1932

Abstract

Astrocytes are morphologically complex, ubiquitous cells that are viewed as a homogeneous population tiling the entire central nervous system (CNS). However, this view has been challenged in the last few years with the availability of RNA sequencing, immunohistochemistry, electron microscopy, morphological reconstruction, and imaging data. These studies suggest that astrocytes represent a diverse population of cells and that they display brain area– and disease–specific properties and functions. In this review, we summarize these observations, emphasize areas where clear conclusions can be made, and discuss potential unifying themes. We also identify knowledge gaps that need to be addressed in order to exploit astrocyte diversity as a biological phenomenon of physiological relevance in the CNS. We thus provide a summary and a perspective on astrocyte diversity in the vertebrate CNS.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-neuro-070918-050443
2019-07-08
2024-12-07
Loading full text...

Full text loading...

/deliver/fulltext/neuro/42/1/annurev-neuro-070918-050443.html?itemId=/content/journals/10.1146/annurev-neuro-070918-050443&mimeType=html&fmt=ahah

Literature Cited

  1. Adamsky A, Kol A, Kreisel T, Doron A, Ozeri-Engelhard N et al. 2018. Astrocytic activation generates de novo neuronal potentiation and memory enhancement. Cell 174:59–71
    [Google Scholar]
  2. Agarwal A, Wu PH, Hughes EG, Fukaya M, Tischfield MA et al. 2017. Transient opening of the mitochondrial permeability transition pore induces microdomain calcium transients in astrocyte processes. Neuron 93:587–605
    [Google Scholar]
  3. Allen NJ. 2014. Astrocyte regulation of synaptic behavior. Annu. Rev. Cell Dev. Biol. 30:439–63
    [Google Scholar]
  4. Allen NJ, Barres BA. 2009. Glia—more than just brain glue. Nature 457:675–77
    [Google Scholar]
  5. Araque A, Carmignoto G, Haydon PG, Oliet SH, Robitaille R, Volterra A 2014. Gliotransmitters travel in time and space. Neuron 81:728–39
    [Google Scholar]
  6. Attwell D, Buchan AM, Charpak S, Lauritzen M, Macvicar BA, Newman EA 2010. Glial and neuronal control of brain blood flow. Nature 468:232–43
    [Google Scholar]
  7. Barres BA. 2008. The mystery and magic of glia: a perspective on their roles in health and disease. Neuron 60:430–40
    [Google Scholar]
  8. Bazargani N, Attwell D. 2016. Astrocyte calcium signalling: the third wave. Nat. Neurosci. 19:182–89
    [Google Scholar]
  9. Benediktsson AM, Schachtele SJ, Green SH, Dailey ME 2005. Ballistic labeling and dynamic imaging of astrocytes in organotypic hippocampal slice cultures. J. Neurosci. Methods 141:41–53
    [Google Scholar]
  10. Bernardinelli Y, Randall J, Janett E, Nikonenko I, König S et al. 2014. Activity-dependent structural plasticity of perisynaptic astrocytic domains promotes excitatory synapse stability. Curr. Biol. 24:1679–88
    [Google Scholar]
  11. Betzig E. 2015. Single molecules, cells, and super-resolution optics. Angew. Chem. Int. Ed. 54:8034–53
    [Google Scholar]
  12. Bindocci E, Savtchouk I, Liaudet N, Becker D, Carriero G, Volterra A 2017. Three-dimensional Ca2+ imaging advances understanding of astrocyte biology. Science 356:6339eaai8185
    [Google Scholar]
  13. Boisvert MM, Erikson GA, Shokhirev MN, Allen NJ 2018. The aging astrocyte transcriptome from multiple regions of the mouse brain. Cell Rep 22:269–85
    [Google Scholar]
  14. Borges S, Berry M. 1978. The effects of dark rearing on the development of the visual cortex of the rat. J. Comp. Neurol. 180:277–300
    [Google Scholar]
  15. Burda JE, Sofroniew MV. 2014. Reactive gliosis and the multicellular response to CNS damage and disease. Neuron 81:229–48
