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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.

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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.

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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.

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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.

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Correspondence to Thomas Nevian.

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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

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