Skip to main content
Log in

A review of functional heterogeneity among astrocytes and the CS56-specific antibody-mediated detection of a subpopulation of astrocytes in adult brains

  • Review Article
  • Published:
Anatomical Science International Aims and scope Submit manuscript

Abstract

Astrocytes comprise the largest class of glial cells in the mammalian central nerve system (CNS). Although astrocytes were long considered to be a homogeneous population of neuron-supporting cells, recent decades have seen a shift toward the recognition that astrocytes exhibit morphological and functional heterogeneities and serve as essential modulators of brain functions. However, the mechanism underlying astrocyte diversity remains unclear, and the different subpopulations are difficult to identify due to a lack of specific cell markers. In this review, I discuss current knowledge regarding astrocyte heterogeneity and introduce a subpopulation that can be detected via labeling with a chondroitin sulfate-specific antibody (CS56). These CS56-positive astrocytes were found to selectively express tenascin-R (TNR) in the adult mouse cerebral cortex. Further research demonstrated significantly lower levels of glutamate uptake activity and glutamate aspartate transporter expression in TNR-knockdown astrocytes relative to controls, suggesting that the expression and secretion of Tnr by a subpopulation of astrocytes may contribute to region-specific neuron–astrocyte interactions. In summary, these results suggest that CS56-specific antibody and Tnr could be used as novel markers to detect an astrocyte subpopulation in the adult CNS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

This research was originally published in the Journal of Biological Chemistry by Okuda et al. (2014)

Fig. 2

This research was originally published in the Journal of Biological Chemistry by Okuda et al. (2014)

Fig. 3

This research was originally published in the Journal of Biological Chemistry by Okuda et al. (2014)

Fig. 4

This research was originally published in the Journal of Biological Chemistry by Okuda et al. (2014)

Similar content being viewed by others

References

  • Anderson CM, Swanson RA (2000) Astrocyte glutamate transport: review of properties, regulation, and physiological functions. Glia 32:1–14

    Article  CAS  PubMed  Google Scholar 

  • Araque A, Parpura V, Sanzgiri RP, Haydon PG (1998) Glutamate-dependent astrocyte modulation of synaptic transmission between cultured hippocampal neurons. Eur J Neurosci 10:2129–2142

    Article  CAS  PubMed  Google Scholar 

  • Araque A, Parpura V, Sanzgiri RP, Haydon PG (1999) Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci 22:208–215

    Article  CAS  PubMed  Google Scholar 

  • Aspberg A, Binkert C, Ruoslahti E (1995) The versican C-type lectin domain recognizes the adhesion protein tenascin-R. Proc Natl Acad Sci USA 92:10590–10594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aspberg A, Miura R, Bourdoulous S, Shimonaka M, Heinegârd D, Schachner M, Ruoslahti E, Yamaguchi Y (1997) The C-type lectin domains of lecticans, a family of aggregating chondroitin sulfate proteoglycans, bind tenascin-R by protein-protein interactions independent of carbohydrate moiety. Proc Natl Acad Sci USA 94:10116–10121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bezzi P, Carmignoto G, Pasti L, Vesce S, Rossi D, Rizzini BL, Pozzan T, Volterra A (1998) Prostaglandins stimulate calcium-dependent glutamate release in astrocytes. Nature 391:281–285

    Article  CAS  PubMed  Google Scholar 

  • Bowman CL, Kimelberg HK (1984) Excitatory amino acids directly depolarize rat brain astrocytes in primary culture. Nature 311:656–659

    Article  CAS  PubMed  Google Scholar 

  • Brenneke F, Bukalo O, Dityatev A, Lie A (2004) Mice deficient for the extracellular matrix glycoprotein tenascin-r show physiological and structural hallmarks of increased hippocampal excitability, but no increased susceptibility to seizures in the pilocarpine model of epilepsy. Neuroscience 124:841–855

    Article  CAS  PubMed  Google Scholar 

  • Brückner G, Grosche J, Schmidt S, Härtig W, Margolis RU, Delpech B, Seidenbecher CI, Czaniera R, Schachner M (2000) Postnatal development of perineuronal nets in wild-type mice and in a mutant deficient in tenascin-R. J Comp Neurol 428:616–629

    Article  PubMed  Google Scholar 

  • Bukalo O, Schachner M, Dityatev A (2001) Modification of extracellular matrix by enzymatic removal of chondroitin sulfate and by lack of tenascin-R differentially affects several forms of synaptic plasticity in the hippocampus. Neuroscience 104:359–369

