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Astrocytic Calcium Signaling: Mechanism and Implications for Functional Brain Imaging

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Dynamic Brain Imaging

Part of the book series: METHODS IN MOLECULAR BIOLOGY™ ((MIMB,volume 489))

Abstract

Astrocytes are electrically non-excitable cells that, on a slow time scale of seconds, integrate synaptic transmission by dynamic increases in cytosolic Ca2+. A number of groups have recently shown that astrocytic Ca2+ signaling regulates vascular tones and that astrocytes play a central role in functional hyperemia by Ca2+-dependent release of Prostaglandin E2 (PGE2). Astrocytes are, however, not simple detectors of excitatory transmission, since a number of neuromodulator and hormones trigger elevations in astrocytic Ca2+ independently of synaptic transmission. Furthermore, astrocytes exhibit ex vivo intrinsic Ca2+ excitability, or spontaneous increases in Ca2+ that are not triggered by receptor activation. The notion that astrocytes can regulate vascular tone independently of synaptic transmission challenges the notion that changes in the blood oxygenation level dependent (BOLD) signal is directly proportional to neuronal activity and may thus require a reevaluation of the large body of data accumulated using functional magnetic resonance imaging (fMRI).

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References

  1. Cornell-Bell, A.H., et al., Glutamate induces calcium waves in cultured astrocytes: long-range glial signaling. Science, 1990. 247(4941): pp. 470–3.

    Article  CAS  PubMed  Google Scholar 

  2. Nedergaard, M., Direct signaling from astrocytes to neurons in cultures of mammalian brain cells. Science, 1994. 263(5154): pp. 1768–71.

    Article  CAS  PubMed  Google Scholar 

  3. Parpura, V., et al., Glutamate-mediated astrocyte-neuron signalling. Nature, 1994. 369(6483): pp. 744–7.

    Article  CAS  PubMed  Google Scholar 

  4. Kang, J., et al., Astrocyte-mediated potentiation of inhibitory synaptic transmission. Nat Neurosci, 1998. 1(8): pp. 683–92.

    Article  CAS  PubMed  Google Scholar 

  5. Porter, J.T. and K.D. McCarthy, Hippocampal astrocytes in situ respond to glutamate released from synaptic terminals. J Neurosci, 1996. 16(16): pp. 5073–81.

    CAS  PubMed  Google Scholar 

  6. Pasti, L., et al., Intracellular calcium oscillations in astrocytes: A highly plastic, bidirectional form of communication between neurons and astrocytes in situ. J Neurosci, 1997. 17(20): pp. 7817–30.

    CAS  PubMed  Google Scholar 

  7. Pascual, O., et al., Astrocytic purinergic signaling coordinates synaptic networks. Science, 2005. 310(5745): pp. 113–6.

    Article  CAS  PubMed  Google Scholar 

  8. Newman, E.A. and K.R. Zahs, Modulation of neuronal activity by glial cells in the retina. J Neurosci, 1998. 18(11): pp. 4022–8.

    CAS  PubMed  Google Scholar 

  9. Wang, X., et al., Astrocytic Ca(2+) signaling evoked by sensory stimulation in vivo. Nat Neurosci, 2006. 9(6): pp. 816–23.

    Article  CAS  PubMed  Google Scholar 

  10. Zonta, M., et al., Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nat Neurosci, 2003. 6(1): pp. 43–50.

    Article  CAS  PubMed  Google Scholar 

  11. Araque, A., et al., Calcium elevation in astrocytes causes an NMDA receptor-dependent increase in the frequency of miniature synaptic currents in cultured hippocampal neurons. J Neurosci, 1998. 18(17): pp. 6822–9.

    CAS  PubMed  Google Scholar 

  12. Rzigalinski, B.A., et al., Intracellular free calcium dynamics in stretch-injured astrocytes. J Neurochem, 1998. 70(6): pp. 2377–85.

    Article  CAS  PubMed  Google Scholar 

  13. Fellin, T., et al., Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors. Neuron, 2004. 43(5): pp. 729–43.

    Article  CAS  PubMed  Google Scholar 

  14. Newman, E.A., Calcium increases in retinal glial cells evoked by light-induced neuronal activity. J Neurosci, 2005. 25(23): pp. 5502–10.

