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The Journal of Neuroscience, March 21, 2007, 27(12):3198-3210; doi:10.1523/JNEUROSCI.4471-06.2007

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Cellular/Molecular
A Mechanism Intrinsic to the Vesicle Fusion Machinery Determines Fast and Slow Transmitter Release at a Large CNS Synapse

Markus Wölfel,¹ Xuelin Lou,¹ and Ralf Schneggenburger^1,2

¹AG Synaptic Dynamics and Modulation, Department of Membrane Biophysics, Max-Planck-Institut für Biophysikalische Chemie, Am Fassberg 11, D-37077 Göttingen, Germany, and ²Laboratory of Synaptic Mechanisms, Brain-Mind Institute, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland

Correspondence should be addressed to Dr. Ralf Schneggenburger, Laboratory of Synaptic mechanisms École Polytechnique Fédérale de Lausanne, Brain Mind Institute, Bâtiment AAB, Station 15, CH-1015 Lausanne, Switzerland. Email: ralf.schneggenburger{at}epfl.ch

Heterogeneity of release probability p between vesicles in the readily releasable pool (RRP) is expected to strongly influence the kinetics of depression at synapses, but the underlying mechanism(s) are not well understood. To test whether differences in the intrinsic Ca²⁺ sensitivity of vesicle fusion might cause heterogeneity of p, we made presynaptic Ca²⁺-uncaging measurements at the calyx of Held and analyzed the time course of transmitter release by EPSC deconvolution. Ca²⁺ uncaging, which produced spatially homogeneous elevations of [Ca²⁺]_i, evoked a fast and a slow component of release over a wide range of [Ca²⁺]_i, showing that mechanism(s) intrinsic to the vesicle fusion machinery cause fast and slow transmitter release. Surprisingly, the number of vesicles released in the fast component increased with Ca²⁺-uncaging stimuli of larger amplitudes, a finding that was most obvious below 10 µM [Ca²⁺]_i and that we call "submaximal release" of fast-releasable vesicles. During trains of action potential-like presynaptic depolarizations, submaximal release was also observed as an increase in the cumulative fast release at enhanced release probabilities. A model that assumes two separate subpools of RRP vesicles with different intrinsic Ca²⁺ sensitivities predicted the observed Ca²⁺ dependencies of fast and slow transmitter release but could not fully account for submaximal release. Thus, fast and slow transmitter release in response to prolonged [Ca²⁺]_i elevations is caused by intrinsic differences between RRP vesicles, and an "a posteriori" reduction of the Ca²⁺ sensitivity of vesicle fusion after the onset of the stimulus might cause submaximal release of fast-releasable vesicles and contribute to short-term synaptic depression.

Key words: synapse; vesicle; Ca²⁺; Ca²⁺ sensor; readily releasable pool; short-term plasticity

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Received Oct. 13, 2006; revised Feb. 9, 2007; accepted Feb. 10, 2007.

Correspondence should be addressed to Dr. Ralf Schneggenburger, Laboratory of Synaptic mechanisms École Polytechnique Fédérale de Lausanne, Brain Mind Institute, Bâtiment AAB, Station 15, CH-1015 Lausanne, Switzerland. Email: ralf.schneggenburger{at}epfl.ch

This article has been cited by other articles:

				X. Lou, N. Korogod, N. Brose, and R. Schneggenburger Phorbol Esters Modulate Spontaneous and Ca2+-Evoked Transmitter Release via Acting on Both Munc13 and Protein Kinase C J. Neurosci., August 13, 2008; 28(33): 8257 - 8267. [Abstract] [Full Text] [PDF]

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				C. G. Inchauspe, I. D. Forsythe, and O. D. Uchitel Changes in synaptic transmission properties due to the expression of N-type calcium channels at the calyx of Held synapse of mice lacking P/Q-type calcium channels J. Physiol., November 1, 2007; 584(3): 835 - 851. [Abstract] [Full Text] [PDF]

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