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.

  • Article
  • Published:

Astrocyte signaling controls spike timing–dependent depression at neocortical synapses

Abstract

Endocannabinoid mediated spike timing–dependent depression (t-LTD) is crucially involved in the development of the sensory neocortex. t-LTD at excitatory synapses in the developing rat barrel cortex requires cannabinoid CB1 receptor (CB1R) activation, as well as activation of NMDA receptors located on the presynaptic terminal, but the exact signaling cascade leading to t-LTD remains unclear. We found that astrocytes are critically involved in t-LTD. Astrocytes gradually increased their Ca2+ signaling specifically during the induction of t-LTD in a CB1R-dependent manner. In this way, astrocytes might act as a memory buffer for previous coincident neuronal activity. Following activation, astrocytes released glutamate, which activated presynaptic NMDA receptors to induce t-LTD. Astrocyte stimulation coincident with afferent activity resulted in long-term depression, indicating that astrocyte activation is sufficient for the induction of synaptic depression. Taken together, our findings describe the retrograde signaling cascade underlying neocortical t-LTD. The critical involvement of astrocytes in this process highlights their importance for experience-dependent sensory remodeling.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: t-LTD induction results in endocannabinoid-dependent increases in astrocyte Ca2+ signaling.
Figure 2: Visualization of functional CB1Rs on cortical astrocytes.
Figure 3: Distribution of astrocyte Ca2+ transients during t-LTD induction.
Figure 4: Spike-timing dependence of astrocytic Ca2+ signaling.
Figure 5: Astrocytic Ca2+ clamp blocks t-LTD in neighboring pyramidal neurons.
Figure 6: t-LTD requires SNARE-mediated exocytosis of glutamate from astrocytes.
Figure 7: Astrocyte stimulation induces LTD in a neighboring pyramidal neuron.

Similar content being viewed by others

References

  1. Bliss, T.V. & Collingridge, G.L. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31–39 (1993).

    Article  CAS  Google Scholar 

  2. Dan, Y. & Poo, M.M. Spike timing-dependent plasticity: from synapse to perception. Physiol. Rev. 86, 1033–1048 (2006).

    Article  Google Scholar 

  3. Feldman, D.E. & Brecht, M. Map plasticity in somatosensory cortex. Science 310, 810–815 (2005).

    Article  CAS  Google Scholar 

  4. Li, L. et al. Endocannabinoid signaling is required for development and critical period plasticity of the whisker map in somatosensory cortex. Neuron 64, 537–549 (2009).

    Article  CAS  Google Scholar 

  5. Bender, K.J., Allen, C.B., Bender, V.A. & Feldman, D.E. Synaptic basis for whisker deprivation–induced synaptic depression in rat somatosensory cortex. J. Neurosci. 26, 4155–4165 (2006).

    Article  CAS  Google Scholar 

  6. Bender, V.A., Bender, K.J., Brasier, D.J. & Feldman, D.E. Two coincidence detectors for spike timing–dependent plasticity in somatosensory cortex. J. Neurosci. 26, 4166–4177 (2006).

    Article  CAS  Google Scholar 

  7. Nevian, T. & Sakmann, B. Spine Ca2+ signaling in spike timing–dependent plasticity. J. Neurosci. 26, 11001–11013 (2006).

    Article  CAS  Google Scholar 

  8. Rodríguez-Moreno, A. & Paulsen, O. Spike timing–dependent long-term depression requires presynaptic NMDA receptors. Nat. Neurosci. 11, 744–745 (2008).

    Article  Google Scholar 

  9. Sjöstrom, P.J., Turrigiano, G.G. & Nelson, S.B. Neocortical LTD via coincident activation of presynaptic NMDA and cannabinoid receptors. Neuron 39, 641–654 (2003).

    Article  Google Scholar 

  10. Corlew, R., Wang, Y., Ghermazien, H., Erisir, A. & Philpot, B.D. Developmental switch in the contribution of presynaptic and postsynaptic NMDA receptors to long-term depression. J. Neurosci. 27, 9835–9845 (2007).