    Article  CAS  PubMed  Google Scholar 

  15. Haydon, P.G. and G. Carmignoto, Astrocyte control of synaptic transmission and neurovascular coupling. Physiol Rev, 2006. 86(3): pp. 1009–31.

    Article  CAS  PubMed  Google Scholar 

  16. Fox, P.T. and M.E. Raichle, Focal physiological uncoupling of cerebral blood flow and oxidative metabolism during somatosensory stimulation in human subjects. Proc Natl Acad Sci U S A, 1986. 83(4): pp. 1140–4.

    Article  CAS  PubMed  Google Scholar 

  17. Mulligan, S.J. and B.A. MacVicar, Calcium transients in astrocyte endfeet cause cerebrovascular constrictions. Nature, 2004. 431(7005): pp. 195–9.

    Article  CAS  PubMed  Google Scholar 

  18. Metea, M.R. and E.A. Newman, Glial cells dilate and constrict blood vessels: A mechanism of neurovascular coupling. J Neurosci, 2006. 26(11): pp. 2862–70.

    Article  CAS  PubMed  Google Scholar 

  19. Filosa, J.A., et al., Local potassium signaling couples neuronal activity to vasodilation in the brain. Nat Neurosci, 2006. 9(11): pp. 1397–403.

    Article  CAS  PubMed  Google Scholar 

  20. Peppiatt, C.M., et al., Bidirectional control of CNS capillary diameter by pericytes. Nature, 2006. 443(7112): pp. 700–4.

    Article  CAS  PubMed  Google Scholar 

  21. Mathiesen, C., K. Caesar, and M. Lauritzen, Temporal coupling between neuronal activity and blood flow in rat cerebellar cortex as indicated by field potential analysis. J Physiol, 2000. 523 Pt 1: pp. 235–46.

    Article  CAS  PubMed  Google Scholar 

  22. Ngai, A.C., et al., Frequency-dependent changes in cerebral blood flow and evoked potentials during somatosensory stimulation in the rat. Brain Res, 1999. 837(1–2): pp. 221–8.

    Article  CAS  PubMed  Google Scholar 

  23. Charles, A.C., Glia-neuron intercellular calcium signaling. Dev Neurosci, 1994. 16(3–4): pp. 196–206.

    Article  CAS  PubMed  Google Scholar 

  24. Porter, J.T. and K.D. McCarthy, Astrocytic neurotransmitter receptors in situ and in vivo. Prog Neurobiol, 1997. 51(4): pp. 439–55.

    Article  CAS  PubMed  Google Scholar 

  25. Duffy, S. and B.A. MacVicar, Adrenergic calcium signaling in astrocyte networks within the hippocampal slice. J Neurosci, 1995. 15(8): pp. 5535–50.

    CAS  PubMed  Google Scholar 

  26. Perea, G. and A. Araque, Properties of synaptically evoked astrocyte calcium signal reveal synaptic information processing by astrocytes. J Neurosci, 2005. 25(9): pp. 2192–203.

    Article  CAS  PubMed  Google Scholar 

  27. Verkhratsky, A., R.K. Orkand, and H. Kettenmann, Glial calcium: Homeostasis and signaling function. Physiol Rev, 1998. 78(1): pp. 99–141.

    CAS  PubMed  Google Scholar 

  28. Volterra, A. and J. Meldolesi, Astrocytes, from brain glue to communication elements: The revolution continues. Nat Rev Neurosci, 2005. 6(8): pp. 626–40.

    Article  CAS  PubMed  Google Scholar 

  29. Bergles, D.E. and C.E. Jahr, Synaptic activation of glutamate transporters in hippocampal astrocytes. Neuron, 1997. 19(6): pp. 1297–308.

