Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Astrocyte function from information processing to cognition and cognitive impairment

Nature Neuroscience volume 22, pages 154–166 (2019)Cite this article

Subjects

Abstract

Astrocytes serve important roles that affect recruitment and function of neurons at the local and network levels. Here we review the contributions of astrocyte signaling to synaptic plasticity, neuronal network oscillations, and memory function. The roles played by astrocytes are not fully understood, but astrocytes seem to contribute to memory consolidation and seem to mediate the effects of vigilance and arousal on memory performance. Understanding the role of astrocytes in cognitive processes may also advance our understanding of how these processes go awry in pathological conditions. Indeed, abnormal astrocytic signaling can cause or contribute to synaptic and network imbalances, leading to cognitive impairment. We discuss evidence for this from animal models of Alzheimer’s disease and multiple sclerosis and from animal studies of sleep deprivation and drug abuse and addiction. Understanding the emerging roles of astrocytes in cognitive function and dysfunction will open up a large array of new therapeutic opportunities.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Plasticity of structural interactions between synaptic elements and PAPs.
Fig. 2: Bidirectional signaling between synaptic elements and PAPs controls synaptic function and plasticity.
Fig. 3: Astrocytes modulate neuronal network oscillations and contribute to memory performance.
Fig. 4: Effects of astrocyte signaling on hippocampus-dependent memory pathways in physiological and pathological conditions.
Fig. 5: Multiscale spatiotemporal integration of astrocytes with synaptic and neuronal networks.

Similar content being viewed by others

References

  1. Araque, A., Parpura, V., Sanzgiri, R. P. & Haydon, P. G. Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci. 22, 208–215 (1999).

    CAS  PubMed  Google Scholar 

  2. Araque, A. et al. Gliotransmitters travel in time and space. Neuron 81, 728–739 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Chung, W. S., Allen, N. J. & Eroglu, C. Astrocytes control synapse formation, function, and elimination. Cold Spring Harb. Perspect. Biol. 7, a020370 (2015).

    PubMed  PubMed Central  Google Scholar 

  4. Savtchouk, I. & Volterra, A. Gliotransmission: beyond black-and-white. J. Neurosci. 38, 14–25 (2018).

    CAS  PubMed  Google Scholar 

  5. Volterra, A., Liaudet, N. & Savtchouk, I. Astrocyte Ca2+ signalling: an unexpected complexity. Nat. Rev. Neurosci. 15, 327–335 (2014).

    CAS  PubMed  Google Scholar 

  6. Sardinha, V. M. et al. Astrocytic signaling supports hippocampal-prefrontal theta synchronization and cognitive function. Glia 65, 1944–1960 (2017).

    PubMed  Google Scholar 

  7. Adamsky, A. et al. Astrocytic activation generates de novo neuronal potentiation and memory enhancement. Cell 174, 59–71.e14 (2018). Using chemogenetic and optogenetic tools, this study demonstrates that astrocyte stimulation promotes hippocampal long-term synaptic potentiation. Astrocytic activation during memory acquisition is also sufficient to improve memory retrieval, hence proving that astrocytes are capable of producing cognitive-enhancing effects.

    CAS  PubMed  Google Scholar 

  8. Pannasch, U. & Rouach, N. Emerging role for astroglial networks in information processing: from synapse to behavior. Trends Neurosci. 36, 405–417 (2013).

    CAS  PubMed  Google Scholar 

  9. Martín, R., Bajo-Grañeras, R., Moratalla, R., Perea, G. & Araque, A. Circuit-specific signaling in astrocyte-neuron networks in basal ganglia pathways. Science 349, 730–734 (2015).

    PubMed  Google Scholar 

  10. Mariotti, L. et al. Interneuron-specific signaling evokes distinctive somatostatin-mediated responses in adult cortical astrocytes. Nat. Commun. 9, 82 (2018).

    PubMed  PubMed Central  Google Scholar 

  11. Covelo, A. & Araque, A. Neuronal activity determines distinct gliotransmitter release from a single astrocyte. eLife 7, e32237 (2018).

    PubMed  PubMed Central  Google Scholar 

  12. Bindocci, E. et al. Three-dimensional Ca2+ imaging advances understanding of astrocyte biology. Science 356, eaai8185 (2017).

    PubMed  Google Scholar 

  13. Stobart, J. L. et al. Cortical circuit activity evokes rapid astrocyte calcium signals on a similar timescale to neurons. Neuron 98, 726–735.e4 (2018).

    CAS  PubMed  Google Scholar 

  14. Wang, X. J. Neurophysiological and computational principles of cortical rhythms in cognition. Physiol. Rev. 90, 1195–1268 (2010).

