38.
    Araque A, Parpura V, Sanzgiri RP et al (1999) Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci 22(5):208–215. CrossRefGoogle Scholar
  39. 39.
    Ziskin JL, Nishiyama A, Rubio M et al (2007) Vesicular release of glutamate from unmyelinated axons in white matter. Nat Neurosci 10(3):321. CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Kukley M, Capetillo-Zarate E, Dietrich D (2007) Vesicular glutamate release from axons in white matter. Nat Neurosci 10(3):311–320. CrossRefPubMedGoogle Scholar
  41. 41.
    Wake H, Lee PR, Fields RD (2011) Control of local protein synthesis and initial events in myelination by action potentials. Science 333(6049):1647–1651. CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Saab AS, Tzvetavona ID, Trevisiol A et al (2016) Oligodendroglial NMDA receptors regulate glucose import and axonal energy metabolism. Neuron 91(1):119–132. CrossRefPubMedGoogle Scholar
  43. 43.
    Rose CR, Ziemens D, Untiet V et al (2018) Molecular and cellular physiology of sodium-dependent glutamate transporters. Brain Res Bull 136:3–16. CrossRefPubMedGoogle Scholar
  44. 44.
    Rothstein JD, Dykes-Hoberg M, Pardo CA et al (1996) Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 16(3):675–686PubMedCrossRefGoogle Scholar
  45. 45.
    Tanaka K, Watase K, Manabe T et al (1997) Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science 276(5319):1699–1702PubMedCrossRefGoogle Scholar
  46. 46.
    Regan MR, Huang YH, Kim YS et al (2007) Variations in promoter activity reveal a differential expression and physiology of glutamate transporters by glia in the developing and mature CNS. J Neurosci 27(25):6607–6619. CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Hassel B, Boldingh KA, Narvesen C et al (2003) Glutamate transport, glutamine synthetase and phosphate-activated glutaminase in rat CNS white matter. A quantitative study. J Neurochem 87(1):230–237. CrossRefPubMedGoogle Scholar
  48. 48.
    Goursaud S, Kozlova EN, Maloteaux J-M et al (2009) Cultured astrocytes derived from corpus callosum or cortical grey matter show distinct glutamate handling properties. J Neurochem 108(6):1442–1452. CrossRefPubMedGoogle Scholar
  49. 49.
    Macnab LT, Pow DV (2007) Expression of the exon 9-skipping form of EAAT2 in astrocytes of rats. Neuroscience 150(3):705–711. CrossRefPubMedGoogle Scholar
  50. 50.
    Stanimirovic DB, Ball R, Small DL et al (1999) Developmental regulation of glutamate transporters and glutamine synthetase activity in astrocyte cultures differentiated in vitro. Int J Dev Neurosci 17(3):173–184PubMedCrossRefGoogle Scholar
  51. 51.
    Maragakis NJ, Dietrich J, Wong V et al (2004) Glutamate transporter expression and function in human glial progenitors. Glia 45(2):133–143. CrossRefPubMedGoogle Scholar
  52. 52.
    Zonta M, Angulo MC, Gobbo S et al (2003) Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nat Neurosci 6(1):43–50PubMedCrossRefGoogle Scholar
  53. 53.
    Gordon GR, Choi HB, Rungta RL et al (2008) Brain metabolism dictates the polarity of astrocyte control over arterioles. Nature 456(7223):745–749PubMedCentralCrossRefPubMedGoogle Scholar
  54. 54.
    Nave KA (2010) Myelination and support of axonal integrity by glia. Nature 468(7321):244–252. CrossRefPubMedGoogle Scholar
  55. 55.
    Fünfschilling U, Supplie LM, Mahad D et al (2012) Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature 485(7399):517–521PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Pellerin L, Magistretti PJ (1994) Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc Natl Acad Sci USA 91:10625–10629PubMedCrossRefGoogle Scholar
  57. 57.
    Allaman I, Bélanger M, Magistretti PJ (2011) Astrocyte-neuron metabolic relationships: for better and for worse. Trends Neurosci 34(2):76–87. CrossRefGoogle Scholar
  58. 58.
    Escartin C, Rouach N (2013) Astroglial networking contributes to neurometabolic coupling. Front Neuroenerg 5(4):1–8. CrossRefGoogle Scholar
  59. 59.
    Stobart JL, Anderson CM (2013) Multifunctional role of astrocytes as gatekeepers of neuronal energy supply. Front Cell Neurosci 7(38):1–21. CrossRefGoogle Scholar
  60. 60.
