Abstract
Astrocytes seem to rely on relatively sluggish and spatially blurred Ca2+ waves to communicate with fast and point-precise neural circuits. This apparent discrepancy could, however, reflect our current inability to understand the microscopic mechanisms involved. Difficulties in detecting and interpreting astrocyte Ca2+ signals may have led to some prominent controversies in the field. Here, we argue that a deeper understanding of astrocyte physiology requires a qualitative leap in our experimental and analytical strategies.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Bergles, D. E. & Jahr, C. E. Synaptic activation of glutamate transporters in hippocampal astrocytes. Neuron 19, 1297–1308 (1997).
Diamond, J. S. Neuronal glutamate transporters limit activation of NMDA receptors by neurotransmitter spillover on CA1 pyramidal cells. J. Neurosci. 21, 8328–8338 (2001).
Hertz, L. Possible role of neuroglia: a potassium-mediated neuronal–neuroglial–neuronal impulse transmission system. Nature 206, 1091–1094 (1965).
Orkand, R. K., Nicholls, J. G. & Kuffler, S. W. Effect of nerve impulses on the membrane potential of glial cells in the central nervous system of amphibia. J. Neurophysiol. 29, 788–806 (1966).
Hamilton, N. B. & Attwell, D. Do astrocytes really exocytose neurotransmitters? Nature Rev. Neurosci. 11, 227–238 (2010).
Cornell-Bell, A. H., Finkbeiner, S. M., Cooper, M. S. & Smith, S. J. Glutamate induces calcium waves in cultured astrocytes: long-range glial signaling. Science 247, 470–473 (1990).
Nedergaard, M. Direct signaling from astrocytes to neurons in cultures of mammalian brain cells. Science 263, 1768–1771 (1994).
Parpura, V. et al. Glutamate-mediated astrocyte–neuron signalling. Nature 369, 744–747 (1994).
Verkhratsky, A., Orkand, R. K. & Kettenmann, H. Glial calcium: homeostasis and signaling function. Physiol. Rev. 78, 99–141 (1998).
Volterra, A. & Meldolesi, J. Astrocytes, from brain glue to communication elements: the revolution continues. Nature Rev. Neurosci. 6, 626–640 (2005).
Haydon, P. G. & Carmignoto, G. Astrocyte control of synaptic transmission and neurovascular coupling. Physiol. Rev. 86, 1009–1031 (2006).
Araque, A. et al. Gliotransmitters travel in time and space. Neuron 81, 728–739 (2014).
Perea, G. & Araque, A. Astrocytes potentiate transmitter release at single hippocampal synapses. Science 317, 1083–1086 (2007).
Henneberger, C., Papouin, T., Oliet, S. H. & Rusakov, D. A. Long-term potentiation depends on release of d-serine from astrocytes. Nature 463, 232–236 (2010).
Agulhon, C., Fiacco, T. A. & McCarthy, K. D. Hippocampal short- and long-term plasticity are not modulated by astrocyte Ca2+ signaling. Science 327, 1250–1254 (2010).
Wang, F. et al. Photolysis of caged Ca2+ but not receptor-mediated Ca2+ signaling triggers astrocytic glutamate release. J. Neurosci. 33, 17404–17412 (2013).
Shigetomi, E., Jackson-Weaver, O., Huckstepp, R. T., O'Dell, T. J. & Khakh, B. S. TRPA1 channels are regulators of astrocyte basal calcium levels and long-term potentiation via constitutive d-serine release. J. Neurosci. 33, 10143–10153 (2013).
Volterra, A., Liaudet, N. & Savtchouk, I. Astrocyte Ca2+ signalling: an unexpected complexity. Nature Rev. Neurosci. 15, 327–335 (2014).
Agulhon, C. et al. What is the role of astrocyte calcium in neurophysiology? Neuron 59, 932–946 (2008).