    [Google Scholar]
  16. Bushong EA, Martone ME, Jones YZ, Ellisman MH 2002. Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains. J. Neurosci. 22:183–92
    [Google Scholar]
  17. Chaboub LS, Deneen B. 2012. Developmental origins of astrocyte heterogeneity: the final frontier of CNS development. Dev. Neurosci. 34:379–88
    [Google Scholar]
  18. Chaboub LS, Deneen B. 2013. Astrocyte form and function in the developing CNS. Semin. Pediatr. Neurol. 20:230–35
    [Google Scholar]
  19. Chaboub LS, Manalo JM, Lee HK, Glasgow SM, Chen F et al. 2016. Temporal profiling of astrocyte precursors reveals parallel roles for Asef during development and after injury. J. Neurosci. 36:11904–17
    [Google Scholar]
  20. Chai H, Diaz-Castro B, Shigetomi E, Monte E, Octeau JC et al. 2017. Neural circuit-specialized astrocytes: transcriptomic, proteomic, morphological, and functional evidence. Neuron 95:531–49.e9
    [Google Scholar]
  21. Charles AC, Merrill JE, Dirksen ER, Sanderson MJ 1991. Intercellular signaling in glial cells: calcium waves and oscillations in response to mechanical stimulation and glutamate. Neuron 6:983–92
    [Google Scholar]
  22. Chen F, Tillberg PW, Boyden ES 2015. Expansion microscopy. Science 347:543–48
    [Google Scholar]
  23. Clapham DE. 2007. Calcium signaling. Cell 131:1047–58
    [Google Scholar]
  24. Clarke LE, Barres BA. 2013. Emerging roles of astrocytes in neural circuit development. Nat. Rev. Neurosci. 14:311–21
    [Google Scholar]
  25. Clarke LE, Liddelow SA, Chakraborty C, Münch AE, Heiman M, Barres BA 2018. Normal aging induces A1-like astrocyte reactivity. PNAS 115:E1896–905
    [Google Scholar]
  26. Cornell-Bell AH, Finkbeiner SM, Cooper MS, Smith SJ 1990. Glutamate induces calcium waves in cultured astrocytes: long-range glial signaling. Science 247:470–73
    [Google Scholar]
  27. DeFelipe J. 2010. Cajal's Butterflies of the Soul: Science and Art New York: Oxford Univ. Press
    [Google Scholar]
  28. Di Castro MA, Chuquet J, Liaudet N, Bhaukaurally K, Santello M et al. 2011. Local Ca2+ detection and modulation of synaptic release by astrocytes. Nat. Neurosci. 10:1276–84
    [Google Scholar]
  29. Ding F, O'Donnell J, Thrane AS, Zeppenfeld D, Kang H et al. 2013. α1-Adrenergic receptors mediate coordinated Ca2+ signaling of cortical astrocytes in awake, behaving mice. Cell Calcium 54:387–94
    [Google Scholar]
  30. Distler C, Weigel H, Hoffmann K-P 1993. Glia cells of the monkey retina. I. Astrocytes. J. Comp. Neurol. 333:134–47
    [Google Scholar]
  31. Dunn KM, Hill-Eubanks DC, Liedtke WB, Nelson MT 2013. TRPV4 channels stimulate Ca2+-induced Ca2+ release in astrocytic endfeet and amplify neurovascular coupling responses. PNAS 110:6157–62
    [Google Scholar]
  32. Eroglu C, Barres BA. 2010. Regulation of synaptic connectivity by glia. Nature 468:223–31
    [Google Scholar]
  33. Farmer WT, Abrahamsson T, Chierzi S, Lui C, Zaelzer C et al. 2016. Neurons diversify astrocytes in the adult brain through sonic hedgehog signaling. Science 351:849–54
    [Google Scholar]
  34. Fiacco TA, Agulhon C, McCarthy KD 2009. Sorting out astrocyte physiology from pharmacology. Annu. Rev. Pharmacol. Toxicol. 49:151–74
    [Google Scholar]
  35. Fiacco TA, McCarthy KD. 2018. Multiple lines of evidence indicate that gliotransmission does not occur under physiological conditions. J. Neurosci. 38:3–13
    [Google Scholar]
  36. Filosa JA, Bonev AD, Straub SV, Meredith AL, Wilkerson MK et al. 2006. Local potassium signaling couples neuronal activity to vasodilation in the brain. Nat. Neurosci. 9:1397–403
    [Google Scholar]