    Nortley R, Attwell D (2017) Control of brain energy supply by astrocytes. Curr Opin Neurobiol 47:80–85. CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Dringen R, Gebhardt R, Hamprecht B (1993) Glycogen in astrocytes: possible function as lactate supply for neighboring cells. Brain Res 623(2):208–214. CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Bak LK, Walls AB, Schousboe A et al (2018) Astrocytic glycogen metabolism in the healthy and diseased brain. J Biol Chem 293(19):7108–7116. CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Cataldo AM, Broadwell RD (1986) Cytochemical identification of cerebral glycogen and glucose-6-phosphatase activity under normal and experimental conditions. II. Choroid plexus and ependymal epithelia, endothelia and pericytes. J Neurocytol 15(4):511–524. CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Sokoloff L, Reivich M, Kennedy C et al (1977) The 14Cdeoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J Neurochem 28(5):897–916PubMedCrossRefGoogle Scholar
  65. 65.
    Morland C, Henjum S, Iversen EG et al (2007) Evidence for a higher glycolytic than oxidative metabolic activity in white matter of rat brain. Neurochem Int 50(5):703–709. CrossRefPubMedGoogle Scholar
  66. 66.
    Shannon C, Salter M, Fern R (2007) GFP imaging of live astrocytes: regional differences in the effects of ischaemia upon astrocytes. J Anat 210(6):684–692. CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Pantoni L, Garcia JH, Gutierrez JA (1996) Cerebral white matter is highly vulnerable to ischemia. Stroke 27(9):1641–1646 discussion 1647PubMedCrossRefGoogle Scholar
  68. 68.
    Pellerin L, Magistretti PJ (2004) Neuroenergetics: calling upon astrocytes to satisfy hungry neurons. Neuroscientist 10(1):53–62PubMedCrossRefGoogle Scholar
  69. 69.
    Winkler U, Seim P, Enzbrenner Y et al (2017) Activity-dependent modulation of intracellular ATP in cultured cortical astrocytes. J Neurosci Res 95(11):2172–2181. CrossRefPubMedGoogle Scholar
  70. 70.
    Köhler S, Winkler U, Sicker M et al (2018) NBCe1 mediates the regulation of the NADH/NAD+ redox state in cortical astrocytes by neuronal signals. Glia 66(10):2233–2245. CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Magistretti PJ, Chatton JY (2005) Relationship between L-glutamate-regulated intracellular Na+ dynamics and ATP hydrolysis in astrocytes. J Neural Transm 112(1):77–85. CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Bittner CX, Valdebenito R, Ruminot I et al (2011) Fast and reversible stimulation of astrocytic glycolysis by K+ and a delayed and persistent effect of glutamate. J Neurosci 31(12):4709–4713. CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Bittner CX, Loaiza A, Ruminot I et al (2010) High resolution measurement of the glycolytic rate. Front Neuroenerg 2:1–11. CrossRefGoogle Scholar
  74. 74.
    Barros LF, Weber B (2018) CrossTalk proposal: An important astrocyte-to-neuron lactate shuttle couples neuronal activity to glucose utilisation in the brain. J Physiol (Lond) 596(3):347–350. CrossRefGoogle Scholar
  75. 75.
    Bak LK, Walls AB (2018) CrossTalk opposing view: lack of evidence supporting an astrocyte-to-neuron lactate shuttle coupling neuronal activity to glucose utilisation in the brain. J Physiol (Lond) 596(3):351–353CrossRefGoogle Scholar
  76. 76.