    PubMed  PubMed Central  Google Scholar 

  15. Kandel, E. R., Dudai, Y. & Mayford, M. R. The molecular and systems biology of memory. Cell 157, 163–186 (2014).

    CAS  PubMed  Google Scholar 

  16. Ghézali, G., Dallérac, G. & Rouach, N. Perisynaptic astroglial processes: dynamic processors of neuronal information. Brain Struct. Funct. 221, 2427–2442 (2016).

    PubMed  Google Scholar 

  17. Genoud, C. et al. Plasticity of astrocytic coverage and glutamate transporter expression in adult mouse cortex. PLoS Biol. 4, e343 (2006).

    PubMed  PubMed Central  Google Scholar 

  18. Panatier, A. et al. Glia-derived D-serine controls NMDA receptor activity and synaptic memory. Cell 125, 775–784 (2006).

    CAS  PubMed  Google Scholar 

  19. 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).

    PubMed  Google Scholar 

  20. Sakers, K. et al. Astrocytes locally translate transcripts in their peripheral processes. Proc. Natl Acad. Sci.USA 114, E3830–E3838 (2017).

    CAS  PubMed  Google Scholar 

  21. Bernardinelli, Y. et al. Activity-dependent structural plasticity of perisynaptic astrocytic domains promotes excitatory synapse stability. Curr. Biol. 24, 1679–1688 (2014). This study showed that induction of Ca 2+ transients in astrocytes increases PAP motility and results in enhanced spine stability. Of note, PAPs were activated at individual synapses, resulting in an increased astrocytic coverage and stability of these spines and not of neighboring spines that were contacted by nonactivated PAPs.

    CAS  PubMed  Google Scholar 

  22. Perez-Alvarez, A., Navarrete, M., Covelo, A., Martin, E. D. & Araque, A. Structural and functional plasticity of astrocyte processes and dendritic spine interactions. J. Neurosci. 34, 12738–12744 (2014).

    PubMed  Google Scholar 

  23. Ostroff, L. E., Manzur, M. K., Cain, C. K. & Ledoux, J. E. Synapses lacking astrocyte appear in the amygdala during consolidation of Pavlovian threat conditioning. J. Comp. Neurol. 522, 2152–2163 (2014).

    PubMed  PubMed Central  Google Scholar 

  24. Pannasch, U. et al. Connexin 30 sets synaptic strength by controlling astroglial synapse invasion. Nat. Neurosci. 17, 549–558 (2014). By using connexin-30-knockout mice, this study found that connexin-30, an astrocyte protein known for its role in gap junctions, is also involved in PAP ensheathment of synapses. Increased synaptic ensheathment is associated with reduced synaptic strength and LTP expression in the hippocampus.

    CAS  PubMed  Google Scholar 

  25. Filosa, A. et al. Neuron-glia communication via EphA4/ephrin-A3 modulates LTP through glial glutamate transport. Nat. Neurosci. 12, 1285–1292 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Murai, K. K., Nguyen, L. N., Irie, F., Yamaguchi, Y. & Pasquale, E. B. Control of hippocampal dendritic spine morphology through ephrin-A3/EphA4 signaling. Nat. Neurosci. 6, 153–160 (2003).

    CAS  PubMed  Google Scholar 

  27. Tanaka, M. et al. Astrocytic Ca2+ signals are required for the functional integrity of tripartite synapses. Mol. Brain 6, 6 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Petravicz, J., Boyt, K. M. & McCarthy, K. D. Astrocyte IP3R2-dependent Ca(2+) signaling is not a major modulator of neuronal pathways governing behavior. Front. Behav. Neurosci. 8, 384 (2014).

    PubMed  PubMed Central  Google Scholar 

  29. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Yang, Y. et al. Contribution of astrocytes to hippocampal long-term potentiation through release of d-serine. Proc. Natl Acad. Sci. USA 100, 15194–15199 (2003).

    CAS  PubMed  Google Scholar 

  31. Benneyworth, M. A., Li, Y., Basu, A. C., Bolshakov, V. Y. & Coyle, J. T. Cell selective conditional null mutations of serine racemase demonstrate a predominate localization in cortical glutamatergic neurons. Cell. Mol. Neurobiol. 32, 613–624 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Papouin, T., Dunphy, J. M., Tolman, M., Dineley, K. T. & Haydon, P. G. Septal cholinergic neuromodulation tunes the astrocyte-dependent gating of hippocampal NMDA receptors to wakefulness. Neuron 94, 840–854.e7 (2017). This study shows that astrocyte-derived d-serine levels oscillate according to sleep–wake cycles and this influences learning and memory performance.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Sultan, S. et al. Synaptic integration of adult-born hippocampal neurons is locally controlled by astrocytes. Neuron 88, 957–972 (2015). Using two different approaches to block vesicular release specifically in astrocytes, this study found that d-serine produced by astrocytes enables the unsilencing of new neurons in the adult hippocampus, dendritic spines formation, and their integration in the network. Interestingly, this effect was seen only on dendritic segments that crossed the territories of transgene-expressing astrocytes, indicating a local effect of individual astrocytes.

