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:

Ca2+-dependent enhancement of release by subthreshold somatic depolarization

Nature Neuroscience volume 14, pages 62–68 (2011)Cite this article

Subjects

Abstract

In many neurons, subthreshold somatic depolarization can spread electrotonically into the axon and modulate subsequent spike-evoked transmission. Although release probability is regulated by intracellular Ca2+, the Ca2+ dependence of this modulatory mechanism has been debated. Using paired recordings from synaptically connected molecular layer interneurons (MLIs) of the rat cerebellum, we observed Ca2+-mediated strengthening of release following brief subthreshold depolarization of the soma. Two-photon microscopy revealed that, at the axon, somatic depolarization evoked Ca2+ influx through voltage-sensitive Ca2+ channels and facilitated spike-evoked Ca2+ entry. Exogenous Ca2+ buffering diminished these Ca2+ transients and eliminated the strengthening of release. Axonal Ca2+ entry elicited by subthreshold somatic depolarization also triggered asynchronous transmission that may deplete vesicle availability and thereby temper release strengthening. In this cerebellar circuit, activity-dependent presynaptic plasticity depends on Ca2+ elevations resulting from both sub- and suprathreshold electrical activity initiated at the soma.

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

Figure 1: Subthreshold somatic depolarization enhances spike-evoked release in MLIs.
Figure 2: Subthreshold somatic depolarization evokes and enhances axonal Ca2+ entry.
Figure 3: Subthreshold depolarization–dependent Ca2+ signaling is EGTA sensitive.
Figure 4: EGTA inhibits enhancement of release elicited by subthreshold depolarization.
Figure 5: Subthreshold depolarization evokes asynchronous release.
Figure 6: Depolarization-dependent asynchronous release is triggered by VSCCs.
Figure 7: Burst firing reduces the capacity for release enhancement caused by depolarization.

Similar content being viewed by others

References

  1. Alle, H. & Geiger, J.R.P. Combined analog and action potential coding in hippocampal mossy fibers. Science 311, 1290–1293 (2006).

    Article  CAS  Google Scholar 

  2. Shu, Y., Hasenstaub, A., Duque, A., Yu, Y. & McCormick, D.A. Modulation of intracortical synaptic potentials by presynaptic somatic membrane potential. Nature 441, 761–765 (2006).

    Article  CAS  Google Scholar 

  3. Kole, M.H.P., Letzkus, J.J. & Stuart, G.J. Axon initial segment Kv1 channels control action potential waveform and synaptic efficacy. Neuron 55, 633–647 (2007).

    Article  CAS  Google Scholar 

  4. Bollmann, J.H., Sakmann, B. & Borst, J.G.G. Calcium sensitivity of a glutamate release in a calyx-type terminal. Science 289, 953–957 (2000).

    Article  CAS  Google Scholar 

  5. Schneggenburger, R. & Neher, E. Intracellular calcium dependence of transmitter release rates at a fast synapse. Nature 406, 889–893 (2000).

    Article  CAS  Google Scholar 

  6. Zucker, R.S. & Regehr, W.G. Short-term synaptic plasticity. Annu. Rev. Physiol. 64, 355–405 (2002).

    Article  CAS  Google Scholar 

  7. Sabatini, B.L. & Regehr, W.G. Control of neurotransmitter release by presynaptic waveform at the granule to Purkinje cell synapse. J. Neurosci. 17, 3425–3435 (1997).

    Article  CAS  Google Scholar 

  8. Borst, J.G.G. & Sakmann, B. Calcium influx and transmitter release in a fast CNS synapse. Nature 383, 431–434 (1996).

    Article  CAS  Google Scholar 

  9. Bischofberger, J., Geiger, J.R. & Jonas, P. Timing and efficacy of Ca2+ channel activation in hippocampal mossy fiber boutons. J. Neurosci. 22, 10593–10602 (2002).

    Article  CAS  Google Scholar 

  10. Brenowitz, S.D. & Regehr, W.G. Reliability and heterogeneity of calcium signaling at single presynaptic boutons of cerebellar granule cells. J. Neurosci. 27, 7888–7898 (2007).

    Article  CAS  Google Scholar 

  11. Awatramani, G.B., Price, G.D. & Trussell, L.O. Modulation of transmitter release by presynaptic resting potential and background calcium levels. Neuron 48, 109–121 (2005).

    Article  CAS  Google Scholar 

  12. Hori, T. & Takahashi, T. Mechanisms underlying short-term modulation of transmitter release by presynaptic depolarization. J. Physiol. (Lond.) 587, 2987–3000 (2009).

    Article  CAS  Google Scholar 

  13. 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).

    Article  CAS  Google Scholar 

  14. Trigo, F.F. et al. Presynaptic miniature Gabaergic currents in developing interneurons. Neuron 66, 235–247 (2010).

    Article  CAS  Google Scholar 

  15. Palay, S.L. & Chan-Palay, V. Cerebellar Cortex: Cytology and Organization (Springer-Verlag, New York, 1974).

  16. Mejia-Gervacio, S. et al. Axonal speeding: shaping synaptic potentials in small neurons by the axonal membrane compartment. Neuron 53, 843–855 (2007).

