Presynaptic control of quantal size: kinetic mechanisms and implications for synaptic transmission and plasticity
Introduction
Synaptic transmission is the elementary form of communication among neurons in the central nervous system (CNS). The process of synaptic transmission involves the release of neurotransmitter from presynaptic terminals that results in the activation of postsynaptic receptors. The strength of quantal transmission is consequently determined both presynaptically, through the magnitude of neurotransmitter release, and postsynaptically, by the number and properties of the receptors available for activation. Significant progress has been achieved in understanding the molecular mechanisms that control the number and properties of postsynaptic receptors 1., 2., whereas the mechanisms that govern the presynaptic transmitter flux and the manner in which released transmitter and postsynaptic receptors interact are less well understood. Recently, however, through the rapid refinement of physiological techniques and the concurrent elucidation of several crucial genes, a framework is beginning to emerge for how presynaptic factors could influence the strength of quantal synaptic transmission and contribute to the modification of synaptic strength during synaptic plasticity.
This review focuses specifically on possible presynaptic mechanisms for controlling the activation of fast ionotropic receptors in CNS synapses. Several issues about this topic have been discussed previously 3., 4., 5.; however, this review focuses on more recent progress. In addition, this review does not cover the important developments in the amperometric recording technique, which has made it possible to directly measure the flux of neurotransmitter and provide biophysical detail of the kinetics behind transmitter release, as several other excellent sources have recently summarized this line of work 6., 7.. Similarly, for a full treatment of recent progress in cloning vesicular transporters and examining their biochemical properties the reader is referred to the work of Reimer et al. [8].
Section snippets
Receptor activation by a single package of neurotransmitter
The degree of receptor activation by a single package of transmitter is a central issue to synaptic physiology, in that it dictates whether or not an alteration of synaptic cleft transmitter concentration could be relevant to influencing the strength of quantal (single vesicle) transmission. If all postsynaptic receptors associated with a given synapse were activated by a single package of transmitter, for example, the concentration profile of that transmitter in the synaptic cleft would not
Kinetic explanations for receptor non-saturation by single vesicles
Despite the abundant examples of receptor non-saturation across multiple brain regions involving various receptor types, from a biophysical point of view it is still somewhat puzzling why a single package of transmitter is insufficient to saturate all postsynaptic receptors. A typical synaptic vesicle contains 2000–10 000 transmitter molecules, and routinely generates a synaptic cleft transmitter concentration that reaches the millimolar range. Though such concentrations are much higher than
Receptor activation by transmitters from multiple vesicles
Even if transmitter released from an individual vesicle is incapable of activating all the corresponding postsynaptic receptors, it may still be possible to achieve receptor saturation within a single synapse through the recently proposed possibility of multivesicular release 22.••, 25.••, 29., 43., 44., 45., 46.. Here, summing the transmitter from simultaneous release of multiple vesicles to the same cleft would increase the level of postsynaptic receptor activation, perhaps to the point of
Implications to synaptic transmission and plasticity
What are the implications of these properties for the physiological function of neural connections? The saturation of postsynaptic receptors associated with the release of multiple vesicles by a single action potential would provide for reliable signal transduction. Such a synapse could utilize receptor saturation to ensure high fidelity in the propagation of the temporal structure of the signal to the next stage of neurons for processing. At the same time, the non-saturation of postsynaptic
Conclusions
It seems clear from an increasing number of studies of synaptic transmission at single synapses that a single package of transmitter is insufficient to activate all postsynaptic receptors 9., 16., 17., 18., 19., 20., 21., 22.••, 24., 27.•, 28., 29., 30., 48.•, 60., 61.. However, the transmitter content released by the simultaneous fusion of multiple vesicles can sufficiently summate to activate all available receptors 22.••, 25.••, 29., 43., 44., 45., 46.. If the probability of multi-vesicular
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
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of special interest
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of outstanding interest
Acknowledgements
I thank N Wilson for help in revising an early draft of the manuscript, and T Leung for the artwork of Figure 1. This study was supported by grants from the National Institutes of Health and the RIKEN-MIT Neuroscience Research Center.
References (71)
- et al.
Saturation of postsynaptic receptors at central synapses?
Curr. Opin. Neurobiol.
(1996) Transmitter timecourse in the synaptic cleft: its role in central synaptic function
Trends Neurosci.
(1996)- et al.
Splitting the quantum: regulation of quantal release during vesicle fusion
Trends Neurosci.
(2002) - et al.
The essence of excitation
Curr. Opin. Cell Biol.
(2001) - et al.
Quantal release of serotonin
Neuron.
(2000) - et al.
Heterogeneous release properties of visualized individual hippocampal synapses
Neuron.
(1997) - et al.
Differences in synaptic GABAA receptor number underlie variation in GABA mini amplitude
Neuron.
(1997) - et al.
Cell type and pathway dependence of synaptic AMPA receptor number and variability in the hippocampus
Neuron.
(1998) - et al.
Variability of neurotransmitter concentration and nonsaturation of postsynaptic AMPA receptors at synapses in hippocampal cultures and slices
Neuron.
(1999) - et al.
Non-NMDA glutamate receptor occupancy and open probability at a rat cerebellar synapse with single and multiple release sites
J. Physiol.
(1996)