Nedergaard, M. & Verkhratsky, A. Artifact versus reality — how astrocytes contribute to synaptic events. Glia 60, 1013–1023 (2012).
Sun, W. et al. Glutamate-dependent neuroglial calcium signaling differs between young and adult brain. Science 339, 197–200 (2013).
Di Castro, M. A. et al. Local Ca2+ detection and modulation of synaptic release by astrocytes. Nature Neurosci. 14, 1276–1284 (2011).
Panatier, A. et al. Astrocytes are endogenous regulators of basal transmission at central synapses. Cell 146, 785–798 (2011).
Shigetomi, E. et al. Imaging calcium microdomains within entire astrocyte territories and endfeet with GCaMPs expressed using adeno-associated viruses. J. Gen. Physiol. 141, 633–647 (2013).
Shigetomi, E., Kracun, S., Sofroniew, M. V. & Khakh, B. S. A genetically targeted optical sensor to monitor calcium signals in astrocyte processes. Nature Neurosci. 13, 599–766 (2010).
Shigetomi, E., Tong, X., Kwan, K. Y., Corey, D. P. & Khakh, B. S. TRPA1 channels regulate astrocyte resting calcium and inhibitory synapse efficacy through GAT-3. Nature Neurosci. 15, 70–80 (2012).
Kanemaru, K. et al. In vivo visualization of subtle, transient, and local activity of astrocytes using an ultrasensitive Ca2+ indicator. Cell Rep. 8, 311–318 (2014).
Haustein, M. D. et al. Conditions and constraints for astrocyte calcium signaling in the hippocampal mossy fiber pathway. Neuron 82, 413–429 (2014).
Rio-Ortega, P. La microglia y su transformación en células en bastoncito y corpúsculos granuloadiposos. Trab. Lab. Invest. Biol. 18, 37–82 (in Spanish) (1920).
Spacek, J. 3-dimensional analysis of dendritic spines. III. Glial sheath. Anat. Embryol. 171, 245–252 (1985).
Ventura, R. & Harris, K. M. Three-dimensional relationships between hippocampal synapses and astrocytes. J. Neurosci. 19, 6897–6906 (1999).
Haber, M., Zhou, L. & Murai, K. K. Cooperative astrocyte and dendritic spine dynamics at hippocampal excitatory synapses. J. Neurosci. 26, 8881–8891 (2006).
Bernardinelli, Y. et al. Activity-dependent structural plasticity of perisynaptic astrocytic domains promotes excitatory synapse stability. Curr. Biol. 24, 1679–1688 (2014).
Henneberger, C. & Rusakov, D. A. Monitoring local synaptic activity with astrocytic patch pipettes. Nature Protoc. 7, 2171–2179 (2012).
Giaume, C., Koulakoff, A., Roux, L., Holcman, D. & Rouach, N. Astroglial networks: a step further in neuroglial and gliovascular interactions. Nature Rev. Neurosci. 11, 87–99 (2010).
Nagy, J. I., Ochalski, P. A. Y., Li, J. & Hertzberg, E. L. Evidence for the co-localization of another connexin with connexin-43 at astrocytic gap junctions in rat brain. Neuroscience 78, 533–548 (1997).
Wolff, J. R. et al. Autocellular coupling by gap junctions in cultured astrocytes: a new view on cellular autoregulation during process formation. Glia 24, 121–140 (1998).
Gosejacob, D. et al. Role of astroglial connexin30 in hippocampal gap junction coupling. Glia 59, 511–519 (2011).
Rouach, N., Koulakoff, A., Abudara, V., Willecke, K. & Giaume, C. Astroglial metabolic networks sustain hippocampal synaptic transmission. Science 322, 1551–1555 (2008).
Pannasch, U. & Rouach, N. Emerging role for astroglial networks in information processing: from synapse to behavior. Trends Neurosci. 36, 405–417 (2013).
Verkhratsky, A. & Kettenmann, H. Calcium signalling in glial cells. Trends Neurosci. 19, 346–352 (1996).