    Article  CAS  Google Scholar 

  11. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Haydon, P.G. & Carmignoto, G. Astrocyte control of synaptic transmission and neurovascular coupling. Physiol. Rev. 86, 1009–1031 (2006).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  17. Parpura, V. et al. Glutamate-mediated astrocyte-neuron signaling. Nature 369, 744–747 (1994).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  20. Feldman, D.E. Timing-based LTP and LTD at vertical inputs to layer II/III pyramidal cells in rat barrel cortex. Neuron 27, 45–56 (2000).

    Article  CAS  Google Scholar 

  21. Heifets, B.D. & Castillo, P.E. Endocannabinoid signaling and long-term synaptic plasticity. Annu. Rev. Physiol. 71, 283–306 (2009).

    Article  CAS  Google Scholar 

  22. Bodor, A.L. et al. Endocannabinoid signaling in rat somatosensory cortex: laminar differences and involvement of specific interneuron types. J. Neurosci. 25, 6845–6856 (2005).

    Article  CAS  Google Scholar 

  23. Schiavo, G. et al. Tetanus and botulinum-B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin. Nature 359, 832–835 (1992).

    Article  CAS  Google Scholar 

  24. Bezzi, P. et al. Astrocytes contain a vesicular compartment that is competent for regulated exocytosis of glutamate. Nat. Neurosci. 7, 613–620 (2004).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  26. Bellocchio, E.E., Reimer, R.J., Fremeau, R.T. Jr. & Edwards, R.H. Uptake of glutamate into synaptic vesicles by an inorganic phosphate transporter. Science 289, 957–960 (2000).

    Article  CAS  Google Scholar 

  27. Harkany, T. et al. Endocannabinoid-independent retrograde signaling at inhibitory synapses in layer 2/3 of neocortex: involvement of vesicular glutamate transporter 3. J. Neurosci. 24, 4978–4988 (2004).

    Article  CAS  Google Scholar 

  28. Kang, J., Jiang, L., Goldman, S.A. & Nedergaard, M. Astrocyte-mediated potentiation of inhibitory synaptic transmission. Nat. Neurosci. 1, 683–692 (1998).

    Article  CAS  Google Scholar 

  29. Gordon, G.R. et al. Astrocyte-mediated distributed plasticity at hypothalamic glutamate synapses. Neuron 64, 391–403 (2009).

    Article  CAS  Google Scholar 

  30. Kakegawa, W. et al. D-serine regulates cerebellar LTD and motor coordination through the delta2 glutamate receptor. Nat. Neurosci. 14, 603–611 (2011).

    Article  CAS  Google Scholar 

  31. Duguid, I. & Sjostrom, P.J. Novel presynaptic mechanisms for coincidence detection in synaptic plasticity. Curr. Opin. Neurobiol. 16, 312–322 (2006).

    Article  CAS  Google Scholar 

  32. Fortin, D.A. & Levine, E.S. Differential effects of endocannabinoids on glutamatergic and GABAergic inputs to layer 5 pyramidal neurons. Cereb. Cortex 17, 163–174 (2007).

    Article  Google Scholar 

  33. Hill, E.L. et al. Functional CB1 receptors are broadly expressed in neocortical GABAergic and glutamatergic neurons. J. Neurophysiol. 97, 2580–2589 (2007).

    Article  CAS  Google Scholar 

  34. Hashimotodani, Y. et al. Phospholipase Cbeta serves as a coincidence detector through its Ca2+ dependency for triggering retrograde endocannabinoid signal. Neuron 45, 257–268 (2005).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  36. Larsen, R.S. et al. NR3A-containing NMDARs promote neurotransmitter release and spike timing-dependent plasticity. Nat. Neurosci. 14, 338–344 (2011).

    Article  CAS  Google Scholar 

  37. Chevaleyre, V., Heifets, B.D., Kaeser, P.S., Sudhof, T.C. & Castillo, P.E. Endocannabinoid-mediated long-term plasticity requires cAMP/PKA signaling and RIM1alpha. Neuron 54, 801–812 (2007).

    Article  CAS  Google Scholar 

  38. Heifets, B.D., Chevaleyre, V. & Castillo, P.E. Interneuron activity controls endocannabinoid-mediated presynaptic plasticity through calcineurin. Proc. Natl. Acad. Sci. USA 105, 10250–10255 (2008).