    Article  CAS  PubMed  Google Scholar 

  30. Porter, J.T. and K.D. McCarthy, - Astrocytic neurotransmitter receptors in situ and in vivo. 1997. 51: p. 455.

    Google Scholar 

  31. Matsui, K. and C.E. Jahr, Ectopic release of synaptic vesicles. Neuron, 2003. 40(6): pp. 1173–83.

    Article  CAS  PubMed  Google Scholar 

  32. Zoli, M., et al., The emergence of the volume transmission concept. Brain Res Brain Res Rev, 1998. 26(2–3): pp. 136–47.

    Article  CAS  PubMed  Google Scholar 

  33. Cotrina, M.L., J.H. Lin, and M. Nedergaard, Cytoskeletal assembly and ATP release regulate astrocytic calcium signaling. J Neurosci, 1998. 18(21): pp. 8794–804.

    CAS  PubMed  Google Scholar 

  34. Schell, M.J., M.E. Molliver, and S.H. Snyder, D-serine, an endogenous synaptic modulator: Localization to astrocytes and glutamate-stimulated release. Proc Natl Acad Sci U S A, 1995. 92(9): pp. 3948–52.

    Article  CAS  PubMed  Google Scholar 

  35. Beattie, E.C., et al., Control of synaptic strength by glial TNFalpha. Science, 2002. 295(5563): pp. 2282–5.

    Article  CAS  PubMed  Google Scholar 

  36. Simard, M., et al., Signaling at the gliovascular interface. J Neurosci, 2003. 23(27): pp. 9254–62.

    CAS  PubMed  Google Scholar 

  37. Price, D.L., et al., Distribution of rSlo Ca2+-activated K+ channels in rat astrocyte perivascular endfeet. Brain Res, 2002. 956(2): pp. 183–93.

    Article  CAS  PubMed  Google Scholar 

  38. Filosa, J.A., A.D. Bonev, and M.T. Nelson, Calcium dynamics in cortical astrocytes and arterioles during neurovascular coupling. Circ Res, 2004. 95(10): pp. e73–81.

    Article  CAS  PubMed  Google Scholar 

  39. Denk, W., J.H. Strickler, and W.W. Webb, Two-photon laser scanning fluorescence microscopy. Science, 1990. 248(4951): pp. 73–6.

    Article  CAS  PubMed  Google Scholar 

  40. Stosiek, C., et al., In vivo two-photon calcium imaging of neuronal networks. Proc Natl Acad Sci U S A, 2003. 100(12): pp. 7319–24.

    Article  CAS  PubMed  Google Scholar 

  41. Hirase, H., et al., Calcium dynamics of cortical astrocytic networks in vivo. PLoS Biol, 2004. 2(4): pp. E96.

    Article  PubMed  Google Scholar 

  42. Svoboda, K. and R. Yasuda, Principles of two-photon excitation microscopy and its applications to neuroscience. Neuron, 2006. 50(6): pp. 823–39.

    Article  CAS  PubMed  Google Scholar 

  43. Svoboda, K., et al., Spread of dendritic excitation in layer 2/3 pyramidal neurons in rat barrel cortex in vivo. Nat Neurosci, 1999. 2(1): pp. 65–73.

    Article  CAS  PubMed  Google Scholar 

  44. Nimmerjahn, A., et al., Sulforhodamine 101 as a specific marker of astroglia in the neocortex in vivo. Nat Methods, 2004. 1(1): pp. 31–7.

    Article  CAS  PubMed  Google Scholar 

  45. Friedberg, M.H., S.M. Lee, and F.F. Ebner, Modulation of receptive field properties of thalamic somatosensory neurons by the depth of anesthesia. J Neurophysiol, 1999. 81(5): pp. 2243–52.

    CAS  PubMed  Google Scholar 

  46. Kerr, J.N., D. Greenberg, and F. Helmchen, Imaging input and output of neocortical networks in vivo. Proc Natl Acad Sci U S A, 2005. 102(39): pp. 14063–8.

    Article  CAS  PubMed  Google Scholar 

  47. Kang, J., et al., Astrocyte-mediated potentiation of inhibitory synaptic transmission. Nat Neurosci, 1998. 1(8): pp. 683–92.