    Article  CAS  PubMed  Google Scholar 

  • Chiquet-Ehrismann R (1995) Tenascins, a growing family of extracellular matrix proteins. Experientia 51:853–862

    Article  CAS  PubMed  Google Scholar 

  • Chiquet-Ehrismann R, Hagios C, Matsumoto K (1994) The tenascin gene family. Perspect Dev Neurobiol 2:3–7

    CAS  PubMed  Google Scholar 

  • Coco S, Calegari F, Pravettoni E, Pozzi D, Taverna E, Rosa P, Matteoli M, Verderio C (2003) Storage and release of ATP from astrocytes in culture. J Biol Chem 278:1354–1362

    Article  CAS  PubMed  Google Scholar 

  • Cornell-Bell AH, Finkbeiner SM, Cooper MS, Smith SJ (1990) Glutamate induces calcium waves in cultured astrocytes: long-range glial signaling. Science 247:470–473

    Article  CAS  PubMed  Google Scholar 

  • Coulter DA, Eid T (2012) Astrocytic regulation of glutamate homeostasis in epilepsy. Glia 60:1215–1226

    Article  PubMed  PubMed Central  Google Scholar 

  • Deneen B, Ho R, Lukaszewicz A, Hochstim CJ, Gronostajski RM, Anderson DJ (2006) The transcription factor NFIA controls the onset of gliogenesis in the developing spinal cord. Neuron 52:953–968

    Article  CAS  PubMed  Google Scholar 

  • Djukic B, Casper KB, Philpot BD, Chin LS, McCarthy KD (2007) Conditional knock-out of Kir4.1 leads to glial membrane depolarization, inhibition of potassium and glutamate uptake, and enhanced short-term synaptic potentiation. J Neurosci 27:11354–11365

    Article  CAS  PubMed  Google Scholar 

  • Furuta A, Rothstein JD, Martin LJ (1997) Glutamate transporter protein subtypes are expressed differentially during rat CNS development. J Neurosci 17:8363–8375

    CAS  PubMed  Google Scholar 

  • Golgi C (1871) Contribuzione alla fina Anatomia degli organi centrali del sistema nervosos. Rivista clinica di Bologna, Bologna

    Google Scholar 

  • Golgi C (1885) Sulla fina anatomia degli organi centrali del sistema nervoso. Riv Sper Fremiat Med Leg Alienazione Ment 11:72–123

    Google Scholar 

  • Gurevicius K, Gureviciene I, Valjakka A, Schachner M, Tanila H (2004) Enhanced cortical and hippocampal neuronal excitability in mice deficient in the extracellular matrix glycoprotein tenascin-R. Mol Cell Neurosci 25:515–523

    Article  CAS  PubMed  Google Scholar 

  • Hagihara K, Miura R, Kosaki R, Berglund E, Ranscht B, Yamaguchi Y (1999) Immunohistochemical evidence for the brevican-tenascin-R interaction: colocalization in perineuronal nets suggests a physiological role for the interaction in the adult rat brain. J Comp Neurol 410:256–264

    Article  CAS  PubMed  Google Scholar 

  • Halassa MM, Florian C, Fellin T, Munoz JR, Lee SY, Abel T, Haydon PG, Frank MG (2009) Astrocytic modulation of sleep homeostasis and cognitive consequences of sleep loss. Neuron 61:213–219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haunsø A, Ibrahim M, Bartsch U, Letiembre M, Celio M, Menoud P (2000) Morphology of perineuronal nets in tenascin-R and parvalbumin single and double knockout mice. Brain Res 864:142–145

    Article  PubMed  Google Scholar 

  • Hayashi N, Tatsumi K, Okuda H, Yoshikawa M, Ishizaka S, Miyata S, Manabe T, Wanaka A (2007) DACS, novel matrix structure composed of chondroitin sulfate proteoglycan in the brain. Biochem Biophys Res Commun 364:410–415

    Article  CAS  PubMed  Google Scholar 

  • Henneberger C, Papouin T, Oliet SH, Rusakov DA (2010) Long-term potentiation depends on release of d-serine from astrocytes. Nature 463:232–236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hochstim C, Deneen B, Lukaszewicz A, Zhou Q, Anderson DJ (2008) Identification of positionally distinct astrocyte subtypes whose identities are specified by a homeodomain code. Cell 133:510–522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Höft S, Griemsmann S, Seifert G, Steinhäuser C (2014) Heterogeneity in expression of functional ionotropic glutamate and GABA receptors in astrocytes across brain regions: insights from the thalamus. Philos Trans R Soc Lond B Biol Sci 369:20130602

