Abstract
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.
References
Somjen GG (1988) Nervenkitt: notes on the history of the concept of neuroglia. Glia 1(1):2–9
Matyash V, Kettenmann H (2010) Heterogeneity in astrocyte morphology and physiology. Brain Res Rev 63(1–2):2–10
Oberheim NA, Wang X, Goldman S et al (2006) Astrocytic complexity distinguishes the human brain. Trends Neurosci 29(10):547–553. https://doi.org/10.1016/j.tins.2006.08.004
Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119(1):7–35. https://doi.org/10.1007/s00401-009-0619-8
Miller RH, Raff MC (1984) Fibrous and protoplasmic astrocytes are biochemically and developmentally distinct. J Neurosci 4(2):585–592
Chaboub LS, Deneen B (2012) Developmental origins of astrocyte heterogeneity: the final frontier of CNS development. Dev Neurosci 34(5):379–388. https://doi.org/10.1159/000343723
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. https://doi.org/10.1016/0006-8993(72)90398-8
Aberg F, Kozlova EN (2000) Metastasis-associated mts1 (S100A4) protein in the developing and adult central nervous system. J Comp Neurol 424(2):269–282
Wang DD, Bordey A (2008) The astrocyte odyssey. Prog Neurobiol 86(4):342–367. https://doi.org/10.1016/j.pneurobio.2008.09.015
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. https://doi.org/10.1017/S1740925X06000202
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. https://doi.org/10.1002/glia.21089
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. https://doi.org/10.1523/JNEUROSCI.4178-07.2008
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):8384–8389
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. https://doi.org/10.1002/glia.20845
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. https://doi.org/10.1038/nature11405
Schitine C, Nogaroli L, Costa MR et al (2015) Astrocyte heterogeneity in the brain: from development to disease. Front Cell Neurosci 9:76. https://doi.org/10.3389/fncel.2015.00076
Luskin MB, McDermott K (1994) Divergent lineages for oligodendrocytes and astrocytes originating in the neonatal forebrain subventricular zone. Glia 11(3):211–226
Bribián A, Figueres-Oñate M, Martín-López E et al (2016) Decoding astrocyte heterogeneity: new tools for clonal analysis. Neuroscience 323:10–19
García-Marqués J, López-Mascaraque L (2013) Clonal identity determines astrocyte cortical heterogeneity. Cereb Cortex 23(6):1463–1472. https://doi.org/10.1093/cercor/bhs134
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. https://doi.org/10.1242/dev.02847
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. https://doi.org/10.1242/dev.105270
Freeman MR (2010) Specification and morphogenesis of astrocytes. Science 330(6005):774–778
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. https://doi.org/10.1523/JNEUROSCI.1167-14.2014
Molofsky AV, Deneen B (2015) Astrocyte development: a guide for the perplexed. Glia 63(8):1320–1329. https://doi.org/10.1002/glia.22836
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. https://doi.org/10.1016/j.stem.2012.12.015
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. https://doi.org/10.1152/physrev.00036.2013
Falk S, Götz M (2017) Glial control of neurogenesis. Curr Opin Neurobiol 47:188–195. https://doi.org/10.1016/j.conb.2017.10.025
Miller SJ (2018) Astrocyte heterogeneity in the adult central nervous system. Front Cell Neurosci 12:401. https://doi.org/10.3389/fncel.2018.00401
Theis M, Giaume C (2012) Connexin-based intercellular communication and astrocyte heterogeneity. Brain Res 1487:88–98. https://doi.org/10.1016/j.brainres.2012.06.045
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. https://doi.org/10.1096/fj.12-207183
Farmer WT, Murai K (2017) Resolving astrocyte heterogeneity in the CNS. Front Cell Neurosci 11:300. https://doi.org/10.3389/fncel.2017.00300
Lee Y, Su M, Messing A et al (2006) Astrocyte heterogeneity revealed by expression of a GFAP-LacZ transgene. Glia 53(7):677–687
Zhang Y, Barres BA (2010) Astrocyte heterogeneity: an underappreciated topic in neurobiology. Curr Opin Neurobiol 20(5):588–594. https://doi.org/10.1016/j.conb.2010.06.005
Oberheim NA, Goldman SA, Nedergaard M (2012) Heterogeneity of astrocytic form and function. Methods Mol Biol 814:23–45. https://doi.org/10.1007/978-1-61779-452-0_3
Bayraktar OA, Fuentealba LC, Alvarez-Buylla A et al (2015) Astrocyte development and heterogeneity. Cold Spring Harb Perspect Biol 7(1):a020362. https://doi.org/10.1101/cshperspect.a020362
Molders A, Koch A, Menke R et al (2018) Heterogeneity of the astrocytic AMPA-receptor transcriptome. Glia 66(12):2604–2616. https://doi.org/10.1002/glia.23514
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. https://doi.org/10.1002/glia.23545