Grosche, J. et al. Microdomains for neuron–glia interaction: parallel fiber signaling to Bergmann glial cells. Nature Neurosci. 2, 139–143 (1999).
Parpura, V. & Verkhratsky, A. Homeostatic function of astrocytes: Ca2+ and Na+ signalling. Transl. Neurosci. 3, 334–344 (2012).
Ross, W. N. Understanding calcium waves and sparks in central neurons. Nature Rev. Neurosci. 13, 157–168 (2012).
Spacek, J. & Harris, K. M. Three-dimensional organization of smooth endoplasmic reticulum in hippocampal CA1 dendrites and dendritic spines of the immature and mature rat. J. Neurosci. 17, 190–203 (1997).
Cui-Wang, T. et al. Local zones of endoplasmic reticulum complexity confine cargo in neuronal dendrites. Cell 148, 309–321 (2012).
Patrushev, I., Gavrilov, N., Turlapov, V. & Semyanov, A. Subcellular location of astrocytic calcium stores favors extrasynaptic neuron–astrocyte communication. Cell Calcium 54, 343–349 (2013).
Navarrete, M. & Araque, A. Endocannabinoids potentiate synaptic transmission through stimulation of astrocytes. Neuron 68, 113–126 (2010).
Yuste, R., Majewska, A. & Holthoff, K. From form to function: calcium compartmentalization in dendritic spines. Nature Neurosci. 3, 653–659 (2000).
Bloodgood, B. L. & Sabatini, B. L. Neuronal activity regulates diffusion across the neck of dendritic spines. Science 310, 866–869 (2005).
Holcman, D. & Schuss, Z. Brownian needle in dire straits: stochastic motion of a rod in very confined narrow domains. Phys. Rev. E Stat. Nonlin. Soft Matter Phys. 85, 010103 (2012).
Rusakov, D. A., Zheng, K. & Henneberger, C. Astrocytes as regulators of synaptic function: a quest for the Ca2+ master key. Neuroscientist 17, 513–523 (2011).
Grynkiewicz, G., Poenie, M. & Tsien, R. Y. A new generation of Ca2+ indicators with greatly improved fluorescence properties. J. Biol. Chem. 260, 3440–3450 (1985).
Wang, X. et al. Astrocytic Ca2+ signaling evoked by sensory stimulation in vivo. Nature Neurosci. 9, 816–823 (2006).
Terai, T. & Nagano, T. Small-molecule fluorophores and fluorescent probes for bioimaging. Pflugers Arch. 465, 347–359 (2013).
Schäferling, M. The art of fluorescence imaging with chemical sensors. Angew. Chem. Int. Ed. Eng. 51, 3532–3554 (2012).
Higley, M. J. & Sabatini, B. L. Calcium signaling in dendrites and spines: practical and functional considerations. Neuron 59, 902–913 (2008).
Miyawaki, A. Visualization of the spatial and temporal dynamics of intracellular signaling. Dev. Cell 4, 295–305 (2003).
Figueiredo, M. et al. Optogenetic experimentation on astrocytes. Exp. Physiol. 96, 40–50 (2011).
Tong, X. P., Shigetomi, E., Looger, L. L. & Khakh, B. S. Genetically encoded calcium indicators and astrocyte calcium microdomains. Neuroscientist 19, 274–291 (2013).
Wu, L. G. & Saggau, P. Presynaptic calcium is increased during normal synaptic transmission and paired-pulse facilitation, but not in long-term potentiation in area CA1 of hippocampus. J. Neurosci. 14, 645–654 (1994).
Song, L. S., Sham, J. S., Stern, M. D., Lakatta, E. G. & Cheng, H. Direct measurement of SR release flux by tracking 'Ca2+ spikes' in rat cardiac myocytes. J. Physiol. 512, 677–691 (1998).