    Article  PubMed  PubMed Central  Google Scholar 

  • Horii-Hayashi N, Tatsumi K, Matsusue Y, Okuda H, Okuda A, Hayashi M, Yano H, Tsuboi A, Nishi M, Yoshikawa M, Wanaka A (2010) Chondroitin sulfate demarcates astrocytic territories in the mammalian cerebral cortex. Neurosci Lett 483:67–72

    Article  CAS  PubMed  Google Scholar 

  • Jourdain P, Bergersen LH, Bhaukaurally K, Bezzi P, Santello M, Domercq M, Matute C, Tonello F, Gundersen V, Volterra A (2007) Glutamate exocytosis from astrocytes controls synaptic strength. Nat Neurosci 10:331–339

    Article  CAS  PubMed  Google Scholar 

  • Kang P, Lee HK, Glasgow SM, Finley M, Donti T, Gaber ZB, Graham BH, Foster AE, Novitch BG, Gronostajski RM, Deneen B (2012) Sox9 and NFIA coordinate a transcriptional regulatory cascade during the initiation of gliogenesis. Neuron 74:79–94

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kettenmann H, Backus KH, Schachner M (1984) Aspartate, glutamate and gamma-aminobutyric acid depolarize cultured astrocytes. Neurosci Lett 52:25–29

    Article  CAS  PubMed  Google Scholar 

  • Köppe G, Brückner G, Brauer K, Härtig W, Bigl V (1997) Developmental patterns of proteoglycan-containing extracellular matrix in perineuronal nets and neuropil of the postnatal rat brain. Cell Tissue Res 288:33–41

    Article  PubMed  Google Scholar 

  • Krencik R, Weick JP, Liu Y, Zhang ZJ, Zhang SC (2011) Specification of transplantable astroglial subtypes from human pluripotent stem cells. Nat Biotechnol 29:528–534

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kucukdereli H, Allen NJ, Lee AT, Feng A, Ozlu MI, Conatser LM, Chakraborty C, Workman G, Weaver M, Sage EH, Barres BA, Eroglu C (2011) Control of excitatory CNS synaptogenesis by astrocyte-secreted proteins Hevin and SPARC. Proc Natl Acad Sci USA 108:E440–449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lenhossek M (1895) Der Feinere Bau des Nervenssystems im Lichte neuerer Forschung. Gustav Fischer Verlag, Jena

  • Molofsky AV, Kelley KW, Tsai HH, Redmond SA, Chang SM, Madireddy L, Chan JR, Baranzini SE, Ullian EM, Rowitch DH (2014) Astrocyte-encoded positional cues maintain sensorimotor circuit integrity. Nature 509:189–194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morellini F, Sivukhina E, Stoenica L, Oulianova E, Bukalo O, Jakovcevski I, Dityatev A, Irintchev A, Schachner M (2010) Improved reversal learning and working memory and enhanced reactivity to novelty in mice with enhanced GABAergic innervation in the dentate gyrus. Cereb Cortex 20:2712–2727

    Article  PubMed  Google Scholar 

  • Morris NP, Henderson Z (2000) Perineuronal nets ensheath fast spiking, parvalbumin-immunoreactive neurons in the medial septum/diagonal band complex. Eur J Neurosci 12:828–838

    Article  CAS  PubMed  Google Scholar 

  • Muroyama Y, Fujiwara Y, Orkin SH, Rowitch DH (2005) Specification of astrocytes by bHLH protein SCL in a restricted region of the neural tube. Nature 438:360–363

    Article  CAS  PubMed  Google Scholar 

  • Newman EA, Zahs KR (1998) Modulation of neuronal activity by glial cells in the retina. J Neurosci 18:4022–4028

    CAS  PubMed  PubMed Central  Google Scholar 

  • Okuda H, Tatsumi K, Morita S, Shibukawa Y, Korekane H, Horii-Hayashi N, Wada Y, Taniguchi N, Wanaka A (2014) Chondroitin sulfate proteoglycan tenascin-R regulates glutamate uptake by adult brain astrocytes. J Biol Chem 289:2620–2631

    Article  CAS  PubMed  Google Scholar 

  • Oliet SH, Piet R, Poulain DA (2001) Control of glutamate clearance and synaptic efficacy by glial coverage of neurons. Science 292:923–926