    CAS  PubMed  Google Scholar 

  34. Toni, N. & Schinder, A. F. Maturation and functional integration of new granule cells into the adult hippocampus. Cold Spring Harb. Perspect. Biol. 8, a018903 (2015).

    PubMed  Google Scholar 

  35. Pascual, O. et al. Astrocytic purinergic signaling coordinates synaptic networks. Science 310, 113–116 (2005).

    CAS  PubMed  Google Scholar 

  36. Slezak, M. et al. Relevance of exocytotic glutamate release from retinal glia. Neuron 74, 504–516 (2012).

    CAS  PubMed  Google Scholar 

  37. Suzuki, A. et al. Astrocyte-neuron lactate transport is required for long-term memory formation. Cell 144, 810–823 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Pellerin, L. & Magistretti, P. J. Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc. Natl Acad. Sci. USA 91, 10625–10629 (1994).

    CAS  PubMed  Google Scholar 

  39. Steinman, M. Q., Gao, V. & Alberini, C. M. The role of lactate-mediated metabolic coupling between astrocytes and neurons in long-term memory formation. Front. Integr. Neurosci. 10, 10 (2016).

    PubMed  PubMed Central  Google Scholar 

  40. Clasadonte, J., Scemes, E., Wang, Z., Boison, D. & Haydon, P. G. Connexin 43-mediated astroglial metabolic networks contribute to the regulation of the sleep-wake cycle. Neuron 95, 1365–1380.e5 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Magistretti, P. J. & Allaman, I. Lactate in the brain: from metabolic end-product to signalling molecule. Nat. Rev. Neurosci. 19, 235–249 (2018).

    CAS  PubMed  Google Scholar 

  42. Herkenham, M. et al. Cannabinoid receptor localization in brain. Proc. Natl Acad. Sci. USA 87, 1932–1936 (1990).

    CAS  PubMed  Google Scholar 

  43. Araque, A., Castillo, P. E., Manzoni, O. J. & Tonini, R. Synaptic functions of endocannabinoid signaling in health and disease. Neuropharmacology 124, 13–24 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Han, J. et al. Acute cannabinoids impair working memory through astroglial CB1 receptor modulation of hippocampal LTD. cell 148, 1039–1050 (2012).This important study demonstrates that hippocampal LTD occurring upon acute exposure to cannabinoids requires activation of type-1 cannabinoid receptors on astrocytes but not on neurons. This astrocyte-mediated signaling pathway appears to be responsible for the impairment of working memory by marijuana.

    CAS  PubMed  Google Scholar 

  45. Navarrete, M. & Araque, A. Endocannabinoids mediate neuron-astrocyte communication. Neuron 57, 883–893 (2008).

    CAS  PubMed  Google Scholar 

  46. Navarrete, M. & Araque, A. Endocannabinoids potentiate synaptic transmission through stimulation of astrocytes. Neuron 68, 113–126 (2010).

    CAS  PubMed  Google Scholar 

  47. Min, R. & Nevian, T. Astrocyte signaling controls spike timing-dependent depression at neocortical synapses. Nat. Neurosci. 15, 746–753 (2012).

    CAS  PubMed  Google Scholar 

  48. Robin, L. M. et al. Astroglial CB1 receptors determine synaptic d-serine availability to enable recognition memory. Neuron 98, 935–944.e5 (2018).

    CAS  PubMed  Google Scholar 

  49. Gómez-Gonzalo, M. et al. Endocannabinoids induce lateral long-term potentiation of transmitter release by stimulation of gliotransmission. Cereb. Cortex 25, 3699–3712 (2015).

    PubMed  Google Scholar 

  50. Andrade-Talavera, Y., Duque-Feria, P., Paulsen, O. & Rodríguez-Moreno, A. Presynaptic spike timing-dependent long-term depression in the mouse hippocampus. Cereb. Cortex 26, 3637–3654 (2016).

    PubMed  PubMed Central  Google Scholar 

  51. Pankratov, Y. & Lalo, U. Role for astroglial α1-adrenoreceptors in gliotransmission and control of synaptic plasticity in the neocortex. Front. Cell. Neurosci. 9, 230 (2015).

    PubMed  PubMed Central  Google Scholar 

  52. Navarrete, M. et al. Astrocytes mediate in vivo cholinergic-induced synaptic plasticity. PLoS Biol. 10, e1001259 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Takata, N. et al. Astrocyte calcium signaling transforms cholinergic modulation to cortical plasticity in vivo. J. Neurosci. 31, 18155–18165 (2011).

    CAS  PubMed  Google Scholar 

  54. Pabst, M. et al. Astrocyte intermediaries of septal cholinergic modulation in the hippocampus. Neuron 90, 853–865 (2016).