Zador, A. & Koch, C. Linearized models of calcium dynamics — formal equivalence to the cable equation. J. Neurosci. 14, 4705–4715 (1994).
Maravall, M., Mainen, Z. F., Sabatini, B. L. & Svoboda, K. Estimating intracellular calcium concentrations and buffering without wavelength ratioing. Biophys. J. 78, 2655–2667 (2000).
Sabatini, B. L. & Regehr, W. G. Timing of neurotransmission at fast synapses in the mammalian brain. Nature 384, 170–172 (1996).
Scott, R. & Rusakov, D. A. Main determinants of presynaptic Ca2+ dynamics at individual mossy fiber–CA3 pyramidal cell synapses. J. Neurosci. 26, 7071–7081 (2006).
Ermolyuk, Y. S. et al. Independent regulation of basal neurotransmitter release efficacy by variable Ca2+ influx and bouton size at small central synapses. PLoS Biol. 10, e1001396 (2012).
Svoboda, K., Tank, D. W. & Denk, W. Direct measurement of coupling between dendritic spines and shafts. Science 272, 716–719 (1996).
Majewska, A., Brown, E., Ross, J. & Yuste, R. Mechanisms of calcium decay kinetics in hippocampal spines: role of spine calcium pumps and calcium diffusion through the spine neck in biochemical compartmentalization. J. Neurosci. 20, 1722–1734 (2000).
Murthy, V. N., Sejnowski, T. J. & Stevens, C. F. Dynamics of dendritic calcium transients evoked by quantal release at excitatory hippocampal synapses. Proc. Natl Acad. Sci. USA 97, 901–906 (2000).
Franks, K. M., Bartol, T. M. & Sejnowski, T. J. An MCell model of calcium dynamics and frequency-dependence of calmodulin activation in dendritic spines. Neurocomputing 38, 9–16 (2001).
Korkotian, E., Holcman, D. & Segal, M. Dynamic regulation of spine–dendrite coupling in cultured hippocampal neurons. Eur. J. Neurosci. 20, 2649–2663 (2004).
DiGregorio, D. A., Peskoff, A. & Vergara, J. L. Measurement of action potential-induced presynaptic calcium domains at a cultured neuromuscular junction. J. Neurosci. 19, 7846–7859 (1999).
Bennett, M. R., Farnell, L. & Gibson, W. G. The probability of quantal secretion within an array of calcium channels of an active zone. Biophys. J. 78, 2222–2240 (2000).
Meinrenken, C. J., Borst, J. G. G. & Sakmann, B. Local routes revisited: the space and time dependence of the Ca2+ signal for phasic transmitter release at the rat calyx of Held. J. Physiol. 547, 665–689 (2003).
Scott, R., Ruiz, A., Henneberger, C., Kullmann, D. M. & Rusakov, D. A. Analog modulation of mossy fiber transmission is uncoupled from changes in presynaptic Ca2+. J. Neurosci. 28, 7765–7773 (2008).
Eggermann, E., Bucurenciu, I., Goswami, S. P. & Jonas, P. Nanodomain coupling between Ca2+ channels and sensors of exocytosis at fast mammalian synapses. Nature Rev. Neurosci. 13, 7–21 (2012).
Ermolyuk, Y. S. et al. Differential triggering of spontaneous glutamate release by P/Q-, N- and R-type Ca2+ channels. Nature Neurosci. 16, 1754–1763 (2013).
Kang, J., Jiang, L., Goldman, S. A. & Nedergaard, M. Astrocyte-mediated potentiation of inhibitory synaptic transmission. Nature Neurosci. 1, 683–692 (1998).
Mulligan, S. J. & MacVicar, B. A. Calcium transients in astrocyte endfeet cause cerebrovascular constrictions. Nature 431, 195–199 (2004).
Navarrete, M. et al. Astrocytes mediate in vivo cholinergic-induced synaptic plasticity. PLoS Biol. 10, e1001259 (2012).
