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High-frequency firing helps replenish the readily releasable pool of synaptic vesicles

Nature volume 394, pages 384–388 (1998)Cite this article

Abstract

Synapses in the central nervous system undergo various short- and long-term changes in their strength1,2,3, but it is often difficult to distinguish whether presynaptic or postsynaptic mechanisms are responsible for these changes. Using patch-clamp recording from giant synapses in the mouse auditory brainstem4,5,6,7, we show here that short-term synaptic depression can be largely attributed to rapid depletion of a readily releasable pool of vesicles. Replenishment of this pool is highly dependent on the recent history of synaptic activity. High-frequency stimulation of presynaptic terminals significantly enhances the rate of replenishment. Broadening the presynaptic action potential with the potassium-channel blocker tetraethylammonium, which increases Ca2+ entry, further enhances the rate of replenishment. As this increase can be suppressed by the Ca2+-channel blocker Cd2+ or by the Ca2+ buffer EGTA, we conclude that Ca2+ influx through voltage-gated Ca2+ channels is the key signal that dynamically regulates the refilling of the releasable pool of synaptic vesicles in response to different patterns of inputs.

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Figure 1: Use-dependent synaptic depression is independent of postsynaptic desensitization.
Figure 2: Presynaptic Ca2+ currents do not inactivate significantly in response to repetitive stimulation.
Figure 3: Replenishment kinetics are dependent on the frequency of presynaptic inputs.
Figure 4: Presynaptic spike waveform and TEA-induced spike broadening.
Figure 5: Ca2+ enhances the replenishment of the readily releasable pool of synaptic vesicles.
Figure 6: The Ca2+ chelator EGTA blocks the fast phase of replenishment.

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Acknowledgements

We thank I. Forsythe for his helpful insight and for sharing unpublished data, and N.Magoski, M. Whim and W. Joiner for critically reading the manuscript. This work is supported by an NIH grant to L.K.K. and a postdoctoral fellowship from the Eppley Foundation for Research to L.-Y.W.

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Authors and Affiliations

  1. Division of Neurology & The Program in Brain and Behavior, The Hospital for Sick Children and Department of Physiology, University of Toronto, 555 University Avenue, Toronto, M5G 1X8, Ontario, Canada

    Lu-Yang Wang

  2. Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, 06520, Connecticut, USA

    Lu-Yang Wang & Leonard K. Kaczmarek

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  1. Lu-Yang Wang
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Correspondence to Leonard K. Kaczmarek.

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Wang, LY., Kaczmarek, L. High-frequency firing helps replenish the readily releasable pool of synaptic vesicles. Nature 394, 384–388 (1998). https://doi.org/10.1038/28645

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