    CAS  PubMed  Google Scholar 

  55. Araque, A., Martín, E. D., Perea, G., Arellano, J. I. & Buño, W. Synaptically released acetylcholine evokes Ca2+ elevations in astrocytes in hippocampal slices. J. Neurosci. 22, 2443–2450 (2002).

    CAS  PubMed  Google Scholar 

  56. Lewitus, G. M., Pribiag, H., Duseja, R., St-Hilaire, M. & Stellwagen, D. An adaptive role of TNFα in the regulation of striatal synapses. J. Neurosci. 34, 6146–6155 (2014).

    CAS  PubMed  Google Scholar 

  57. Stellwagen, D. & Malenka, R. C. Synaptic scaling mediated by glial TNF-alpha. Nature 440, 1054–1059 (2006).

    CAS  Google Scholar 

  58. Santello, M. & Volterra, A. TNFα in synaptic function: switching gears. Trends Neurosci. 35, 638–647 (2012).

    CAS  PubMed  Google Scholar 

  59. Yang, S., Zhang, L. S., Gibboni, R., Weiner, B. & Bao, S. Impaired development and competitive refinement of the cortical frequency map in tumor necrosis factor-α-deficient mice. Cereb. Cortex 24, 1956–1965 (2014).

    PubMed  Google Scholar 

  60. Jourdain, P. et al. Glutamate exocytosis from astrocytes controls synaptic strength. Nat. Neurosci. 10, 331–339 (2007).

    CAS  PubMed  Google Scholar 

  61. Santello, M., Bezzi, P. & Volterra, A. TNFα controls glutamatergic gliotransmission in the hippocampal dentate gyrus. Neuron 69, 988–1001 (2011).

    CAS  PubMed  Google Scholar 

  62. Habbas, S. et al. Neuroinflammatory TNFα impairs memory via astrocyte signaling. Cell 163, 1730–1741 (2015). This study identifies a specific astrocytic mechanism linking inflammation to cognitive impairment. Local increase of TNFα in the hippocampal dentate gyrus activates astrocyte TNFR1, which in turn triggers persistent alterations of excitatory synapses. Such synaptic alterations are responsible for the memory deficits displayed by a mouse model of multiple sclerosis.

    CAS  PubMed  Google Scholar 

  63. Buzsáki, G. & Draguhn, A. Neuronal oscillations in cortical networks. Science 304, 1926–1929 (2004).

    PubMed  Google Scholar 

  64. Paukert, M. et al. Norepinephrine controls astroglial responsiveness to local circuit activity. Neuron 82, 1263–1270 (2014). This interesting study introduces the concept of ‘astrocytic priming’, an increase in astrocyte responsiveness to local network activity according to general behavioral state. In particular, startle behavior triggers simultaneous α-noradrenergic activation of astrocytes in multiple brain regions. As a result, astrocytes in visual cortex respond more to light stimulation.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Perea, G. & Araque, A. Properties of synaptically evoked astrocyte calcium signal reveal synaptic information processing by astrocytes. J. Neurosci. 25, 2192–2203 (2005).

    CAS  PubMed  Google Scholar 

  66. Marshall, L., Helgadóttir, H., Mölle, M. & Born, J. Boosting slow oscillations during sleep potentiates memory. Nature 444, 610–613 (2006).

    CAS  PubMed  Google Scholar 

  67. Poskanzer, K. E. & Yuste, R. Astrocytic regulation of cortical UP states. Proc. Natl Acad. Sci. USA 108, 18453–18458 (2011).

    CAS  PubMed  Google Scholar 

  68. Fellin, T. et al. Endogenous nonneuronal modulators of synaptic transmission control cortical slow oscillations in vivo. Proc. Natl Acad. Sci. USA 106, 15037–15042 (2009).

    CAS  PubMed  Google Scholar 

  69. Poskanzer, K. E. & Yuste, R. Astrocytes regulate cortical state switching in vivo. Proc. Natl Acad. Sci. USA 113, E2675–E2684 (2016).In this seminal study, the authors demonstrate that astrocytic calcium transients promote the switch of the somatosensory cortical circuit to a low-frequency state, a neocortical rhythm important for sleep and memory. Noninvasive activation of astrocytes produces transient increases in extracellular glutamate, which would mediate the cortical state switch.

    CAS  PubMed  Google Scholar 

  70. Tan, Z. et al. Glia-derived ATP inversely regulates excitability of pyramidal and CCK-positive neurons. Nat. Commun. 8, 13772 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Lee, H. S. et al. Astrocytes contribute to gamma oscillations and recognition memory. Proc. Natl Acad. Sci. USA 111, E3343–E3352 (2014).In this study, the authors specifically induced tetanus toxin expression in astrocytes and found evidence of a reduction in cortical gamma oscillations, which was accompanied by impaired behavioral performance in the novel object recognition test.