  37. García-Marqués J, López-Mascaraque L. 2017. Clonal mapping of astrocytes in the olfactory bulb and rostral migratory stream. Cereb. Cortex 27:2195–209
    [Google Scholar]
  38. Ge W-P, Miyawaki A, Gage FH, Jan YN, Jan LY 2012. Local generation of glia is a major astrocyte source in postnatal cortex. Nature 484:376–80
    [Google Scholar]
  39. Genoud C, Quairiaux C, Steiner P, Hirling H, Welker E, Knott GW 2006. Plasticity of astrocytic coverage and glutamate transporter expression in adult mouse cortex. PLOS Biol 4:e343
    [Google Scholar]
  40. Gokce O, Stanley G, Treutlein B, Neff NF, Camp GJ et al. 2016. Cellular taxonomy of the mouse striatum as revealed by single-cell RNA-Seq. Cell Rep 16:1126–37
    [Google Scholar]
  41. Grillner S, Graybiel AM, eds. 2006. Microcircuits: The Interface Between Neurons and Global Brain Function Cambridge, MA: MIT Press
    [Google Scholar]
  42. Haim LB, Rowitch DH. 2017. Functional diversity of astrocytes in neural circuit regulation. Nat. Rev. Neurosci. 18:31–41
    [Google Scholar]
  43. Hama K, Arii T, Katayama E, Marton M, Ellisman MH 2004. Tri-dimensional morphometric analysis of astrocytic processes with high voltage electron microscopy of thick Golgi preparations. J. Neurocytol. 33:277–85
    [Google Scholar]
  44. Haustein MD, Kracun S, Lu X-H, Shih T, Jackson-Weaver O et al. 2014. Conditions and constraints for astrocyte calcium signaling in the hippocampal mossy fiber pathway. Neuron 82:413–29
    [Google Scholar]
  45. Henneberger C, Rusakov DA. 2012. Monitoring local synaptic activity with astrocytic patch pipettes. Nat. Protoc. 7:2171–79
    [Google Scholar]
  46. Hochstim C, Deneen B, Lukaszewicz A, Zhou Q, Anderson DJ 2008. The spinal cord contains positionally distinct astrocyte subtypes whose identities are specified by a homeodomain transcriptional code. Cell 133:510–22
    [Google Scholar]
  47. Jessell TM. 2000. Neuronal specification in the spinal cord: inductive signals and transcriptional codes. Nat. Rev. Genet. 1:20–29
    [Google Scholar]
  48. Jiang R, Diaz-Castro B, Tong X, Looger LL, Khakh BS 2016. Dysfunctional calcium and glutamate signaling in striatal astrocytes from Huntington's disease model mice. J. Neurosci. 36:3453–70
    [Google Scholar]
  49. Kanemaru K, Sekiya H, Xu M, Satoh K, Kitajima N et al. 2014. In vivo visualization of subtle, transient, and local activity of astrocytes using an ultrasensitive Ca2+ indicator. Cell Rep 8:311–18
    [Google Scholar]
  50. Kasthuri N, Hayworth KJ, Berger DR, Schalek RL, Conchello JA et al. 2015. Saturated reconstruction of a volume of neocortex. Cell 162:648–61
    [Google Scholar]
  51. Kelley KW, Ben Haim L, Schirmer L, Tyzack GE, Tolman M et al. 2018a. Kir4.1-dependent astrocyte-fast motor neuron interactions are required for peak strength. Neuron 98:306–19.e7
    [Google Scholar]
  52. Kelley KW, Nakao-Inoue H, Molofsky AV, Oldham MC 2018b. Variation among intact tissue samples reveals the core transcriptional features of human CNS cell classes. Nat. Neurosci. 21:1171–84
    [Google Scholar]
  53. Kepecs A, Fishell G. 2014. Interneuron cell types are fit to function. Nature 505:318–26
    [Google Scholar]
  54. Khakh BS, McCarthy KD. 2015. Astrocyte calcium signaling: from observations to functions and the challenges therein. Cold Spring Harb. Perspect. Biol. 7:4a020404
    [Google Scholar]
  55. Khakh BS, Sofroniew MV. 2015. Diversity of astrocyte functions and phenotypes in neural circuits. Nat. Neurosci. 18:942–52
    [Google Scholar]
  56. Kosaka T, Hama K. 1986. Three-dimensional structure of astrocytes in the rat dentate gyrus. J. Comp. Neurol. 249:242–60
    [Google Scholar]