    Díaz-García CM, Mongeon R, Lahmann C et al (2017) Neuronal stimulation triggers neuronal glycolysis and not lactate uptake. Cell Metab 26(2):361–374. CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Mächler P, Wyss MT, Elsayed M et al (2016) In vivo evidence for a lactate gradient from astrocytes to neurons. Cell Metab 23(1):94–102. CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Wender R, Brown AM, Fern R et al (2000) Astrocytic glycogen influences axon function and survival during glucose deprivation in central white matter. J Neurosci 20(18):6804–6810PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Fern R (2015) Ischemic tolerance in pre-myelinated white matter: the role of astrocyte glycogen in brain pathology. J Cereb Blood Flow Metab 35(6):951–958PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Brown AM, Ransom BR (2007) Astrocyte glycogen and brain energy metabolism. Glia 55(12):1263–1271. CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Ransom BR, Fern R (1997) Does astrocytic glycogen benefit axon function and survival in CNS white matter during glucose deprivation? Glia 21(1):134–141PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Rash JE (2010) Molecular disruptions of the panglial syncytium block potassium siphoning and axonal saltatory conduction: pertinence to neuromyelitis optica and other demyelinating diseases of the central nervous system. Neuroscience 168(4):982–1008. CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Rose CR, Chatton JY (2016) Astrocyte sodium signaling and neuro-metabolic coupling in the brain. Neuroscience 323:121–134. CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    MacVicar BA, Choi HB (2017) Astrocytes provide metabolic support for neuronal synaptic function in response to extracellular K+. Neurochem Res 42(9):2588–2594. CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Oheim M, Schmidt E, Hirrlinger J (2018) Local energy on demand: are ‘spontaneous’ astrocytic Ca2+-microdomains the regulatory unit for astrocyte-neuron metabolic cooperation? Brain Res Bull 136:54–64. CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Brown AM, Ransom BR (2015) Astrocyte glycogen as an emergency fuel under conditions of glucose deprivation or intense neural activity. Metab Brain Dis 30(1):233–239. CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Choi HB, Gordon GRJ, Zhou N et al (2012) Metabolic communication between astrocytes and neurons via bicarbonate-responsive soluble adenylyl cyclase. Neuron 75(6):1094–1104. CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Hof PR, Pascale E, Magistretti PJ (1988) K+ at concentrations reached in the extracellular space during neuronal activity promotes a Ca2+-dependent glycogen hydrolysis in mouse cerebral cortex. J Neurosci 8(6):1922–1928PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Sotelo-Hitschfeld T, Fernandez-Moncada I, Barros LF (2012) Acute feedback control of astrocytic glycolysis by lactate. Glia 60(4):674–680PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Sotelo-Hitschfeld T, Niemeyer MI, Machler P et al (2015) Channel-mediated lactate release by K+-stimulated astrocytes. J Neurosci 35(10):4168–4178. CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Ruminot I, Gutiérrez R, Peña-Münzenmayer G et al (2011) NBCe1 mediates the acute stimulation of astrocytic glycolysis by extracellular K+. J Neurosci 31(40):14264–14271. CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Ruminot I, Schmälzle J, Leyton B et al (2017) Tight coupling of astrocyte energy metabolism to synaptic activity revealed by genetically encoded FRET nanosensors in hippocampal tissue. J Cereb Blood Flow Metab: 271678 × 17737012. CrossRefGoogle Scholar
  93. 93.
    Ransom BR, Walz W, Davis PK et al (1992) Anoxia-induced changes in extracellular K+ and pH in mammalian central white matter. J Cereb Blood Flow Metab 12(4):593–602PubMedCrossRefPubMedCentralGoogle Scholar
  94. 94.
    Connors BW, Ransom BR, Kunis DM et al (1982) Activity-dependent K+ accumulation in the developing rat optic nerve. Science 216(4552):1341–1343PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Bay V, Butt AM (2012) Relationship between glial potassium regulation and axon excitability: a role for glial Kir4.1 channels. Glia 60(4):651–660. CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Ransom CB, Ransom BR, Sontheimer H (2000) Activity-dependent extracellular K+ accumulation in rat optic nerve: the role of glial and axonal Na+ pumps. J Physiol 522 Pt 3:427–442PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Oe Y, Baba O, Ashida H et al (2016) Glycogen distribution in the microwave-fixed mouse brain reveals heterogeneous astrocytic patterns. Glia 64(9):1532–1545. CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Hirase H, Akther S, Wang X et al (2019) Glycogen distribution in mouse hippocampus. J Neurosci Res 97(8):923–932. CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Montagne A, Barnes SR, Sweeney MD et al (2015) Blood-brain barrier breakdown in the aging human hippocampus. Neuron 85(2):296–302. CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Brown AM (2004) Brain glycogen re-awakened. J Neurochem 89(3):537–552. CrossRefPubMedGoogle Scholar
  101. 101.
    Swanson RA, Sagar SM, Sharp FR (1989) Regional brain glycogen stores and metabolism during complete global ischaemia. Neurol Res 11(1):24–28PubMedCrossRefGoogle Scholar
  102. 102.
    Sagar SM, Sharp FR, Swanson RA (1987) The regional distribution of glycogen in rat brain fixed by microwave irradiation. Brain Res 417(1):172–174PubMedCrossRefGoogle Scholar
  103. 103.
    Rahman B, Kussmaul L, Hamprecht B et al (2000) Glycogen is mobilized during the disposal of peroxides by cultured astroglial cells from rat brain. Neurosci Lett 290(3):169–172PubMedCrossRefGoogle Scholar
  104. 104.