    CAS  PubMed  Google Scholar 

  72. Perea, G. et al. Activity-dependent switch of GABAergic inhibition into glutamatergic excitation in astrocyte-neuron networks. eLife 5, e20362 (2016).

    PubMed  PubMed Central  Google Scholar 

  73. Fellin, T. et al. Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors. Neuron 43, 729–743 (2004).

    CAS  PubMed  Google Scholar 

  74. Sasaki, T., Matsuki, N. & Ikegaya, Y. Action-potential modulation during axonal conduction. Science 331, 599–601 (2011).

    CAS  PubMed  Google Scholar 

  75. Ashhad, S. & Narayanan, R. Active dendrites regulate the impact of gliotransmission on rat hippocampal pyramidal neurons. Proc. Natl Acad. Sci. USA 113, E3280–E3289 (2016).

    CAS  PubMed  Google Scholar 

  76. Bittner, K. C. et al. Conjunctive input processing drives feature selectivity in hippocampal CA1 neurons. Nat. Neurosci. 18, 1133–1142 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Di Castro, M. A. et al. Local Ca2+ detection and modulation of synaptic release by astrocytes. Nat. Neurosci. 14, 1276–1284 (2011).

    PubMed  Google Scholar 

  78. Perea, G. & Araque, A. Astrocytes potentiate transmitter release at single hippocampal synapses. Science 317, 1083–1086 (2007).

    CAS  PubMed  Google Scholar 

  79. Chever, O., Dossi, E., Pannasch, U., Derangeon, M. & Rouach, N. Astroglial networks promote neuronal coordination. Sci. Signal. 9, ra6 (2016).

    PubMed  Google Scholar 

  80. Martin-Fernandez, M. et al. Synapse-specific astrocyte gating of amygdala-related behavior. Nat. Neurosci. 20, 1540–1548 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Newman, L. A., Korol, D. L. & Gold, P. E. Lactate produced by glycogenolysis in astrocytes regulates memory processing. PLoS One 6, e28427 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Jensen, C. J. et al. Astrocytic β2 adrenergic receptor gene deletion affects memory in aged mice. PLoS One 11, e0164721 (2016).

    PubMed  PubMed Central  Google Scholar 

  83. Gao, V. et al. Astrocytic β2-adrenergic receptors mediate hippocampal long-term memory consolidation. Proc. Natl Acad. Sci. USA 113, 8526–8531 (2016).This study reports that noradrenaline signaling via β-receptors, which promotes memory consolidation, occurs in astrocytes and requires release of lactate from these cells. Lactate in turn supports the neuronal molecular changes essential for long-term memory formation.

    CAS  PubMed  Google Scholar 

  84. Dong, J. H. et al. Adaptive activation of a stress response pathway improves learning and memory through Gs and β-arrestin-1-regulated lactate metabolism. Biol. Psychiatry 81, 654–670 (2017).

    CAS  PubMed  Google Scholar 

  85. Abel, T., Havekes, R., Saletin, J. M. & Walker, M. P. Sleep, plasticity and memory from molecules to whole-brain networks. Curr. Biol. 23, R774–R788 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Genzel, L., Kroes, M. C., Dresler, M. & Battaglia, F. P. Light sleep versus slow wave sleep in memory consolidation: a question of global versus local processes? Trends Neurosci. 37, 10–19 (2014).

    CAS  PubMed  Google Scholar 

  87. Norimoto, H. et al. Hippocampal ripples down-regulate synapses. Science 359, 1524–1527 (2018).

    CAS  PubMed  Google Scholar 

  88. Basheer, R., Strecker, R. E., Thakkar, M. M. & McCarley, R. W. Adenosine and sleep-wake regulation. Prog. Neurobiol. 73, 379–396 (2004).

    CAS  PubMed  Google Scholar 

  89. Lalo, U. et al. Exocytosis of ATP from astrocytes modulates phasic and tonic inhibition in the neocortex. PLoS Biol. 12, e1001747 (2014).

    PubMed  PubMed Central  Google Scholar 

  90. Schmitt, L. I., Sims, R. E., Dale, N. & Haydon, P. G. Wakefulness affects synaptic and network activity by increasing extracellular astrocyte-derived adenosine. J. Neurosci. 32, 4417–4425 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Florian, C., Vecsey, C. G., Halassa, M. M., Haydon, P. G. & Abel, T. Astrocyte-derived adenosine and A1 receptor activity contribute to sleep loss-induced deficits in hippocampal synaptic plasticity and memory in mice. J. Neurosci. 31, 6956–6962 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Halassa, M. M. et al. Astrocytic modulation of sleep homeostasis and cognitive consequences of sleep loss. Neuron 61, 213–219 (2009). Using dnSNARE mice (see Box 1 for discussion), this study proposes for the first time a key role for adenosine of astrocytic origin in mediating the negative cognitive consequences of sleep deprivation.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Hamby, M. E. et al. Inflammatory mediators alter the astrocyte transcriptome and calcium signaling elicited by multiple G-protein-coupled receptors. J. Neurosci. 32, 14489–14510 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Teaktong, T. et al. Alzheimer’s disease is associated with a selective increase in alpha7 nicotinic acetylcholine receptor immunoreactivity in astrocytes. Glia 41, 207–211 (2003).