    Article  CAS  PubMed  Google Scholar 

  • Olsen ML, Campbell SL, Sontheimer H (2007) Differential distribution of Kir4.1 in spinal cord astrocytes suggests regional differences in K+ homeostasis. J Neurophysiol 98:786–793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Parpura V, Basarsky TA, Liu F, Jeftinija K, Jeftinija S, Haydon PG (1994) Glutamate-mediated astrocyte-neuron signalling. Nature 369:744–747

    Article  CAS  PubMed  Google Scholar 

  • Pasti L, Zonta M, Pozzan T, Vicini S, Carmignoto G (2001) Cytosolic calcium oscillations in astrocytes may regulate exocytotic release of glutamate. J Neurosci 21:477–484

    CAS  PubMed  Google Scholar 

  • Pfrieger FW (2010) Role of glial cells in the formation and maintenance of synapses. Brain Res Rev 63:39–46

    Article  CAS  PubMed  Google Scholar 

  • Poopalasundaram S, Knott C, Shamotienko OG, Foran PG, Dolly JO, Ghiani CA, Gallo V, Wilkin GP (2000) Glial heterogeneity in expression of the inwardly rectifying K(+) channel, Kir4.1, in adult rat CNS. Glia 30:362–372

    Article  CAS  PubMed  Google Scholar 

  • Probstmeier R, Braunewell K, Pesheva P (2000) Involvement of chondroitin sulfates on brain-derived tenascin-R in carbohydrate-dependent interactions with fibronectin and tenascin-C. Brain Res 863:42–51

    Article  CAS  PubMed  Google Scholar 

  • Queiroz G, Gebicke-Haerter PJ, Schobert A, Starke K, von Kügelgen I (1997) Release of ATP from cultured rat astrocytes elicited by glutamate receptor activation. Neuroscience 78:1203–1208

    Article  CAS  PubMed  Google Scholar 

  • Ramón y Cajal S (1909) Histologie du système nerveux de l’homme et des vertébrés. Maloine Publisher, Paris

  • Ramón y Cajal S (1913) Contribución al conocimiento de la neuroglia del cerebro humano. Trab Lab Invest Biol Univ Madrid 11:255–315

    Google Scholar 

  • Regan MR, Huang YH, Kim YS, Dykes-Hoberg MI, Jin L, Watkins AM, Bergles DE, Rothstein JD (2007) Variations in promoter activity reveal a differential expression and physiology of glutamate transporters by glia in the developing and mature CNS. J Neurosci 27:6607–6619

    Article  CAS  PubMed  Google Scholar 

  • Rothstein JD, Dykes-Hoberg M, Pardo CA, Bristol LA, Jin L, Kuncl RW, Kanai Y, Hediger MA, Wang Y, Schielke JP, Welty DF (1996) Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 16:675–686

    Article  CAS  PubMed  Google Scholar 

  • Schell MJ, Molliver ME, Snyder SH (1995) D-serine, an endogenous synaptic modulator: localization to astrocytes and glutamate-stimulated release. Proc Natl Acad Sci USA 92:3948–3952

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Simard M, Arcuino G, Takano T, Liu QS, Nedergaard M (2003) Signaling at the gliovascular interface. J Neurosci 23:9254–9262

    CAS  PubMed  Google Scholar 

  • Stolt CC, Lommes P, Sock E, Chaboissier MC, Schedl A, Wegner M (2003) The Sox9 transcription factor determines glial fate choice in the developing spinal cord. Genes Dev 17:1677–1689

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sugimori M, Nagao M, Bertrand N, Parras CM, Guillemot F, Nakafuku M (2007) Combinatorial actions of patterning and HLH transcription factors in the spatiotemporal control of neurogenesis and gliogenesis in the developing spinal cord. Development 134:1617–1629

    Article  CAS  PubMed  Google Scholar 

  • Takano T, Tian GF, Peng W, Lou N, Libionka W, Han X, Nedergaard M (2006) Astrocyte-mediated control of cerebral blood flow. Nat Neurosci 9:260–267

    Article  CAS  PubMed  Google Scholar 

  • Tanaka K, Watase K, Manabe T, Yamada K, Watanabe M, Takahashi K, Iwama H, Nishikawa T, Ichihara N, Kikuchi T, Okuyama S, Kawashima N, Hori S, Takimoto M, Wada K (1997) Epilepsy and exacerbation of brain injury in mice lacking glutamate transporter GLT-1. Science 276:1699–1702