    Saez I, Duran J, Sinadinos C et al (2014) Neurons have an active glycogen metabolism that contributes to tolerance to hypoxia. J Cereb Blood Flow Metab 34(6):945–955. CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Duran J, Saez I, Gruart A et al (2013) Impairment in long-term memory formation and learning-dependent synaptic plasticity in mice lacking glycogen synthase in the brain. J Cereb Blood Flow Metab 33(4):550–556PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Gibbs ME, Anderson DG, Hertz L (2006) Inhibition of glycogenolysis in astrocytes interrupts memory consolidation in young chickens. Glia 54(3):214–222. CrossRefPubMedGoogle Scholar
  107. 107.
    Hertz L, O’Dowd BS, Ng KT et al (2003) Reciprocal changes in forebrain contents of glycogen and of glutamate/glutamine during early memory consolidation in the day-old chick. Brain Res 994(2):226–233. CrossRefPubMedGoogle Scholar
  108. 108.
    Rossi DJ, Oshima T, Attwell D (2000) Glutamate release in severe brain ischaemia is mainly by reversed uptake. Nature 403(6767):316–321PubMedCrossRefGoogle Scholar
  109. 109.
    Al-Sarraf H (2002) Transport of 14C-gamma-aminobutyric acid into brain, cerebrospinal fluid and choroid plexus in neonatal and adult rats. Brain Res Dev 139(2):121–129CrossRefGoogle Scholar
  110. 110.
    Xu J, Song D, Xue Z et al (2013) Requirement of glycogenolysis for uptake of increased extracellular K+ in astrocytes: potential implications for K+ homeostasis and glycogen usage in brain. Neurochem Res 38(3):472–485. CrossRefPubMedGoogle Scholar
  111. 111.
    DiNuzzo M, Mangia S, Maraviglia B et al (2013) Regulatory mechanisms for glycogenolysis and K+ uptake in brain astrocytes. Neurochem Int 63(5):458–464. CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    DiNuzzo M, Mangia S, Maraviglia B et al (2012) The role of astrocytic glycogen in supporting the energetics of neuronal activity. Neurochem Res 37(11):2432–2438. CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Sickmann HM, Walls AB, Schousboe A et al (2009) Functional significance of brain glycogen in sustaining glutamatergic neurotransmission. J Neurochem 109(Suppl 1):80–86. CrossRefPubMedGoogle Scholar
  114. 114.
    Dienel GA, Ball KK, Cruz NF (2007) A glycogen phosphorylase inhibitor selectively enhances local rates of glucose utilization in brain during sensory stimulation of conscious rats: implications for glycogen turnover. J Neurochem 102(2):466–478. CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Brown AM, Sickmann HM, Fosgerau K et al (2005) Astrocyte glycogen metabolism is required for neural activity during aglycemia or intense stimulation in mouse white matter. J Neurosci Res 79(1–2):74–80. CrossRefPubMedGoogle Scholar
  116. 116.
    Hirrlinger J, Nave KA (2014) Adapting brain metabolism to myelination and long-range signal transduction. Glia 62(11):1749–1761. CrossRefPubMedGoogle Scholar
  117. 117.
    Meyer N, Richter N, Fan Z et al (2018) Oligodendrocytes in the mouse corpus callosum maintain axonal function by delivery of glucose. Cell Rep 22(9):2383–2394. CrossRefPubMedGoogle Scholar
  118. 118.
    Borowsky IW, Collins RC (1989) Metabolic anatomy of brain: a comparison of regional capillary density, glucose metabolism, and enzyme activities. J Comp Neurol 288(3):401–413PubMedCrossRefGoogle Scholar
  119. 119.
    Wilhelm I, Nyúl-Tóth Á, Suciu M et al (2016) Heterogeneity of the blood-brain barrier. Tissue Barriers 4(1):e1143544. CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    Schlageter KE, Molnar P, Lapin GD et al (1999) Microvessel organization and structure in experimental brain tumors: microvessel populations with distinctive structural and functional properties. Microvasc Res 58(3):312–328. CrossRefGoogle Scholar
  121. 121.
    Murugesan N, Demarest TG, Madri JA et al (2012) Brain regional angiogenic potential at the neurovascular unit during normal aging. Neurobiol Aging 33(5):1004.e1–1004.e16. CrossRefGoogle Scholar
  122. 122.
    Lundgaard I, Osorio MJ, Kress BT et al (2014) White matter astrocytes in health and disease. Neuroscience 276:161–173. CrossRefPubMedGoogle Scholar
  123. 123.
    Nyúl-Tóth Á, Suciu M, Molnár J et al (2016) Differences in the molecular structure of the blood-brain barrier in the cerebral cortex and white matter: an in silico, in vitro, and ex vivo study. Am J Physiol Heart Circ Physiol 310(11):H1702–H1714. CrossRefPubMedGoogle Scholar
  124. 124.