Araque A, Parpura V, Sanzgiri RP et al (1999) Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci 22(5):208–215. https://doi.org/10.1016/S0166-2236(98)01349-6
Ziskin JL, Nishiyama A, Rubio M et al (2007) Vesicular release of glutamate from unmyelinated axons in white matter. Nat Neurosci 10(3):321. https://doi.org/10.1038/nn1854
Kukley M, Capetillo-Zarate E, Dietrich D (2007) Vesicular glutamate release from axons in white matter. Nat Neurosci 10(3):311–320. https://doi.org/10.1038/nn1850
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. https://doi.org/10.1126/science.1206998
Saab AS, Tzvetavona ID, Trevisiol A et al (2016) Oligodendroglial NMDA receptors regulate glucose import and axonal energy metabolism. Neuron 91(1):119–132. https://doi.org/10.1016/j.neuron.2016.05.016
Rose CR, Ziemens D, Untiet V et al (2018) Molecular and cellular physiology of sodium-dependent glutamate transporters. Brain Res Bull 136:3–16. https://doi.org/10.1016/j.brainresbull.2016.12.013
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):675–686
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):1699–1702
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. https://doi.org/10.1523/JNEUROSCI.0790-07.2007
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. https://doi.org/10.1046/j.1471-4159.2003.01984.x
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. https://doi.org/10.1111/j.1471-4159.2009.05889.x
Macnab LT, Pow DV (2007) Expression of the exon 9-skipping form of EAAT2 in astrocytes of rats. Neuroscience 150(3):705–711. https://doi.org/10.1016/j.neuroscience.2007.09.049
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):173–184
Maragakis NJ, Dietrich J, Wong V et al (2004) Glutamate transporter expression and function in human glial progenitors. Glia 45(2):133–143. https://doi.org/10.1002/glia.10310
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):43–50
Gordon GR, Choi HB, Rungta RL et al (2008) Brain metabolism dictates the polarity of astrocyte control over arterioles. Nature 456(7223):745–749
Nave KA (2010) Myelination and support of axonal integrity by glia. Nature 468(7321):244–252. https://doi.org/10.1038/nature09614
Fünfschilling U, Supplie LM, Mahad D et al (2012) Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature 485(7399):517–521
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 91:10625–10629
Allaman I, Bélanger M, Magistretti PJ (2011) Astrocyte-neuron metabolic relationships: for better and for worse. Trends Neurosci 34(2):76–87. https://doi.org/10.1016/j.tins.2010.12.001
Escartin C, Rouach N (2013) Astroglial networking contributes to neurometabolic coupling. Front Neuroenerg 5(4):1–8. https://doi.org/10.3389/fnene.2013.00004
Stobart JL, Anderson CM (2013) Multifunctional role of astrocytes as gatekeepers of neuronal energy supply. Front Cell Neurosci 7(38):1–21. https://doi.org/10.3389/fncel.2013.00038
Nortley R, Attwell D (2017) Control of brain energy supply by astrocytes. Curr Opin Neurobiol 47:80–85. https://doi.org/10.1016/j.conb.2017.09.012
Dringen R, Gebhardt R, Hamprecht B (1993) Glycogen in astrocytes: possible function as lactate supply for neighboring cells. Brain Res 623(2):208–214. https://doi.org/10.1016/0006-8993(93)91429-V
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. https://doi.org/10.1074/jbc.R117.803239
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. https://doi.org/10.1007/BF01611733
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):897–916
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. https://doi.org/10.1016/j.neuint.2007.01.003
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. https://doi.org/10.1111/j.1469-7580.2007.00731.x
Pantoni L, Garcia JH, Gutierrez JA (1996) Cerebral white matter is highly vulnerable to ischemia. Stroke 27(9):1641–1646 discussion 1647
Pellerin L, Magistretti PJ (2004) Neuroenergetics: calling upon astrocytes to satisfy hungry neurons. Neuroscientist 10(1):53–62
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. https://doi.org/10.1002/jnr.24020
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. https://doi.org/10.1002/glia.23504
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. https://doi.org/10.1007/s00702-004-0171-6
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. https://doi.org/10.1523/JNEUROSCI.5311-10.2011
Bittner CX, Loaiza A, Ruminot I et al (2010) High resolution measurement of the glycolytic rate. Front Neuroenerg 2:1–11. https://doi.org/10.3389/fnene.2010.00026
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. https://doi.org/10.1113/JP274944
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):351–353
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. https://doi.org/10.1016/j.cmet.2017.06.021
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. https://doi.org/10.1016/j.cmet.2015.10.010