    Article  CAS  Google Scholar 

  39. Tsetsenis, T. et al. Rab3B protein is required for long-term depression of hippocampal inhibitory synapses and for normal reversal learning. Proc. Natl. Acad. Sci. USA 108, 14300–14305 (2011).

    Article  CAS  Google Scholar 

  40. Castillo, P.E. et al. Rab3A is essential for mossy fibre long-term potentiation in the hippocampus. Nature 388, 590–593 (1997).

    CAS  PubMed  Google Scholar 

  41. Castillo, P.E., Schoch, S., Schmitz, F., Sudhof, T.C. & Malenka, R.C. RIM1alpha is required for presynaptic long-term potentiation. Nature 415, 327–330 (2002).

    CAS  PubMed  Google Scholar 

  42. Fourcaudot, E. et al. cAMP/PKA signaling and RIM1alpha mediate presynaptic LTP in the lateral amygdala. Proc. Natl. Acad. Sci. USA 105, 15130–15135 (2008).

    Article  CAS  Google Scholar 

  43. Froemke, R.C., Poo, M.M. & Dan, Y. Spike timing–dependent synaptic plasticity depends on dendritic location. Nature 434, 221–225 (2005).

    Article  CAS  Google Scholar 

  44. Zilberter, M. et al. Input specificity and dependence of spike timing–dependent plasticity on preceding postsynaptic activity at unitary connections between neocortical layer 2/3 pyramidal cells. Cereb. Cortex 19, 2308–2320 (2009).

    Article  Google Scholar 

  45. Chevaleyre, V. & Castillo, P.E. Heterosynaptic LTD of hippocampal GABAergic synapses: a novel role of endocannabinoids in regulating excitability. Neuron 38, 461–472 (2003).

    Article  CAS  Google Scholar 

  46. Huang, Y., Yasuda, H., Sarihi, A. & Tsumoto, T. Roles of endocannabinoids in heterosynaptic long-term depression of excitatory synaptic transmission in visual cortex of young mice. J. Neurosci. 28, 7074–7083 (2008).

    Article  CAS  Google Scholar 

  47. 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).

    Article  CAS  Google Scholar 

  48. Grosche, J. et al. Microdomains for neuron-glia interaction: parallel fiber signaling to Bergmann glial cells. Nat. Neurosci. 2, 139–143 (1999).

    Article  CAS  Google Scholar 

  49. Verkhratsky, A. & Kettenmann, H. Calcium signaling in glial cells. Trends Neurosci. 19, 346–352 (1996).

    Article  CAS  Google Scholar 

  50. Harvey, C.D., Yasuda, R., Zhong, H. & Svoboda, K. The spread of Ras activity triggered by activation of a single dendritic spine. Science 321, 136–140 (2008).

    Article  CAS  Google Scholar 

  51. Agmon, A. & Connors, B.W. Thalamocortical responses of mouse somatosensory (barrel) cortex in vitro. Neuroscience 41, 365–379 (1991).

    Article  CAS  Google Scholar 

  52. Göbel, W., Kampa, B.M. & Helmchen, F. Imaging cellular network dynamics in three dimensions using fast 3D laser scanning. Nat. Methods 4, 73–79 (2007).

    Article  Google Scholar 

Download references

Acknowledgements

We thank A. Volterra, H.D. Mansvelder, H.-R. Lüscher, M. Santello, L.M. Palmer and E. Perez-Garci for their comments on the manuscript. This work was supported by the Swiss National Science Foundation (T.N., grant 3100A0-118395) and an Equipment grant of the Berne University Research Foundation.

Author information

Authors and Affiliations

Authors

Contributions

R.M. and T.N. designed the experiments. R.M. performed the experiments. R.M. and T.N. analyzed the data and wrote the manuscript.

Corresponding author

Correspondence to Thomas Nevian.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5 (PDF 1374 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Min, R., Nevian, T. Astrocyte signaling controls spike timing–dependent depression at neocortical synapses. Nat Neurosci 15, 746–753 (2012). https://doi.org/10.1038/nn.3075

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.3075

This article is cited by

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