    Article  CAS  Google Scholar 

  17. Glitsch, M. & Marty, A. Presynaptic effects of NMDA in cerebellar Purkinje cells and interneurons. J. Neurosci. 19, 511–519 (1999).

    Article  CAS  Google Scholar 

  18. Christie, J.M. & Jahr, C.E. Dendritic NMDA receptors activate axonal calcium channels. Neuron 60, 298–307 (2008).

    Article  CAS  Google Scholar 

  19. Vincent, P. & Marty, A. Fluctuations of inhibitory postsynaptic currents in Purkinje cells from rat cerebellar slices. J. Physiol. (Lond.) 494, 183–199 (1996).

    Article  CAS  Google Scholar 

  20. Diana, M.A. & Marty, A. Characterization of depolarization-induced suppression of inhibition using paired interneuron–Purkinje cell recordings. J. Neurosci. 23, 5906–5918 (2003).

    Article  CAS  Google Scholar 

  21. Llano, I., Tan, Y.P. & Caputo, C. Spatial heterogeneity of intracellular Ca2+ signals in axons of basket cells from the rat cerebellar slices. J. Physiol. (Lond.) 502, 509–519 (1997).

    Article  CAS  Google Scholar 

  22. Forti, L., Pouzat, C. & Llano, I. Action potential–evoked Ca2+ signals and calcium channels in the axons of developing cerebellar interneurons. J. Physiol. (Lond.) 527, 33–48 (2000).

    Article  CAS  Google Scholar 

  23. Tottene, A., Moretti, A. & Pietrobon, D. Functional diversity of P-type and R-type calcium channels in rat cerebellar neurons. J. Neurosci. 16, 6353–6363 (1996).

    Article  CAS  Google Scholar 

  24. Metz, A.E., Jarsky, T., Martina, M. & Spruston, N. R-type calcium channels contribute to afterdepolarization and bursting in hippocampal CA1 pyramidal neurons. J. Neurosci. 25, 5763–5773 (2005).

    Article  CAS  Google Scholar 

  25. Borst, J.G.G. & Sakmann, B. Facilitation of presynaptic calcium currents in the rat brainstem. J. Physiol. (Lond.) 513, 149–155 (1998).

    Article  CAS  Google Scholar 

  26. Cuttle, M.F., Tsujimoto, T., Forsythe, I.D. & Takahashi, T. Facilitation of the presynaptic calcium current at an auditory synapse in the rat brainstem. J. Physiol. (Lond.) 512, 723–729 (1998).

    Article  CAS  Google Scholar 

  27. Atluri, P.P. & Regehr, W.G. Determinants of the time course of facilitation at the granule cell to Purkinje cell synapse. J. Neurosci. 16, 5661–5671 (1996).

    Article  CAS  Google Scholar 

  28. Bucurenciu, I., Kulik, A., Schwaller, B., Frotscher, M. & Jonas, P. Nanodomain coupling between Ca2+ channels and Ca2+ sensors promotes fast and efficient transmitter release at a cortical GABAergic synapse. Neuron 57, 536–545 (2008).

    Article  CAS  Google Scholar 

  29. Bucurenciu, I., Bischofberger, J. & Jonas, P. A small number of open Ca2+ channels trigger transmitter release at a central GABAergic synapse. Nat. Neurosci. 13, 19–21 (2010).

    Article  CAS  Google Scholar 

  30. Dittman, J.S., Kreitzer, A.C. & Regehr, W.G. Interplay between facilitation, depression, and residual calcium at three presynaptic terminals. J. Neurosci. 20, 1374–1385 (2000).

    Article  CAS  Google Scholar 

  31. Müller, M., Goutman, J.D., Kochubey, O. & Schneggenburger, R. Interaction between facilitation and depression at a large CNS synapse reveals mechanisms of short-term plasticity. J. Neurosci. 30, 2007–2016 (2010).

    Article  Google Scholar 

  32. Atluri, P.P. & Regehr, W.G. Delayed release of neurotransmitter from cerebellar granule cells. J. Neurosci. 18, 8214–8227 (1998).

    Article  CAS  Google Scholar 

  33. Lu, T. & Trussell, L.O. Inhibitory transmission mediated by asynchronous transmitter release. Neuron 26, 683–694 (2000).

    Article  CAS  Google Scholar 

  34. Otsu, Y. et al. Competition between phasic and synchronous release for recovered synaptic vesicles at developing hippocampal autaptic synapses. J. Neurosci. 24, 420–433 (2004).

    Article  CAS  Google Scholar 

  35. Christie, J.M. & Jahr, C.E. Selective expression of ligand-gated ion channels in L5 pyramidal cell axons. J. Neurosci. 29, 11441–11450 (2009).