  57. Lakowicz JR. 2006. Principles of Fluorescence Spectroscopy New York: Springer. , 3rd ed..
    [Google Scholar]
  58. Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ et al. 2017. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541:481–87
    [Google Scholar]
  59. Lin C-CJ, Yu K, Hatcher A, Huang T-W, Lee HK et al. 2017. Identification of diverse astrocyte populations and their malignant analogs. Nat. Neurosci. 20:396–405
    [Google Scholar]
  60. Livet J, Weissman TA, Kang H, Draft RW, Lu J et al. 2007. Transgenic strategies for combinatorial expression of fluorescent proteins in the nervous system. Nature 450:56–62
    [Google Scholar]
  61. López‐Hidalgo M, Hoover WB, Schummers J 2016. Spatial organization of astrocytes in ferret visual cortex. J. Comp. Neurol. 524:3561–76
    [Google Scholar]
  62. Ma Z, Stork T, Bergles DE, Freeman MR 2016. Neuromodulators signal through astrocytes to alter neural circuit activity and behaviour. Nature 539:428–32
    [Google Scholar]
  63. Mehina EMF, Murphy-Royal C, Gordon GR 2017. Steady-state free Ca2+ in astrocytes is decreased by experience and impacts arteriole tone. J. Neurosci. 37:8150–65
    [Google Scholar]
  64. Molofsky AV, Glasgow SM, Chaboub LS, Tsai H-H, Murnen AT et al. 2013. Expression profiling of Aldh1l1-precursors in the developing spinal cord reveals glial lineage-specific genes and direct Sox9-Nfe2l1 interactions. Glia 61:1518–32
    [Google Scholar]
  65. Molofsky AV, Kelley KW, Tsai HH, Redmond SA, Chang SM et al. 2014. Astrocyte-encoded positional cues maintain sensorimotor circuit integrity. Nature 509:7499189–94
    [Google Scholar]
  66. Molofsky AV, Krenick R, Ullian E, Tsai H-H, Deneen B et al. 2012. Astrocytes and disease: a neurodevelopmental perspective. Genes Dev 26:891–907
    [Google Scholar]
  67. Molotkov D, Zobova S, Arcas JM, Khiroug L 2013. Calcium-induced outgrowth of astrocytic peripheral processes requires actin binding by Profilin-1. Cell Calcium 53:338–48
    [Google Scholar]
  68. Morel L, Chiang MSR, Higashimori H, Shoneye T, Iyer LK et al. 2017. Molecular and functional properties of regional astrocytes in the adult brain. J. Neurosci. 37:8706–17
    [Google Scholar]
  69. Müller CM. 1990. Dark-rearing retards the maturation of astrocytes in restricted layers of cat visual cortex. Glia 3:487–94
    [Google Scholar]
  70. Nimmerjahn A, Mukamel EA, Schnitzer MJ 2009. Motor behavior activates Bergmann glial networks. Neuron 62:400–12
    [Google Scholar]
  71. Oberheim NA, Goldman SA, Nedergaard M 2012. Heterogeneity of astrocytic form and function. Methods Mol. Biol. 814:23–45
    [Google Scholar]
  72. Oberheim NA, Takano T, Han X, He W, Lin JHC et al. 2009. Uniquely hominid features of adult human astrocytes. J. Neurosci. 29:3276–87
    [Google Scholar]
  73. Octeau JC, Chai H, Jiang R, Bonanno SL, Martin KC, Khakh BS 2018. An optical neuron-astrocyte proximity assay at synaptic distance scales. Neuron 98:49–66
    [Google Scholar]
  74. Otsu Y, Couchman K, Lyons DG, Collot M, Agarwal A et al. 2015. Calcium dynamics in astrocyte processes during neurovascular coupling. Nat. Neurosci. 18:210–18
    [Google Scholar]
  75. Panatier A, Vallée J, Haber M, Murai KK, Lacaille JC, Robitaille R 2011. Astrocytes are endogenous regulators of basal transmission at central synapses. Cell 146:785–98
    [Google Scholar]