    Liedtke W, Edelmann W, Bieri PL et al (1996) GFAP is necessary for the integrity of CNS white matter architecture and long-term maintenance of myelination. Neuron 17(4):607–615CrossRefGoogle Scholar
  125. 125.
    Pekny M, Stanness KA, Eliasson C et al (1998) Impaired induction of blood-brain barrier properties in aortic endothelial cells by astrocytes from GFAP-deficient mice. Glia 22(4):390–400PubMedCrossRefGoogle Scholar
  126. 126.
    Daneman R, Prat A (2015) The blood-brain barrier. Cold Spring Harb Perspect Biol 7(1):1–23. CrossRefGoogle Scholar
  127. 127.
    Noumbissi ME, Galasso B, Stins MF (2018) Brain vascular heterogeneity: implications for disease pathogenesis and design of in vitro blood-brain barrier models. Fluids Barriers CNS 15(1):12. CrossRefPubMedPubMedCentralGoogle Scholar
  128. 128.
    Winkler EA, Sengillo JD, Bell RD et al (2012) Blood-spinal cord barrier pericyte reductions contribute to increased capillary permeability. J Cereb Blood Flow Metab 32(10):1841–1852. CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Shaw CM, Alvord EC, Berry JR RG (1959) Swelling of the brain following ischemic infarction with arterial occlusion. Arch Neurol 1:161–177PubMedCrossRefGoogle Scholar
  130. 130.
    Wang W-W, Xie C-l, Zhou L-L et al (2014) The function of aquaporin4 in ischemic brain edema. Clin Neurol Neurosurg 127:5–9. CrossRefPubMedGoogle Scholar
  131. 131.
    Walberer M, Ritschel N, Nedelmann M et al (2008) Aggravation of infarct formation by brain swelling in a large territorial stroke: a target for neuroprotection? J Neurosurg 109(2):287–293PubMedCrossRefGoogle Scholar
  132. 132.
    Stokum JA, Gerzanich V, Simard JM (2016) Molecular pathophysiology of cerebral edema. J Cereb Blood Flow Metab 36(3):513–538. CrossRefGoogle Scholar
  133. 133.
    Stokum JA, Mehta RI, Ivanova S et al (2015) Heterogeneity of aquaporin-4 localization and expression after focal cerebral ischemia underlies differences in white versus grey matter swelling. Acta Neuropathol Commun 3:61. CrossRefPubMedCentralPubMedGoogle Scholar
  134. 134.
    Arciénega II, Brunet JF, Bloch J et al (2010) Cell locations for AQP1, AQP4 and 9 in the non-human primate brain. Neuroscience 167(4):1103–1114. CrossRefPubMedGoogle Scholar
  135. 135.
    Badaut J, Fukuda AM, Jullienne A et al (2014) Aquaporin and brain diseases. Biochim Biophys Acta 1840(5):1554–1565. CrossRefPubMedGoogle Scholar
  136. 136.
    Clément T, Rodriguez-Grande B, Badaut J (2018) Aquaporins in brain edema. J Neurosci Res. CrossRefPubMedGoogle Scholar
  137. 137.
    Yang X, Ransom BR, Ma J-F (2016) The role of AQP4 in neuromyelitis optica: more answers, more questions. J Neuroimmunol 298:63–70. CrossRefGoogle Scholar
  138. 138.
    Lafrenaye AD, Simard JM (2019) Bursting at the seams: molecular mechanisms mediating astrocyte swelling. Int J Mol Sci 20(2):330. CrossRefPubMedCentralPubMedGoogle Scholar
  139. 139.
    Frydenlund DS, Bhardwaj A, Otsuka T et al (2006) Temporary loss of perivascular aquaporin-4 in neocortex after transient middle cerebral artery occlusion in mice. Proc Natl Acad Sci USA 103(36):13532–13536PubMedCrossRefGoogle Scholar
  140. 140.
    Steiner E, Enzmann GU, Lin S et al (2012) Loss of astrocyte polarization upon transient focal brain ischemia as a possible mechanism to counteract early edema formation. Glia 60(11):1646–1659. CrossRefPubMedGoogle Scholar
  141. 141.
    Nesic O, Lee J, Unabia GC et al (2008) Aquaporin 1 - a novel player in spinal cord injury. J Neurochem 105(3):628–640. CrossRefPubMedCentralPubMedGoogle Scholar
  142. 142.
    Satoh J-i, Tabunoki H, Yamamura T et al (2007) Human astrocytes express aquaporin-1 and aquaporin-4 in vitro and in vivo. Neuropathology 27(3):245–256. CrossRefPubMedGoogle Scholar
  143. 143.