Min, R. & Nevian, T. Astrocyte signaling controls spike timing-dependent depression at neocortical synapses. Nature Neurosci. 15, 746–753 (2012).
Yasuda, R. et al. Imaging calcium concentration dynamics in small neuronal compartments. Sci. STKE 2004, pl5 (2004).
Sabatini, B. L. & Regehr, W. G. Optical measurement of presynaptic calcium currents. Biophys. J. 74, 1549–1563 (1998).
Schneggenburger, R., Sakaba, T. & Neher, E. Vesicle pools and short-term synaptic depression: lessons from a large synapse. Trends Neurosci. 25, 206–212 (2002).
Witcher, M. R., Kirov, S. A. & Harris, K. M. Plasticity of perisynaptic astroglia during synaptogenesis in the mature rat hippocampus. Glia 55, 13–23 (2007).
Lushnikova, I., Skibo, G., Muller, D. & Nikonenko, I. Synaptic potentiation induces increased glial coverage of excitatory synapses in CA1 hippocampus. Hippocampus 19, 753–762 (2009).
Medvedev, N. et al. Glia selectively approach synapses on thin dendritic spines. Phil. Trans. R. Soc. B 369, 20140047 (2014).
Scott, R. S. et al. Neuronal adaptation involves rapid expansion of the action potential initiation site. Nature Commun. 5, 3817 (2014).
Acknowledgements
This work was supported by the Wellcome Trust Principal Research Fellowship, the European Research Council Advanced Grant (323113 NETSIGNAL), the UK Biology and Biotechnology Sciences Research Council and the UK Medical Research Council. The author thanks K. Volynski for his help with advanced kinetic modelling software.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The author declares no competing financial interests.
Glossary
- Ca2+ dye saturation
-
The scenario when nearly all Ca2+ indicator molecules are already bound to Ca2+: thus, the indicator fluorescence will be mostly insensitive to further increases in Ca2+ levels.
- In silico
-
A theoretical experiment performed by a computer or through computer simulations.
- Optical diffraction limit
-
The minimum size of a light spot, and thus optical resolution, at a given wavelength and light convergence angle. In conventional optics, two objects cannot be distinguished at distances smaller than the diffraction limit.
- Photolytic release
-
A photo-stimulated (light-triggered) chemical reaction that converts a chemical compound from its inactive state into its biologically active state, often by removing a chemical 'cage'. It is also referred to as 'uncaging'.
- Point-spread function
-
(PSF). The combined effect of diffraction-limited optics in a given imaging system.
- Ratiometric Ca2+ sensors
-
Ca2+ indicators that shift their emission spectrum upon Ca2+ binding or unbinding; thus, the intensity ratio for the two chosen emission wavelengths provides a readout of Ca2+ concentration, which is insensitive to bleaching, focus changes or excitation intensity (but could be sensitive to scattering in organized tissue).
- Steady-state approximations
-
Approximations of a kinetic reaction theory that can greatly simplify calculations when some of the reactions run at a much slower rate than others and therefore can be ignored when considering rapid-timescale events.
Rights and permissions
About this article
Cite this article
Rusakov, D. Disentangling calcium-driven astrocyte physiology. Nat Rev Neurosci 16, 226–233 (2015). https://doi.org/10.1038/nrn3878
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrn3878
This article is cited by
-
Astrocytes: new evidence, new models, new roles
Biophysical Reviews (2023)
-
Calcineurin Signalling in Astrocytes: From Pathology to Physiology and Control of Neuronal Functions
Neurochemical Research (2023)
-
Avoiding interpretational pitfalls in fluorescence imaging of the brain
Nature Reviews Neuroscience (2022)
-
Sex-dependent calcium hyperactivity due to lysosomal-related dysfunction in astrocytes from APOE4 versus APOE3 gene targeted replacement mice
Molecular Neurodegeneration (2020)
-
Immune cell regulation of glia during CNS injury and disease
Nature Reviews Neuroscience (2020)