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):6804–6810
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):951–958
Brown AM, Ransom BR (2007) Astrocyte glycogen and brain energy metabolism. Glia 55(12):1263–1271. https://doi.org/10.1002/glia.20557
Ransom BR, Fern R (1997) Does astrocytic glycogen benefit axon function and survival in CNS white matter during glucose deprivation? Glia 21(1):134–141
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. https://doi.org/10.1016/j.neuroscience.2009.10.028
Rose CR, Chatton JY (2016) Astrocyte sodium signaling and neuro-metabolic coupling in the brain. Neuroscience 323:121–134. https://doi.org/10.1016/j.neuroscience.2015.03.002
MacVicar BA, Choi HB (2017) Astrocytes provide metabolic support for neuronal synaptic function in response to extracellular K+. Neurochem Res 42(9):2588–2594. https://doi.org/10.1007/s11064-017-2315-8
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. https://doi.org/10.1016/j.brainresbull.2017.04.011
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. https://doi.org/10.1007/s11011-014-9588-2
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. https://doi.org/10.1016/j.neuron.2012.08.032
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):1922–1928
Sotelo-Hitschfeld T, Fernandez-Moncada I, Barros LF (2012) Acute feedback control of astrocytic glycolysis by lactate. Glia 60(4):674–680
Sotelo-Hitschfeld T, Niemeyer MI, Machler P et al (2015) Channel-mediated lactate release by K+-stimulated astrocytes. J Neurosci 35(10):4168–4178. https://doi.org/10.1523/JNEUROSCI.5036-14.2015
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. https://doi.org/10.1523/JNEUROSCI.2310-11.2011
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. https://doi.org/10.1177/0271678X17737012
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):593–602
Connors BW, Ransom BR, Kunis DM et al (1982) Activity-dependent K+ accumulation in the developing rat optic nerve. Science 216(4552):1341–1343
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. https://doi.org/10.1002/glia.22299
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 3:427–442
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. https://doi.org/10.1002/glia.23020
Hirase H, Akther S, Wang X et al (2019) Glycogen distribution in mouse hippocampus. J Neurosci Res 97(8):923–932. https://doi.org/10.1002/jnr.24386
Montagne A, Barnes SR, Sweeney MD et al (2015) Blood-brain barrier breakdown in the aging human hippocampus. Neuron 85(2):296–302. https://doi.org/10.1016/j.neuron.2014.12.032
Brown AM (2004) Brain glycogen re-awakened. J Neurochem 89(3):537–552. https://doi.org/10.1111/j.1471-4159.2004.02421.x
Swanson RA, Sagar SM, Sharp FR (1989) Regional brain glycogen stores and metabolism during complete global ischaemia. Neurol Res 11(1):24–28
Sagar SM, Sharp FR, Swanson RA (1987) The regional distribution of glycogen in rat brain fixed by microwave irradiation. Brain Res 417(1):172–174
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):169–172
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. https://doi.org/10.1038/jcbfm.2014.33
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):550–556
Gibbs ME, Anderson DG, Hertz L (2006) Inhibition of glycogenolysis in astrocytes interrupts memory consolidation in young chickens. Glia 54(3):214–222. https://doi.org/10.1002/glia.20377
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. https://doi.org/10.1016/j.brainres.2003.09.044
Rossi DJ, Oshima T, Attwell D (2000) Glutamate release in severe brain ischaemia is mainly by reversed uptake. Nature 403(6767):316–321
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):121–129
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. https://doi.org/10.1007/s11064-012-0938-3
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. https://doi.org/10.1016/j.neuint.2013.08.004
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. https://doi.org/10.1007/s11064-012-0802-5
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. https://doi.org/10.1111/j.1471-4159.2009.05915.x
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. https://doi.org/10.1111/j.1471-4159.2007.04595.x
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. https://doi.org/10.1002/jnr.20335
Hirrlinger J, Nave KA (2014) Adapting brain metabolism to myelination and long-range signal transduction. Glia 62(11):1749–1761. https://doi.org/10.1002/glia.22737
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. https://doi.org/10.1016/j.celrep.2018.02.022
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):401–413
Wilhelm I, Nyúl-Tóth Á, Suciu M et al (2016) Heterogeneity of the blood-brain barrier. Tissue Barriers 4(1):e1143544. https://doi.org/10.1080/21688370.2016.1143544