    Hirt L, Price M, Mastour N et al (2018) Increase of aquaporin 9 expression in astrocytes participates in astrogliosis. J Neurosci Res 96(2):194–206. CrossRefPubMedGoogle Scholar
  144. 144.
    Ribeiro MdC, Hirt L, Bogousslavsky J et al (2006) Time course of aquaporin expression after transient focal cerebral ischemia in mice. J Neurosci Res 83(7):1231–1240. CrossRefGoogle Scholar
  145. 145.
    Cotrina ML, Nedergaard M (2012) Brain connexins in demyelinating diseases: therapeutic potential of glial targets. Brain Res 1487:61–68. CrossRefPubMedPubMedCentralGoogle Scholar
  146. 146.
    Nagy JI, Rash JE (2000) Connexins and gap junctions of astrocytes and oligodendrocytes in the CNS. Brain Res Rev 32(1):29–44PubMedCrossRefGoogle Scholar
  147. 147.
    Bedner P, Steinhäuser C, Theis M (2012) Functional redundancy and compensation among members of gap junction protein families? Biochim Biophys Acta 1818(8):1971–1984. CrossRefPubMedGoogle Scholar
  148. 148.
    Lee SH, Kim WT, Cornell-Bell AH et al (1994) Astrocytes exhibit regional specificity in gap-junction coupling. Glia 11(4):315–325. CrossRefPubMedGoogle Scholar
  149. 149.
    Haas B, Schipke CG, Peters O et al (2006) Activity-dependent ATP-waves in the mouse neocortex are independent from astrocytic calcium waves. Cereb Cortex 16(2):237–246. CrossRefPubMedGoogle Scholar
  150. 150.
    Kunzelmann P, Schroder W, Traub O et al (1999) Late onset and increasing expression of the gap junction protein connexin30 in adult murine brain and long-term cultured astrocytes. Glia 25(2):111–119PubMedCrossRefGoogle Scholar
  151. 151.
    Nagy JI, Patel D, Ochalski PA et al (1999) Connexin30 in rodent, cat and human brain: selective expression in gray matter astrocytes, co-localization with connexin43 at gap junctions and late developmental appearance. Neuroscience 88(2):447–468PubMedCrossRefGoogle Scholar
  152. 152.
    Rouach N, Avignone E, Meme W et al (2002) Gap junctions and connexin expression in the normal and pathological central nervous system. Biol Cell 94(7–8):457–475PubMedCrossRefGoogle Scholar
  153. 153.
    Yamamoto T, Ochalski A, Hertzberg EL et al (1990) LM and EM immunolocalization of the gap junctional protein connexin 43 in rat brain. Brain Res 508(2):313–319PubMedCrossRefGoogle Scholar
  154. 154.
    Maglione M, Tress O, Haas B et al (2010) Oligodendrocytes in mouse corpus callosum are coupled via gap junction channels formed by connexin47 and connexin32. Glia 58(9):1104–1117. CrossRefPubMedGoogle Scholar
  155. 155.
    Theis M, Jauch R, Zhuo L et al (2003) Accelerated hippocampal spreading depression and enhanced locomotory activity in mice with astrocyte-directed inactivation of connexin43. J Neurosci 23(3):766–776PubMedCentralCrossRefPubMedGoogle Scholar
  156. 156.
    Nakase T, Fushiki S, Naus CCG (2003) Astrocytic gap junctions composed of connexin 43 reduce apoptotic neuronal damage in cerebral ischemia. Stroke 34(8):1987–1993. CrossRefGoogle Scholar
  157. 157.
    Spray DC, Ye Z-C, Ransom BR (2006) Functional connexin “hemichannels”: a critical appraisal. Glia 54(7):758–773. CrossRefPubMedGoogle Scholar
  158. 158.
    Rose CR, Ransom BR (1997) Gap junctions equalize intracellular Na+ concentration in astrocytes. Glia 20(4):299–307PubMedCrossRefGoogle Scholar
  159. 159.
    Kofuji P, Newman EA (2004) Potassium buffering in the central nervous system. Neuroscience 129(4):1045–1056PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Bernardinelli Y, Magistretti PJ, Chatton JY (2004) Astrocytes generate Na+-mediated metabolic waves. Proc Natl Acad Sci USA 101(41):14937–14942PubMedCrossRefPubMedCentralGoogle Scholar
  161. 161.
    Charles AC, Merrill JE, Dirksen ER et al (1991) Intercellular signaling in glial cells: calcium waves and oscillations in response to mechanical stimulation and glutamate. Neuron 6(6):983–992PubMedCrossRefGoogle Scholar
  162. 162.