    Article  CAS  Google Scholar 

  36. Li, L., Bischofberger, J. & Jonas, P. Differential gating and recruitment of P/Q-, N-, and R-type Ca2+ channels in hippocampal mossy fiber boutons. J. Neurosci. 27, 13420–13429 (2007).

    Article  CAS  Google Scholar 

  37. Wu, L.-G., Borst, J.G.G. & Sakmann, B. R-type Ca2+ currents evoke transmitter release at a rat central synapse. Proc. Natl. Acad. Sci. USA 95, 4720–4725 (1998).

    Article  CAS  Google Scholar 

  38. Llano, I. et al. Presynaptic calcium stores underlie large-amplitude miniature IPSCs and spontaneous calcium transients. Nat. Neurosci. 3, 1256–1265 (2000).

    Article  CAS  Google Scholar 

  39. Tsujimoto, T., Jeromin, A., Saitoh, N., Roder, J.C. & Takahashi, T. Neural calcium sensor 1 and activity-dependent facilitation of P/Q-type calcium currents at presynaptic nerve terminals. Science 295, 2276–2279 (2002).

    Article  CAS  Google Scholar 

  40. Jinno, S., Jeromin, A., Roder, J. & Kosaka, T. Immunocytochemical localization of neural calcium sensor 1 in the hippocampus and cerebellum of the mouse, with special reference to presynaptic terminals. Neuroscience 113, 449–461 (2002).

    Article  CAS  Google Scholar 

  41. Jinno, S., Jeromin, A. & Kasaka, T. Expression and possible role of neuronal calcium sensor-1 in the cerebellum. Cerebellum 3, 83–88 (2004).

    Article  CAS  Google Scholar 

  42. Geiger, J.R.P. & Jonas, P. Dynamic control of presynaptic Ca2+ inflow by fast-inactivating K+ channels in hippocampal mossy fiber boutons. Neuron 28, 927–939 (2000).

    Article  CAS  Google Scholar 

  43. Turecek, R. & Trussell, L.O. Presynaptic glycine receptors enhance transmitter release at a mammalian central synapse. Nature 411, 587–590 (2001).

    Article  CAS  Google Scholar 

  44. Felmy, F., Neher, E. & Schneggenburger, R. Probing the intracellular calcium sensitivity of transmitter release during synaptic facilitation. Neuron 37, 801–811 (2003).

    Article  CAS  Google Scholar 

  45. Müller, M., Felmy, F. & Schneggenburger, R. A limited contribution of Ca2+ current facilitation to paired-pulse facilitation of transmitter release at the rat calyx of Held. J. Physiol. (Lond.) 586, 5503–5520 (2008).

    Article  Google Scholar 

  46. Tang, Y., Schlumpberger, T., Kim, T., Lueker, M. & Zucker, R.S. Effects of mobile buffers on facilitation: experimental and computational studies. Biophys. J. 78, 2735–2751 (2000).

    Article  CAS  Google Scholar 

  47. Heidelberger, R., Heinemann, C., Neher, E. & Matthews, G. Calcium dependence of the rate of exocytosis in a synaptic terminal. Nature 371, 513–515 (1994).

    Article  CAS  Google Scholar 

  48. Wu, L.-G. & Borst, J.G.G. The reduced release probability of releasable vesicles during recovery from short-term synaptic depression. Neuron 23, 821–832 (1999).

    Article  CAS  Google Scholar 

  49. Dodt, H.U., Eder, M., Schierloh, A. & Zieglgansberger, W. Infrared-guided laser stimulation of neurons in brain slices. Sci. STKE 120, 12 (2002).

    Google Scholar 

  50. Rae, J., Cooper, K., Gates, P. & Watsky, M. Low access resistance perforated patch recordings using amphotericin B. J. Neurosci. Methods 37, 15–26 (1991).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank M. Herman, M. McGinley, B. Nahir and J. Pugh for their helpful discussions and comments on the manuscript. This work was supported by US National Institutes of Health grant NS066037 (C.E.J.).

Author information

Authors and Affiliations

  1. Vollum Institute, Oregon Health & Science University, Portland, Oregon, USA

    Jason M Christie, Delia N Chiu & Craig E Jahr

  2. Neuroscience Graduate Program, Oregon Health & Science University, Portland, Oregon, USA

    Delia N Chiu

Authors
  1. Jason M Christie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Delia N Chiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Craig E Jahr
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Each of the authors contributed extensively to the design and implementation of the experiments, interpretation of the data and writing of the manuscript.

Corresponding author

Correspondence to Jason M Christie.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figure 1 (PDF 325 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Christie, J., Chiu, D. & Jahr, C. Ca2+-dependent enhancement of release by subthreshold somatic depolarization. Nat Neurosci 14, 62–68 (2011). https://doi.org/10.1038/nn.2718

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.2718

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