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. https://doi.org/10.1006/mvre.1999.2188
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. https://doi.org/10.1016/j.neurobiolaging.2011.09.022
Lundgaard I, Osorio MJ, Kress BT et al (2014) White matter astrocytes in health and disease. Neuroscience 276:161–173. https://doi.org/10.1016/j.neuroscience.2013.10.050
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. https://doi.org/10.1152/ajpheart.00774.2015
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):607–615
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):390–400
Daneman R, Prat A (2015) The blood-brain barrier. Cold Spring Harb Perspect Biol 7(1):1–23. https://doi.org/10.1101/cshperspect.a020412
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. https://doi.org/10.1186/s12987-018-0097-2
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. https://doi.org/10.1038/jcbfm.2012.113
Shaw CM, Alvord EC, Berry JR RG (1959) Swelling of the brain following ischemic infarction with arterial occlusion. Arch Neurol 1:161–177
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. https://doi.org/10.1016/j.clineuro.2014.09.012
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):287–293
Stokum JA, Gerzanich V, Simard JM (2016) Molecular pathophysiology of cerebral edema. J Cereb Blood Flow Metab 36(3):513–538. https://doi.org/10.1177/0271678X15617172
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. https://doi.org/10.1186/s40478-015-0239-6
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. https://doi.org/10.1016/j.neuroscience.2010.02.059
Badaut J, Fukuda AM, Jullienne A et al (2014) Aquaporin and brain diseases. Biochim Biophys Acta 1840(5):1554–1565. https://doi.org/10.1016/j.bbagen.2013.10.032
Clément T, Rodriguez-Grande B, Badaut J (2018) Aquaporins in brain edema. J Neurosci Res. https://doi.org/10.1002/jnr.24354
Yang X, Ransom BR, Ma J-F (2016) The role of AQP4 in neuromyelitis optica: more answers, more questions. J Neuroimmunol 298:63–70. https://doi.org/10.1016/j.jneuroim.2016.06.002
Lafrenaye AD, Simard JM (2019) Bursting at the seams: molecular mechanisms mediating astrocyte swelling. Int J Mol Sci 20(2):330. https://doi.org/10.3390/ijms20020330
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):13532–13536
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. https://doi.org/10.1002/glia.22383
Nesic O, Lee J, Unabia GC et al (2008) Aquaporin 1 - a novel player in spinal cord injury. J Neurochem 105(3):628–640. https://doi.org/10.1111/j.1471-4159.2007.05177.x
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. https://doi.org/10.1111/j.1440-1789.2007.00774.x
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. https://doi.org/10.1002/jnr.24061
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. https://doi.org/10.1002/jnr.20819
Cotrina ML, Nedergaard M (2012) Brain connexins in demyelinating diseases: therapeutic potential of glial targets. Brain Res 1487:61–68. https://doi.org/10.1016/j.brainres.2012.07.003
Nagy JI, Rash JE (2000) Connexins and gap junctions of astrocytes and oligodendrocytes in the CNS. Brain Res Rev 32(1):29–44
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. https://doi.org/10.1016/j.bbamem.2011.10.016
Lee SH, Kim WT, Cornell-Bell AH et al (1994) Astrocytes exhibit regional specificity in gap-junction coupling. Glia 11(4):315–325. https://doi.org/10.1002/glia.440110404
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. https://doi.org/10.1093/cercor/bhi101
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):111–119
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):447–468
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):457–475
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):313–319
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. https://doi.org/10.1002/glia.20991
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):766–776
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. https://doi.org/10.1161/01.STR.0000079814.72027.34
Spray DC, Ye Z-C, Ransom BR (2006) Functional connexin “hemichannels”: a critical appraisal. Glia 54(7):758–773. https://doi.org/10.1002/glia.20429
Rose CR, Ransom BR (1997) Gap junctions equalize intracellular Na+ concentration in astrocytes. Glia 20(4):299–307
Kofuji P, Newman EA (2004) Potassium buffering in the central nervous system. Neuroscience 129(4):1045–1056
Bernardinelli Y, Magistretti PJ, Chatton JY (2004) Astrocytes generate Na+-mediated metabolic waves. Proc Natl Acad Sci USA 101(41):14937–14942
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):983–992
Cornell-Bell AH, Thomas PG, Smith SJ (1990) The excitatory neurotransmitter glutamate causes filopodia formation in cultured hippocampal astrocytes. Glia 3(5):322–334
Finkbeiner S (1992) Calcium waves in astrocytes-filling in the gaps. Neuron 8(6):1101–1108