    Cornell-Bell AH, Thomas PG, Smith SJ (1990) The excitatory neurotransmitter glutamate causes filopodia formation in cultured hippocampal astrocytes. Glia 3(5):322–334PubMedCrossRefGoogle Scholar
  163. 163.
    Finkbeiner S (1992) Calcium waves in astrocytes-filling in the gaps. Neuron 8(6):1101–1108PubMedCrossRefGoogle Scholar
  164. 164.
    Schipke CG, Boucsein C, Ohlemeyer C et al (2002) Astrocyte Ca2+ waves trigger responses in microglial cells in brain slices. FASEB J 16(2):255–257CrossRefGoogle Scholar
  165. 165.
    Hamilton N, Vayro S, Kirchhoff F et al (2008) Mechanisms of ATP- and glutamate-mediated calcium signaling in white matter astrocytes. Glia 56(7):734–749. CrossRefPubMedGoogle Scholar
  166. 166.
    Rouach N, Koulakoff A, Abudara V et al (2008) Astroglial metabolic networks sustain hippocampal synaptic transmission. Science 322(5907):1551–1555PubMedCrossRefGoogle Scholar
  167. 167.
    Gandhi GK, Cruz NF, Ball KK et al (2009) Selective astrocytic gap junctional trafficking of molecules involved in the glycolytic pathway: impact on cellular brain imaging. J Neurochem 110(3):857–869PubMedPubMedCentralCrossRefGoogle Scholar
  168. 168.
    Giaume C, Tabernero A, Medina JM (1997) Metabolic trafficking through astrocytic gap junctions. Glia 21(1):114–123PubMedCrossRefGoogle Scholar
  169. 169.
    Tabernero A, Giaume C, Medina JM (1996) Endothelin-1 regulates glucose utilization in cultured astrocytes by controlling intercellular communication through gap junctions. Glia 16(3): 187–195PubMedCrossRefGoogle Scholar
  170. 170.
    Enkvist MO, McCarthy KD (1994) Astroglial gap junction communication is increased by treatment with either glutamate or high K+ concentration. J Neurochem 62(2):489–495. CrossRefPubMedGoogle Scholar
  171. 171.
    Pina-Benabou MH de, Srinivas M, Spray DC et al (2001) Calmodulin kinase pathway mediates the K+-induced increase in Gap junctional communication between mouse spinal cord astrocytes. J Neurosci 21(17):6635–6643PubMedCentralCrossRefPubMedGoogle Scholar
  172. 172.
    Langer J, Stephan J, Theis M et al (2012) Gap junctions mediate intercellular spread of sodium between hippocampal astrocytes in situ. Glia 60(2):239–252. CrossRefGoogle Scholar
  173. 173.
    Dienel GA (2013) Astrocytic energetics during excitatory neurotransmission: what are contributions of glutamate oxidation and glycolysis? Neurochem Int 63(4):244–258. CrossRefPubMedPubMedCentralGoogle Scholar
  174. 174.
    Wasseff SK, Scherer SS (2011) Cx32 and Cx47 mediate oligodendrocyte:astrocyte and oligodendrocyte: oligodendrocyte gap junction coupling. Neurobiol Dis 42(3):506–513. CrossRefPubMedPubMedCentralGoogle Scholar
  175. 175.
    Tress O, Maglione M, May D et al (2012) Panglial gap junctional communication is essential for maintenance of myelin in the CNS. J Neurosci 32(22):7499–7518. CrossRefPubMedPubMedCentralGoogle Scholar
  176. 176.
    Magnotti LM, Goodenough DA, Paul DL (2011) Deletion of oligodendrocyte Cx32 and astrocyte Cx43 causes white matter vacuolation, astrocyte loss and early mortality. Glia 59(7):1064–1074. CrossRefPubMedPubMedCentralGoogle Scholar
  177. 177.
    Wu O, Cloonan L, Mocking SJT et al (2015) Role of acute lesion topography in initial ischemic stroke severity and long-term functional outcomes. Stroke 46(9):2438–2444PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    Helenius J, Henninger N (2015) Leukoaraiosis burden significantly modulates the association between infarct volume and National Institutes of Health Stroke Scale in Ischemic Stroke. Stroke 46(7):1857–1863PubMedCrossRefPubMedCentralGoogle Scholar
  179. 179.
    Wang Y, Liu G, Hong D et al (2016) White matter injury in ischemic stroke. Prog Neurobiol 141:45–60. CrossRefPubMedPubMedCentralGoogle Scholar
  180. 180.
    Curtze S, Melkas S, Sibolt G et al (2015) Cerebral computed tomography-graded white matter lesions are associated with worse outcome after thrombolysis in patients with stroke. Stroke 46(6):1554–1560PubMedCrossRefPubMedCentralGoogle Scholar
  181. 181.