    Article  CAS  PubMed  Google Scholar 

  • Tello F (1911) La influencia del neurotropismo en la regeneracion de los centros nerviosos. Trab Lab Invest Univ Madrid 9:123–159

    Google Scholar 

  • Tsai HH, Li H, Fuentealba LC, Molofsky AV, Taveira-Marques R, Zhuang H, Tenney A, Murnen AT, Fancy SP, Merkle F, Kessaris N, Alvarez-Buylla A, Richardson WD, Rowitch DH (2012) Regional astrocyte allocation regulates CNS synaptogenesis and repair. Science 337:358–362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ulloa F, Briscoe J (2007) Morphogens and the control of cell proliferation and patterning in the spinal cord. Cell Cycle 6:2640–2649

    Article  CAS  PubMed  Google Scholar 

  • Uwechue NM, Marx MC, Chevy Q, Billups B (2012) Activation of glutamate transport evokes rapid glutamine release from perisynaptic astrocytes. J Physiol 590:2317–2331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Verkhratsky A, Kirchhoff F (2007) Glutamate-mediated neuronal-glial transmission. J Anat 210:651–660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Viggiano D (2000) The two faces of perineuronal nets. NeuroReport 11:2087–2090

    Article  CAS  PubMed  Google Scholar 

  • Virchow R (1846) Über das granulierte Aussehen der Wandungen des Gehirnvenrtikels. Zeitschrift für Psychiatrie, book 2

  • Virchow R (1856) Gesammelte Abhandlungen zur wissenschaftlichen Medizin. Meidinger Sohn and Co, Frankfurt

    Google Scholar 

  • Wang LP, Cheung G, Kronenberg G, Gertz K, Ji S, Kempermann G, Endres M, Kettenmann H (2008) Mild brain ischemia induces unique physiological properties in striatal astrocytes. Glia 56:925–934

    Article  PubMed  Google Scholar 

  • Watase K, Hashimoto K, Kano M, Yamada K, Watanabe M, Inoue Y, Okuyama S, Sakagawa T, Ogawa S, Kawashima N, Hori S, Takimoto M, Wada K, Tanaka K (1998) Motor discoordination and increased susceptibility to cerebellar injury in GLAST mutant mice. Eur J Neurosci 10:976–988

    Article  CAS  PubMed  Google Scholar 

  • Weber P, Bartsch U, Rasband MN, Czaniera R, Lang Y, Bluethmann H, Margolis RU, Levinson SR, Shrager P, Montag D, Schachner M (1999) Mice deficient for tenascin-R display alterations of the extracellular matrix and decreased axonal conduction velocities in the CNS. J Neurosci 19:4245–4262

    CAS  PubMed  Google Scholar 

  • Wintergerst E, Rathjen F, Schwaller B, Eggli P, Celio M (2001) Tenascin-R associates extracellularly with parvalbumin immunoreactive neurones but is synthesised by another neuronal population in the adult rat cerebral cortex. J Neurocytol 30:293–301

    Article  CAS  PubMed  Google Scholar 

  • Woodworth A, Pesheva P, Fiete D, Baenziger JU (2004) Neuronal-specific synthesis and glycosylation of tenascin-R. J Biol Chem 279:10413–10421

    Article  CAS  PubMed  Google Scholar 

  • Wu Y, La Pierre D, Wu J, Yee A, Yang B (2005) The interaction of versican with its binding partners. Cell Res 15:483–494

    Article  CAS  PubMed  Google Scholar 

  • Xiao ZC, Bartsch U, Margolis RK, Rougon G, Montag D, Schachner M (1997) Isolation of a tenascin-R binding protein from mouse brain membranes. A phosphacan-related chondroitin sulfate proteoglycan. J Biol Chem 272:32092–32101

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The author is grateful to Prof. Akio Wanaka, Dr. Kouko Tatsumi, and Dr. Noriko Horii-Hayashi of Nara Medical University for their kind contributions to this study and mentorship. This work was supported by the Japan Society for the Promotion of Science (Grant Numbers 24592141 to H.O.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hiroaki Okuda.

Ethics declarations

Conflict of interest

The author declares that there are no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Okuda, H. A review of functional heterogeneity among astrocytes and the CS56-specific antibody-mediated detection of a subpopulation of astrocytes in adult brains. Anat Sci Int 93, 161–168 (2018). https://doi.org/10.1007/s12565-017-0420-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12565-017-0420-z

Keywords

Navigation