    Article  CAS  PubMed  Google Scholar 

  48. Sosnik, R., S. Haidarliu, and E. Ahissar, Temporal frequency of whisker movement. I. Representations in brain stem and thalamus. J Neurophysiol, 2001. 86(1): pp. 339–53.

    CAS  PubMed  Google Scholar 

  49. Pinto, D.J., J.C. Brumberg, and D.J. Simons, Circuit dynamics and coding strategies in rodent somatosensory cortex. J Neurophysiol, 2000. 83(3): pp. 1158–66.

    CAS  PubMed  Google Scholar 

  50. Petersen, C.C., A. Grinvald, and B. Sakmann, Spatiotemporal dynamics of sensory responses in layer 2/3 of rat barrel cortex measured in vivo by voltage-sensitive dye imaging combined with whole-cell voltage recordings and neuron reconstructions. J Neurosci, 2003. 23(4): pp. 1298–309.

    CAS  PubMed  Google Scholar 

  51. Takano, T., et al., Astrocyte-mediated control of cerebral blood flow. Nat Neurosci, 2006. 9(2): pp. 260–7.

    Article  CAS  PubMed  Google Scholar 

  52. Logothetis, N.K. and B.A. Wandell, Interpreting the BOLD signal. Annu Rev Physiol, 2004. 66: pp. 735–69.

    Article  CAS  PubMed  Google Scholar 

  53. Mathiesen, C., et al., Modification of activity-dependent increases of cerebral blood flow by excitatory synaptic activity and spikes in rat cerebellar cortex. J Physiol, 1998. 512 (Pt 2): pp. 555–66.

    Article  CAS  PubMed  Google Scholar 

  54. Peppiatt, C. and D. Attwell, Neurobiology: Feeding the brain. Nature, 2004. 431(7005): pp. 137–8.

    Article  CAS  PubMed  Google Scholar 

  55. Lauritzen, M., Reading vascular changes in brain imaging: Is dendritic calcium the key? Nat Rev Neurosci, 2005. 6(1): pp. 77–85.

    Article  CAS  PubMed  Google Scholar 

  56. Bergles, D.E., J.S. Diamond, and C.E. Jahr, Clearance of glutamate inside the synapse and beyond. Curr Opin Neurobiol, 1999. 9(3): pp. 293–8.

    Article  CAS  PubMed  Google Scholar 

  57. Pellerin, L. and P.J. Magistretti, Food for thought: Challenging the dogmas. J Cereb Blood Flow Metab, 2003. 23(11): pp. 1282–6.

    Article  PubMed  Google Scholar 

  58. Pellerin, L. and P.J. Magistretti, Glutamate uptake into astrocytes stimulates aerobic glycolysis: A mechanism coupling neuronal activity to glucose utilization. Proc Natl Acad Sci U S A, 1994. 91(22): pp. 10625–9.

    Article  CAS  PubMed  Google Scholar 

  59. Dienel, G.A. and N.F. Cruz, Nutrition during brain activation: Does cell-to-cell lactate shuttling contribute significantly to sweet and sour food for thought? Neurochem Int, 2004. 45(2–3): pp. 321–51.

    Google Scholar 

  60. Pysh, Y. and T. Khan, Variation in mitochondrial structure and content of neurons and neuroglia in rat brain: An electron microscopic study. Brain Research, 1972. 36(1):pp. 1–18.

    Article  CAS  PubMed  Google Scholar 

  61. Peters, A., L.P. Sandford, and H.D. Webster, Fine structure of the Nervous System: Neurons and Their Supporting Cells. 3rd edition ed. 1991: Oxford University Press, Oxford.

    Google Scholar 

  62. Hertz, L., L. Peng, and G. Dienel, Energy metabolism in astrocytes: High rate of oxidative metabolism and spatiotemporal dependence on glycolysis/glycogenolysis. Journal of Cerebral Blood Flow & Metabolism, 2007. 27: pp. 219–249.

    Article  CAS  Google Scholar 

  63. van den Pol, A.N., C. Romano, and P. Ghosh, Metabotropic glutamate receptor mGluR5 subcellular distribution and developmental expression in hypothalamus. J Comp Neurol, 1995. 362(1): pp. 134–50.