    PubMed  Google Scholar 

  95. Pirttimaki, T. M. et al. α7 Nicotinic receptor-mediated astrocytic gliotransmitter release: Aβ effects in a preclinical Alzheimer’s mouse model. PLoS One 8, e81828 (2013).

    PubMed  PubMed Central  Google Scholar 

  96. Talantova, M. et al. Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Proc. Natl Acad. Sci. USA 110, E2518–E2527 (2013).

    CAS  PubMed  Google Scholar 

  97. Lim, D. et al. Amyloid beta deregulates astroglial mGluR5-mediated calcium signaling via calcineurin and Nf-kB. Glia 61, 1134–1145 (2013).

    PubMed  Google Scholar 

  98. Delekate, A. et al. Metabotropic P2Y1 receptor signalling mediates astrocytic hyperactivity in vivo in an Alzheimer’s disease mouse model. Nat. Commun. 5, 5422 (2014).

    PubMed  Google Scholar 

  99. Orr, A. G. et al. Astrocytic adenosine receptor A2A and Gs-coupled signaling regulate memory. Nat. Neurosci. 18, 423–434 (2015). Using cell-specific mouse genetics, this study reveals the regulatory role of astrocyte adenosine A 2A receptor and its downstream Gs-mediated signaling on long-term memory formation. Prominent upregulation of the system in Alzheimer’s disease patients and mouse models would contribute to memory loss.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Hardt, O., Nader, K. & Nadel, L. Decay happens: the role of active forgetting in memory. Trends Cogn. Sci. 17, 111–120 (2013).

    PubMed  Google Scholar 

  101. Orr, A. G. et al. Istradefylline reduces memory deficits in aging mice with amyloid pathology. Neurobiol. Dis. 110, 29–36 (2018).

    CAS  PubMed  Google Scholar 

  102. Matos, M. et al. Deletion of adenosine A2A receptors from astrocytes disrupts glutamate homeostasis leading to psychomotor and cognitive impairment: relevance to schizophrenia. Biol. Psychiatry 78, 763–774 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Mitew, S., Kirkcaldie, M. T., Dickson, T. C. & Vickers, J. C. Altered synapses and gliotransmission in Alzheimer’s disease and AD model mice. Neurobiol. Aging 34, 2341–2351 (2013).

    CAS  PubMed  Google Scholar 

  104. Wu, Z., Guo, Z., Gearing, M. & Chen, G. Tonic inhibition in dentate gyrus impairs long-term potentiation and memory in an Alzheimer’s disease model. Nat. Commun. 5, 4159 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Jo, S. et al. GABA from reactive astrocytes impairs memory in mouse models of Alzheimer’s disease. Nat. Med. 20, 886–896 (2014).

    CAS  PubMed  Google Scholar 

  106. Busche, M. A. & Konnerth, A. Impairments of neural circuit function in Alzheimer’s disease. Phil. Trans. R. Soc. Lond. B 371, 20150429 (2016).

    Google Scholar 

  107. Palop, J. J. & Mucke, L. Amyloid-beta-induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks. Nat. Neurosci. 13, 812–818 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Li, S. et al. Soluble oligomers of amyloid Beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron 62, 788–801 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Fogel, H. et al. APP homodimers transduce an amyloid-β-mediated increase in release probability at excitatory synapses. Cell Rep. 7, 1560–1576 (2014).

    CAS  PubMed  Google Scholar 

  110. Verret, L. et al. Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model. Cell 149, 708–721 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Kuchibhotla, K. V., Lattarulo, C. R., Hyman, B. T. & Bacskai, B. J. Synchronous hyperactivity and intercellular calcium waves in astrocytes in Alzheimer mice. Science 323, 1211–1215 (2009). By measuring Ca 2+ dynamics in astrocytes in vivo in a mouse model of Alzheimer’s disease, this study was the first to identify a functional alteration (hyperactivity) of glial networks, in complement to the imbalances observed by others in neuronal networks.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Gómez-Gonzalo, M. et al. Neuron-astrocyte signaling is preserved in the aging brain. Glia 65, 569–580 (2017).

    PubMed  PubMed Central  Google Scholar 

  113. Abramov, A. Y., Canevari, L. & Duchen, M. R. Changes in intracellular calcium and glutathione in astrocytes as the primary mechanism of amyloid neurotoxicity. J. Neurosci. 23, 5088–5095 (2003).