    Podgorska A, Hier DB, Pytlewski A et al (2002) Leukoaraiosis and stroke outcome. J Stroke Cerebrovasc Dis 11(6):336–340CrossRefGoogle Scholar
  182. 182.
    Zhang K, Sejnowski TJ (2000) A universal scaling law between gray matter and white matter of cerebral cortex. Proc Natl Acad Sci USA 97(10):5621–5626PubMedCrossRefPubMedCentralGoogle Scholar
  183. 183.
    Matute C (2011) Glutamate and ATP signalling in white matter pathology. J Anat 219(1):53–64. CrossRefPubMedPubMedCentralGoogle Scholar
  184. 184.
    Adams JD J, Wang B, Klaidman LK et al (1993) New aspects of brain oxidative stress induced by tert-butylhydroperoxide. Free Radic Biol Med 15(2):195–202PubMedCrossRefPubMedCentralGoogle Scholar
  185. 185.
    Rosenzweig S, Carmichael ST (2015) The axon-glia unit in white matter stroke: mechanisms of damage and recovery. Brain Res 1623:123–134. CrossRefPubMedPubMedCentralGoogle Scholar
  186. 186.
    Iadecola C, Park L, Capone C (2009) Threats to the mind: aging, amyloid, and hypertension. Stroke 40(3 Suppl):S40–S44CrossRefGoogle Scholar
  187. 187.
    O’Sullivan M, Lythgoe DJ, Pereira AC et al (2002) Patterns of cerebral blood flow reduction in patients with ischemic leukoaraiosis. Neurology 59(3):321–326PubMedCrossRefPubMedCentralGoogle Scholar
  188. 188.
    Tekkök SB, Brown AM, Ransom BR (2003) Axon function persists during anoxia in mammalian white matter. J Cereb Blood Flow Metab 23(11):1340–1347. CrossRefPubMedPubMedCentralGoogle Scholar
  189. 189.
    Hamner MA, Moller T, Ransom BR (2011) Anaerobic function of CNS white matter declines with age. J Cereb Blood Flow Metab 31(4):996–1002PubMedCrossRefPubMedCentralGoogle Scholar
  190. 190.
    Tekkok SB, Ransom BR (2004) Anoxia effects on CNS function and survival: regional differences. Neurochem Res 29(11):2163–2169CrossRefGoogle Scholar
  191. 191.
    Goldberg MP, Weiss JH, Pham PC et al (1987) N-methyl-D-aspartate receptors mediate hypoxic neuronal injury in cortical culture. J Pharmacol Exp Ther 243(2):784–791PubMedPubMedCentralGoogle Scholar
  192. 192.
    Foster RE, Connors BW, Waxman SG (1982) Rat optic nerve: electrophysiological, pharmacological and anatomical studies during development. Brain Res 255(3):371–386. CrossRefPubMedPubMedCentralGoogle Scholar
  193. 193.
    Waxman SG, Davis PK, Black JA et al (1990) Anoxic injury of mammalian central white matter: decreased susceptibility in myelin-deficient optic nerve. Ann Neurol 28(3):335–340PubMedCrossRefPubMedCentralGoogle Scholar
  194. 194.
    Micu I, Jiang Q, Coderre E et al (2006) NMDA receptors mediate calcium accumulation in myelin during chemical ischaemia. Nature 439(7079):988–992. CrossRefPubMedPubMedCentralGoogle Scholar
  195. 195.
    Micu I, Plemel JR, Lachance C et al (2016) The molecular physiology of the axo-myelinic synapse. Exp Neurol 276:41–50. CrossRefPubMedPubMedCentralGoogle Scholar
  196. 196.
    Domercq M, Perez-Samartin A, Aparicio D et al (2010) P2 × 7 receptors mediate ischemic damage to oligodendrocytes. Glia 58(6):730–740. CrossRefPubMedPubMedCentralGoogle Scholar
  197. 197.
    Saab AS, Tzvetanova ID, Nave KA (2013) The role of myelin and oligodendrocytes in axonal energy metabolism. Curr Opin Neurobiol 23(6):1065–1072. CrossRefPubMedPubMedCentralGoogle Scholar
  198. 198.
    Marques S, Zeisel A, Codeluppi S et al (2016) Oligodendrocyte heterogeneity in the mouse juvenile and adult central nervous system. Science 352(6291):1326–1329. CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Carl-Ludwig-Institute for Physiology, Faculty of MedicineUniversity of LeipzigLeipzigGermany
  2. 2.Department of NeurogeneticsMax-Planck-Institute for Experimental MedicineGöttingenGermany

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