  76. Pannasch U, Freche D, Dallérac G, Ghézali G, Escartin C et al. 2014. Connexin 30 sets synaptic strength by controlling astroglial synapse invasion. Nat. Neurosci. 17:549–58
    [Google Scholar]
  77. Paukert M, Agarwal A, Jaepyeong C, Doze VA, Kang JU, Bergles DW 2014. Norepinephrine controls astroglial responsiveness to local circuit activity. Neuron 82:1263–70
    [Google Scholar]
  78. Perez-Alvarez A, Navarrete M, Covelo A, Martin ED, Araque A 2014. Structural and functional plasticity of astrocyte processes and dendritic spine interactions. J. Neurosci. 34:12738–44
    [Google Scholar]
  79. Porter JT, McCarthy KD. 1997. Astrocytic neurotransmitter receptors in situ and in vivo. Prog. Neurobiol. 51:439–55
    [Google Scholar]
  80. Poskanzer KE, Yuste R. 2011. Astrocytic regulation of cortical UP states. PNAS 108:18453–58
    [Google Scholar]
  81. Poskanzer KE, Yuste R. 2016. Astrocytes regulate cortical state switching in vivo. PNAS 113:E2675–84
    [Google Scholar]
  82. Robillard KN, Lee KM, Chiu KB, MacLean AG 2016. Glial cell morphological and density changes through the lifespan of rhesus macaques. Brain Behav. Immun. 55:60–69
    [Google Scholar]
  83. Rosenegger DG, Tran CHT, Wamsteeker Cusulin JI, Gordon GR 2015. Tonic local brain blood flow control by astrocytes independent of phasic neurovascular coupling. J. Neurosci. 35:13463–74
    [Google Scholar]
  84. Roth BL. 2016. DREADDs for neuroscientists. Neuron 89:683–94
    [Google Scholar]
  85. Sakmann B, Neher E, eds. 1995. Single-Channel Recording New York: Springer. , 2nd ed..
    [Google Scholar]
  86. Sasaki T, Ishikawa T, Abe R, Nakayama R, Asada A et al. 2014. Astrocyte calcium signalling orchestrates neuronal synchronization in organotypic hippocampal slices. J. Physiol. 592:2771–83
    [Google Scholar]
  87. Sasaki T, Matsuki N, Ikegaya Y 2011. Action-potential modulation during axonal conduction. Science 331:599–601
    [Google Scholar]
  88. Savtchouk I, Volterra A. 2018. Gliotransmission: beyond black-and-white. J. Neurosci. 38:14–25
    [Google Scholar]
  89. Shepherd GM, Grillner S, eds. 2010. Handbook of Brain Microcircuits New York: Oxford Univ. Press
    [Google Scholar]
  90. Shigetomi E, Bushong EA, Haustein MD, Tong X, Jackson-Weaver O et al. 2013. Imaging calcium microdomains within entire astrocyte territories and endfeet with GCaMPs expressed using adeno-associated viruses. J. Gen. Physiol. 141:633–47
    [Google Scholar]
  91. Shigetomi E, Kracun S, Sofroniew MV, Khakh BS 2010. A genetically targeted optical sensor to monitor calcium signals in astrocyte processes. Nat. Neurosci. 13:759–66
    [Google Scholar]
  92. Shigetomi E, Patel S, Khakh BS 2016. Probing the complexities of astrocyte calcium signaling. Trends Cell Biol 26:300–12
    [Google Scholar]
  93. Shigetomi E, Tong X, Kwan KY, Corey DP, Khakh BS 2011. TRPA1 channels regulate astrocyte resting calcium and inhibitory synapse efficacy through GAT-3. Nat. Neurosci. 15:70–80
    [Google Scholar]
  94. Smith SJ. 1992. Do astrocytes process neural information. ? Prog. Brain Res. 94:119–36
    [Google Scholar]
  95. Smith SJ. 1994. Neural signalling. Neuromodulatory astrocytes. Curr. Biol. 4:807–10
    [Google Scholar]
  96. Sofroniew MV. 2014. Astrogliosis. Cold Spring Harb. Perspect. Biol. 7:2a020420
    [Google Scholar]
