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Transmitter timecourse in the synaptic cleft: its role in central synaptic function

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Abstract

The speed of clearance of transmitter from the cleft influences many aspects of synaptic function, including the timecourse of the postsynaptic response and the peak postsynaptic receptor occupancy. The timecourse of transmitter clearance can be estimated either by detailed theoretical modelling, or from the attenuation of synaptic transmission produced by a low-affinity competitive antagonist. These approaches have been applied to several classes of central synapse, and results obtained are in broad agreement. The average concentration of transmitter peaks in the range 1–5 mm, and clearance is biphasic, with time constants of approximately 100 μs and 2 ms. The pulse of transmitter, although very brief, can prolong the timecourse of the fastest AMPA synaptic currents, and is sufficient to saturate postsynaptic GABA, glycine or NMDA receptors. Trends Neurosci. (1996) 19, 163–171

Section snippets

Transmitter timecourse at CNS synapses

The timecourse of transmitter concentration in an individual synaptic cleft following elicited release is determined by the following parameters: (1) the number of vesicles simultaneously released into the cleft; (2) the location(s) at which they are released; (3) the concentration of transmitter in the vesicle(s) and their volume; (4) the rate of transmitter release through the vesicle fusion pore into the cleft; (5) the transmitter diffusion coefficient; (6) the geometry of the cleft and

Peak postsynaptic receptor occupancy

The timecourse of transmitter concentration in the cleft, together with the binding rate of the postsynaptic receptor, stoichiometry and Kd, determines the peak level of receptor occupancy following synaptic release. All these parameters have been estimated for NMDA channels. Assuming a monophasic timecourse (initial amplitude, 1 mm; decay time constant, 1 ms) for released glutamate, about 97% of NMDA receptors will bind the two molecules of glutamate needed for activation[6]. The peak

Mechanisms of transmitter release and clearance

Many of the proteins involved in the release of vesicles containing transmitter have been identified by recent molecular and biochemical studies, but the detailed nature of the vesicle fusion process remains unclear. In particular, the opening rate of the fusion pore is not known. Simulation studies of the diffusion of transmitter out of the vesicle suggest that the pore must open to a diameter of ≥10 nm within a few tens of microseconds to achieve the observed transmitter timecourse[5](Fig. 6

Multivesicular release

Studies using EM have revealed specialized structures in the presynaptic terminal that are probably vesicle release sites (VRS) (39, 40). If VRS function independently, several vesicles could be released simultaneously from an individual terminal (multivesicular release). The probability of transmitter release (Pr) at an individual terminal ranges from 0.05–0.5 in rat hippocampal neurones under normal physiological conditions41, 42, so multivesicular release could occur with a probability of Pr2

Variability in mEPSC and mIPSC amplitudes

Assuming that a single vesicle of transmitter is sufficient to saturate postsynaptic receptors, variations in the transmitter content between vesicles will not produce variability of the postsynaptic response at an individual terminal. Thus, the amplitudes of mEPSCs and mIPSCs should have low coefficients of variation if release is restricted to a single site2, 3, 29, 46. Some residual variability will remain due to random opening and closing of postsynaptic channels3, 29. Low amplitude

Concluding remarks

The speed of transmitter clearance from the synaptic cleft is a fundamental parameter influencing many aspects of synaptic function. Recently developed techniques for measuring and manipulating transmitter timecourse have permitted the study of synaptic transmission in unprecedented detail. Evidence has been found for saturation of postsynaptic receptors following elicited transmitter release, although AMPA receptors are probably not saturated following spontaneous transmitter release.

Acknowledgements

J.D. Clements is supported by a QEII Research Fellowship from the ARC. I am very grateful to Tom Bartol and Joel Stiles for the considerable time and effort they put into preparing the beautiful and informative images in Fig. 2, Fig. 3. Thanks also to Lindi Wahl for supplying the simulation results used to create Fig. 6, and to Craig Jahr, John Bekkers, Tom Bartol, Alain Destexhe and Zah Mainen for helpful comments on the manuscript.

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