Schipke CG, Boucsein C, Ohlemeyer C et al (2002) Astrocyte Ca2+ waves trigger responses in microglial cells in brain slices. FASEB J 16(2):255–257
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. https://doi.org/10.1002/glia.20649
Rouach N, Koulakoff A, Abudara V et al (2008) Astroglial metabolic networks sustain hippocampal synaptic transmission. Science 322(5907):1551–1555
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):857–869
Giaume C, Tabernero A, Medina JM (1997) Metabolic trafficking through astrocytic gap junctions. Glia 21(1):114–123
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): 187–195
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. https://doi.org/10.1046/j.1471-4159.1994.62020489.x
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):6635–6643
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. https://doi.org/10.1002/glia.21259
Dienel GA (2013) Astrocytic energetics during excitatory neurotransmission: what are contributions of glutamate oxidation and glycolysis? Neurochem Int 63(4):244–258. https://doi.org/10.1016/j.neuint.2013.06.015
Wasseff SK, Scherer SS (2011) Cx32 and Cx47 mediate oligodendrocyte:astrocyte and oligodendrocyte: oligodendrocyte gap junction coupling. Neurobiol Dis 42(3):506–513. https://doi.org/10.1016/j.nbd.2011.03.003
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. https://doi.org/10.1523/JNEUROSCI.0392-12.2012
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. https://doi.org/10.1002/glia.21179
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):2438–2444
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):1857–1863
Wang Y, Liu G, Hong D et al (2016) White matter injury in ischemic stroke. Prog Neurobiol 141:45–60. https://doi.org/10.1016/j.pneurobio.2016.04.005
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):1554–1560
Podgorska A, Hier DB, Pytlewski A et al (2002) Leukoaraiosis and stroke outcome. J Stroke Cerebrovasc Dis 11(6):336–340
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):5621–5626
Matute C (2011) Glutamate and ATP signalling in white matter pathology. J Anat 219(1):53–64. https://doi.org/10.1111/j.1469-7580.2010.01339.x
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):195–202
Rosenzweig S, Carmichael ST (2015) The axon-glia unit in white matter stroke: mechanisms of damage and recovery. Brain Res 1623:123–134. https://doi.org/10.1016/j.brainres.2015.02.019
Iadecola C, Park L, Capone C (2009) Threats to the mind: aging, amyloid, and hypertension. Stroke 40(3 Suppl):S40–S44
O’Sullivan M, Lythgoe DJ, Pereira AC et al (2002) Patterns of cerebral blood flow reduction in patients with ischemic leukoaraiosis. Neurology 59(3):321–326
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. https://doi.org/10.1097/01.WCB.0000091763.61714.B7
Hamner MA, Moller T, Ransom BR (2011) Anaerobic function of CNS white matter declines with age. J Cereb Blood Flow Metab 31(4):996–1002
Tekkok SB, Ransom BR (2004) Anoxia effects on CNS function and survival: regional differences. Neurochem Res 29(11):2163–2169
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):784–791
Foster RE, Connors BW, Waxman SG (1982) Rat optic nerve: electrophysiological, pharmacological and anatomical studies during development. Brain Res 255(3):371–386. https://doi.org/10.1016/0165-3806(82)90005-0
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):335–340
Micu I, Jiang Q, Coderre E et al (2006) NMDA receptors mediate calcium accumulation in myelin during chemical ischaemia. Nature 439(7079):988–992. https://doi.org/10.1038/nature04474
Micu I, Plemel JR, Lachance C et al (2016) The molecular physiology of the axo-myelinic synapse. Exp Neurol 276:41–50. https://doi.org/10.1016/j.expneurol.2015.10.006
Domercq M, Perez-Samartin A, Aparicio D et al (2010) P2 × 7 receptors mediate ischemic damage to oligodendrocytes. Glia 58(6):730–740. https://doi.org/10.1002/glia.20958
Saab AS, Tzvetanova ID, Nave KA (2013) The role of myelin and oligodendrocytes in axonal energy metabolism. Curr Opin Neurobiol 23(6):1065–1072. https://doi.org/10.1016/j.conb.2013.09.008
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. https://doi.org/10.1126/science.aaf6463
Acknowledgements
JH would like to thank Klaus-Armin Nave, Göttingen, for longstanding collaboration and ongoing support.
Funding
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.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Special Issue: In Honor of Professor Juan Bolanos.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Köhler, S., Winkler, U. & Hirrlinger, J. Heterogeneity of Astrocytes in Grey and White Matter. Neurochem Res 46, 3–14 (2021). https://doi.org/10.1007/s11064-019-02926-x
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11064-019-02926-x