    CAS  PubMed  Google Scholar 

  114. Makitani, K., Nakagawa, S., Izumi, Y., Akaike, A. & Kume, T. Inhibitory effect of donepezil on bradykinin-induced increase in the intracellular calcium concentration in cultured cortical astrocytes. J. Pharmacol. Sci. 134, 37–44 (2017).

    CAS  PubMed  Google Scholar 

  115. Reichenbach, N. et al. P2Y1 receptor blockade normalizes network dysfunction and cognition in an Alzheimer’s disease model. J. Exp. Med. 215, 1649–1663 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Fischer, R., Kontermann, R. E. & Maier, O. Targeting sTNF/TNFR1 signaling as a new therapeutic strategy. Antibodies (Basel) 4, (48–70 (2015).

    Google Scholar 

  117. Cavanagh, C. et al. Inhibiting tumor necrosis factor-α before amyloidosis prevents synaptic deficits in an Alzheimer’s disease model. Neurobiol. Aging 47, 41–49 (2016).

    CAS  PubMed  Google Scholar 

  118. D’Ascenzo, M., Podda, M. V. & Grassi, C. The role of d-serine as co-agonist of NMDA receptors in the nucleus accumbens: relevance to cocaine addiction. Front. Synaptic Neurosci. 6, 16 (2014).

    PubMed  PubMed Central  Google Scholar 

  119. Scofield, M. D. et al. Gq-DREADD selectively initiates glial glutamate release and inhibits cue-induced cocaine seeking. Biol. Psychiatry 78, 441–451 (2015).

    CAS  PubMed  Google Scholar 

  120. Curcio, L. et al. Reduced d-serine levels in the nucleus accumbens of cocaine-treated rats hinder the induction of NMDA receptor-dependent synaptic plasticity. Brain 136, 1216–1230 (2013). In this study, the authors show that cocaine-treated rats present reduced d-serine levels in the nucleus accumbens. This reduction impairs long-term synaptic plasticity, thereby favoring behavioral sensitization to cocaine.

    PubMed  Google Scholar 

  121. Liu, Z. Q. et al. d-Serine in the nucleus accumbens region modulates behavioral sensitization and extinction of conditioned place preference. Pharmacol. Biochem. Behav. 143, 44–56 (2016).

    CAS  PubMed  Google Scholar 

  122. Hammond, S., Seymour, C. M., Burger, A. & Wagner, J. J. d-Serine facilitates the effectiveness of extinction to reduce drug-primed reinstatement of cocaine-induced conditioned place preference. Neuropharmacology 64, 464–471 (2013).

    CAS  PubMed  Google Scholar 

  123. Kelamangalath, L. & Wagner, J. J. d-Serine treatment reduces cocaine-primed reinstatement in rats following extended access to cocaine self-administration. Neuroscience 169, 1127–1135 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Seif, T. et al. d-Serine and d-cycloserine reduce compulsive alcohol intake in rats. Neuropsychopharmacology 40, 2357–2367 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Wu, J., Zhao, R., Guo, L. & Zhen, X. Morphine-induced inhibition of Ca2+ -dependent d-serine release from astrocytes suppresses excitability of GABAergic neurons in the nucleus accumbens. Addict. Biol. 22, 1289–1303 (2017).

    CAS  PubMed  Google Scholar 

  126. Boury-Jamot, B. et al. Disrupting astrocyte-neuron lactate transfer persistently reduces conditioned responses to cocaine. Mol. Psychiatry 21, 1070–1076 (2016).

    CAS  PubMed  Google Scholar 

  127. Zhang, Y. et al. Inhibition of lactate transport erases drug memory and prevents drug relapse. Biol. Psychiatry 79, 928–939 (2016).

    CAS  PubMed  Google Scholar 

  128. Panatier, A. Astrocytes are endogenous regulators of basal transmission at central synapses. Cell 146, 785–798 (2011).

    CAS  PubMed  Google Scholar 

  129. Halassa, M. M., Fellin, T., Takano, H., Dong, J. H. & Haydon, P. G. Synaptic islands defined by the territory of a single astrocyte. J. Neurosci. 27, 6473–6477 (2007).

    CAS  PubMed  Google Scholar 

  130. Fields, R. D. et al. Glial biology in learning and cognition. Neuroscientist 20, 426–431 (2014).

    PubMed  PubMed Central  Google Scholar 

  131. Porto-Pazos, A. B. et al. Artificial astrocytes improve neural network performance. PLoS One 6, e19109 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Amiri, M., Hosseinmardi, N., Bahrami, F. & Janahmadi, M. Astrocyte- neuron interaction as a mechanism responsible for generation of neural synchrony: a study based on modeling and experiments. J. Comput. Neurosci. 34, 489–504 (2013).

    PubMed  Google Scholar 

  133. Tewari, S. & Parpura, V. A possible role of astrocytes in contextual memory retrieval: An analysis obtained using a quantitative framework. Front. Comput. Neurosci. 7, 145 (2013).