    Article  PubMed  Google Scholar 

  64. Munoz, A., X.B. Liu, and E.G. Jones, Development of metabotropic glutamate receptors from trigeminal nuclei to barrel cortex in postnatal mouse. J Comp Neurol, 1999. 409(4): pp. 549–66.

    Article  CAS  PubMed  Google Scholar 

  65. Brookes, P.S., et al., Calcium, ATP, and ROS: A mitochondrial love-hate triangle. Am J Physiol Cell Physiol, 2004. 287(4): pp. C817–33.

    Article  CAS  PubMed  Google Scholar 

  66. Attwell, D. and S. Laughlin, An Energy Budget for Signaling in the Grey Matter of the Brain. Journal of Cerebral Blood Flow and Metabolism, 2001. 21: pp. 1133–1145.

    CAS  PubMed  Google Scholar 

  67. Lebon, V., et al., Astroglial Contribution to Brain Energy Metabolism in Humans Revealed by 13C Nuclear Magnetic Resonance Spectroscopy: Elucidation of the Dominant Pathway for Neurotransmitter Glutamate Repletion and Measurement of Astrocytic Oxidative Metabolism. J Neurosci, 2002. 22(5): pp. 1523–1531.

    CAS  PubMed  Google Scholar 

  68. Oz, G., et al., Neuroglial Metabolism in the Awake Rat Brain: CO2 Fixation Increases with Brain Activity. The Journal of Neuroscience, 2004. 22(50): pp. 11273–11279.

    Article  Google Scholar 

  69. Kahlert, S. and G. Reiser, Requirement of Glycolytic and Mitochondrial Energy Supply for Loading of Ca2+ Stores and InsP3-Mediated Ca2+ Signaling in Rat Hippocampus Astrocytes. J Neurosci Res, 2000. 61: pp. 409–420.

    Article  CAS  PubMed  Google Scholar 

  70. Feustel, P.J., Y. Jin, and H.K. Kimelberg, Volume-regulated anion channels are the predominant contributors to release of excitatory amino acids in the ischemic cortical penumbra. 2004. 35: p. 1168.

    Google Scholar 

  71. Arcuino, G., et al., Intercellular calcium signaling mediated by point-source burst release of ATP. Proc Natl Acad Sci U S A, 2002. 99(15): pp. 9840–5.

    Article  CAS  PubMed  Google Scholar 

  72. Zhang, J.M., et al., ATP released by astrocytes mediates glutamatergic activity-dependent heterosynaptic suppression. Neuron, 2003. 40(5): pp. 971–82.

    Article  CAS  PubMed  Google Scholar 

  73. Davalos, D., et al., ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci, 2005. 8(6): pp. 752–8.

    Article  CAS  PubMed  Google Scholar 

  74. Brennan, A.M., J.A. Connor, and C.W. Shuttleworth, NAD(P)H fluorescent transients after synaptic activity in brain slices: Predominant role of mitochondrial function. J Cereb Blood Flow Metab, 2006. 26(11): pp. 1389–406.

    Article  CAS  PubMed  Google Scholar 

  75. Takano, T., et al., Cortical spreading depression causes and coincides with tissue hypoxia. Nat Neurosci, 2007. 10(6): pp. 754–62.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by NINDS/NIH NS030007, NS038073, NS50315.

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Authors and Affiliations

  1. Center for Aging and Developmental Biology, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY

    Xiaohai Wang, Takahiro Takano & Maiken Nedergaard

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  1. Xiaohai Wang
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  2. Takahiro Takano
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  3. Maiken Nedergaard
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  1. Yale University, New Haven, CT, USA

    Fahmeed Hyder

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Wang, X., Takano, T., Nedergaard, M. (2009). Astrocytic Calcium Signaling: Mechanism and Implications for Functional Brain Imaging. In: Hyder, F. (eds) Dynamic Brain Imaging. METHODS IN MOLECULAR BIOLOGY™, vol 489. Humana Press. https://doi.org/10.1007/978-1-59745-543-5_5

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  • DOI: https://doi.org/10.1007/978-1-59745-543-5_5

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