  97. Srinivasan R, Huang BS, Venugopal S, Johnston AD, Chai H et al. 2015. Ca2+ signaling in astrocytes from Ip3r2−/− mice in brain slices and during startle responses in vivo. Nat. Neurosci. 18:708–17
    [Google Scholar]
  98. Stobart JL, Ferrari KD, Barrett MJP, Glück C, Stobart MJ et al. 2018. Cortical circuit activity evokes rapid astrocyte calcium signals on a similar timescale to neurons. Neuron 98:726–35.e4
    [Google Scholar]
  99. Stobart JL, Ferrari KD, Barrett MJP, Stobart MJ, Looser ZJ et al. 2016. Long-term in vivo calcium imaging of astrocytes reveals distinct cellular compartment responses to sensory stimulation. Cereb. Cortex 28:184–98
    [Google Scholar]
  100. Stogsdill JA, Ramirez J, Liu D, Kim YH, Baldwin KT et al. 2017. Astrocytic neuroligins control astrocyte morphogenesis and synaptogenesis. Nature 551:192–97
    [Google Scholar]
  101. Straub SV, Bonev AD, Wilkerson MK, Nelson MT 2006. Dynamic inositol trisphosphate-mediated calcium signals within astrocytic endfeet underlie vasodilation of cerebral arterioles. J. Gen. Physiol. 128:659–69
    [Google Scholar]
  102. Sun D, Jakobs TC. 2012. Structural remodeling of astrocytes in the injured CNS. Neuroscientist 18:567–88
    [Google Scholar]
  103. Tong X, Shigetomi E, Looger LL, Khakh BS 2013. Genetically encoded calcium indicators and astrocyte calcium microdomains. Neuroscientist 19:274–91
    [Google Scholar]
  104. Tsai H-H, Li H, Fuentealba LC, Molofsky AV, Taveira-Marques R et al. 2012. Regional astrocyte allocation regulates CNS synaptogenesis and repair. Science 337:358–62
    [Google Scholar]
  105. Ulloa F, Briscoe J. 2007. Morphogens and the control of cell proliferation and patterning in the spinal cord. Cell Cycle 6:2640–49
    [Google Scholar]
  106. Ventura R, Harris KM. 1999. Three-dimensional relationships between hippocampal synapses and astrocytes. J. Neurosci. 19:6897–906
    [Google Scholar]
  107. Verkhratsky A, Nedergaard M. 2018. Physiology of astroglia. Physiol. Rev. 98:239–389
    [Google Scholar]
  108. Volterra A, Liaudet N, Savtchouk I 2014. Astrocyte Ca2+ signalling: an unexpected complexity. Nat. Rev. Neurosci. 15:327–35
    [Google Scholar]
  109. Wilhelmsson U, Bushong EA, Price DL, Smarr BL, Phung V et al. 2006. Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury. PNAS 103:17513–18
    [Google Scholar]
  110. Yu X, Taylor AMW, Nagai J, Golshani P, Evans CJ et al. 2018. Reducing astrocyte calcium signaling in vivo alters striatal microcircuits and causes repetitive behavior. Neuron 99:1170–87.e9
    [Google Scholar]
  111. Zeisel A, Muñoz-Manchado AB, Codeluppi S, Lönnerberg P, La Manno G et al. 2015. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq. Science 347:1138–42
    [Google Scholar]
  112. Zhang Y, Barres BA. 2010. Astrocyte heterogeneity: an underappreciated topic in neurobiology. Curr. Opin. Neurobiol. 20:588–94
    [Google Scholar]
  113. Zhang Y, Sloan SA, Clarke LE, Caneda C, Plaza CA et al. 2016. Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron 89:37–53
    [Google Scholar]
  114. Zheng K, Bard L, Reynolds JP, King C, Jensen TP et al. 2015. Time-resolved imaging reveals heterogeneous landscapes of nanomolar Ca2+ in neurons and astroglia. Neuron 88:277–88
    [Google Scholar]
/content/journals/10.1146/annurev-neuro-070918-050443
Loading
/content/journals/10.1146/annurev-neuro-070918-050443
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error