    PubMed  PubMed Central  Google Scholar 

  134. 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).

    CAS  PubMed  Google Scholar 

  135. Otte, D. M. et al. Effects of chronic d-serine elevation on animal models of depression and anxiety-related behavior. PLoS One 8, e67131 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Chen, N. et al. Nucleus basalis-enabled stimulus-specific plasticity in the visual cortex is mediated by astrocytes. Proc. Natl Acad. Sci. USA 109, E2832–E2841 (2012).

    CAS  PubMed  Google Scholar 

  137. Saab, A. S. et al. Bergmann glial AMPA receptors are required for fine motor coordination. Science 337, 749–753 (2012).

    CAS  PubMed  Google Scholar 

  138. Fiacco, T. A. et al. Selective stimulation of astrocyte calcium in situ does not affect neuronal excitatory synaptic activity. Neuron 54, 611–626 (2007).

    CAS  PubMed  Google Scholar 

  139. Fujita, T. et al. Neuronal transgene expression in dominant-negative SNARE mice. J. Neurosci. 34, 16594–16604 (2014).

    PubMed  PubMed Central  Google Scholar 

  140. Chai, H. et al. Neural circuit-specialized astrocytes: transcriptomic, proteomic, morphological, and functional evidence. Neuron 95, 531–549.e9 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Sharma, K. et al. Cell type- and brain region-resolved mouse brain proteome. Nat. Neurosci. 18, 1819–1831 (2015).

    CAS  PubMed  Google Scholar 

  142. Jahn, H. M., Scheller, A. & Kirchhoff, F. Genetic control of astrocyte function in neural circuits. Front. Cell. Neurosci. 9, 310 (2015).

    PubMed  PubMed Central  Google Scholar 

  143. Hirrlinger, P. G., Scheller, A., Braun, C., Hirrlinger, J. & Kirchhoff, F. Temporal control of gene recombination in astrocytes by transgenic expression of the tamoxifen-inducible DNA recombinase variant CreERT2. Glia 54, 11–20 (2006).

    PubMed  Google Scholar 

  144. Srinivasan, R. et al. New transgenic mouse lines for selectively targeting astrocytes and studying calcium signals in astrocyte processes in situ and in vivo. Neuron 92, 1181–1195 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Winchenbach, J. et al. Inducible targeting of CNS astrocytes in Aldh1l1-CreERT2 BAC transgenic mice. F1000Res. 5, 2934 (2016).

    PubMed  PubMed Central  Google Scholar 

  146. Metzger, D., Clifford, J., Chiba, H. & Chambon, P. Conditional site-specific recombination in mammalian cells using a ligand-dependent chimeric Cre recombinase. Proc. Natl Acad. Sci. USA 92, 6991–6995 (1995).

    CAS  PubMed  Google Scholar 

  147. Sauer, B. & Henderson, N. Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. Proc. Natl Acad. Sci. USA 85, 5166–5170 (1988).

    CAS  PubMed  Google Scholar 

  148. Gossen, M. & Bujard, H. Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc. Natl Acad. Sci. USA 89, 5547–5551 (1992).

    CAS  PubMed  Google Scholar 

  149. Gebara, E. et al. Heterogeneity of radial glia-like cells in the adult hippocampus. Stem Cells 34, 997–1010 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Mori, T. et al. Inducible gene deletion in astroglia and radial glia--a valuable tool for functional and lineage analysis. Glia 54, 21–34 (2006).

    PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank I. Savtchouk for helpful discussions and support in figure preparation and S. Berry for proofreading the manuscript. Research in the Volterra laboratory is supported by the ERC Advanced grant 340368 “Astromnesis”, by Swiss National Science Foundation grants 31003A 173124/1, NCCR “Synapsy” (51NF40-158776) and NCCR “Transcure” (51NF40-160620), and by Synapsis Foundation. M.S. is supported by the Swiss National Science Foundation “Ambizione” grant PP00P3_176838 and by the Novartis Foundation for medical-biological Research grant #17C157. N.T. is supported by the Swiss National Science Foundation, grant 31003A-173128.

Author information

Authors and Affiliations

  1. Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland

    Mirko Santello

  2. Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland

    Mirko Santello

  3. Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Prilly-Lausanne, Switzerland

    Nicolas Toni

  4. Department of Fundamental Neuroscience, University of Lausanne, Lausanne, Switzerland

    Andrea Volterra

Authors
  1. Mirko Santello
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicolas Toni
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrea Volterra
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andrea Volterra.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Santello, M., Toni, N. & Volterra, A. Astrocyte function from information processing to cognition and cognitive impairment. Nat Neurosci 22, 154–166 (2019). https://doi.org/10.1038/s41593-018-0325-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41593-018-0325-8

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing