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(The FASEB Journal. 2003;17:130-135.)
© 2003 FASEB

SNAREs and control of synaptic release probabilities

KUANG HU and BAZBEK DAVLETOV1

MRC Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 2QH, UK

1Correspondence: MRC Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 2QH, UK. E-mail: baz{at}mrc-lmb.cam.ac.uk


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 WHERE DOES STOCHASTICITY ARISE...
 HYPOTHESIS OF STOCHASTIC SNARE...
 t-SNARE HETERODIMERS AND VESICLE...
 SUMMARY
 APPENDIX 1
 REFERENCES
 
Since quantal release was first described, it has been clear that release of neurotransmitters is a stochastic process. Modulation of neurotransmitter release probability by regulatory factors likely affects the transfer of information within the nervous system. Although many rules governing release probabilities at the synapse have been discovered, their molecular basis is still under investigation. Here we analyze stimulus-evoked probabilistic assembly of the SNARE fusion machinery and show that a simple SNARE-based mechanism can account quantitatively for the classical binomial behavior of stochastic neurotransmitter release. Our analysis highlights for the first time how the fusion machinery, which is directly responsible for neurotransmitter release, may also contribute to the rich variety of synaptic responses.—Hu, K., Davletov, B. SNAREs and control of synaptic release probabilities.


Key Words: neurotransmission • synapse • exocytosis • vesicle • stochastic


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
WHERE DOES STOCHASTICITY ARISE...
 HYPOTHESIS OF STOCHASTIC SNARE...
 t-SNARE HETERODIMERS AND VESICLE...
 SUMMARY
 APPENDIX 1
 REFERENCES
 
A QUANTUM OF neurotransmitter is released when a synaptic vesicle fuses with the plasma membrane (1 2 3) . It has long been recognized that stimulus-evoked release of neurotransmitter occurs in a stochastic manner (1 , 2) . For example, in central synapses the occurrence of quantal release is clearly probabilistic, being unpredictable with respect to any individual stimulus (4 5 6) . Synaptic release probabilities are heterogeneous across synapses and depend on the history of activity (7 , 8) . Such variations in the probability of synaptic release are likely to affect the transfer of information within the nervous system (9) . An important challenge therefore is to determine the origin of the stochastic rules that govern synaptic release.

Here we examine the role of stimulus-evoked assembly of the bipartite SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) fusion machinery in synaptic release. We demonstrate that the sophisticated array of responses exhibited by synapses may originate in the simple molecular expedient of allowing probabilistic assembly of a fusion machinery that was originally in inactive parts. Our quantitative analysis of this simple mechanism yields an excellent match with well-established electrophysiological and morphological observations, and thus the mechanism is likely sufficient to explain the stochastic nature of synaptic release. Our analysis also reveals a prominent role for target SNARE (t-SNARE) heterodimers in the priming of vesicle release probabilities.


   WHERE DOES STOCHASTICITY ARISE IN NEUROTRANSMISSION?
TOP
 ABSTRACT
 INTRODUCTION
 WHERE DOES STOCHASTICITY ARISE...
HYPOTHESIS OF STOCHASTIC SNARE...
 t-SNARE HETERODIMERS AND VESICLE...
 SUMMARY
 APPENDIX 1
 REFERENCES
 
Neurotransmission involves a cascade of events that results in transfer of a signal from one neuron to its target cell (2 , 3) . Arrival of an action potential at the nerve terminal triggers opening of voltage-gated calcium channels. This produces an influx of extracellular calcium into the nerve terminal where synaptic vesicles are lying in wait, docked at the presynaptic membrane. Calcium influx rapidly (<0.2 ms) triggers fusion of a small proportion of the docked synaptic vesicles with the presynaptic membrane. This results in release of neurotransmitter that diffuses across the synaptic cleft and activates postsynaptic neurotransmitter receptors in the target cell. In turn, this leads to excitation of the postsynaptic cell, thereby completing the intercellular transfer of information. It is well established that neurotransmission is stochastic and obeys binomial laws (1 , 10) . Although stochasticity could in principle arise at any point in the described chain of events, we focus here on the calcium-triggered release of neurotransmitter from the nerve terminal. It is in fact at this point that the stochastic properties of neurotransmission have been shown primarily to arise (4 , 9) .

Originally, it was proposed that stochasticity arises principally from the probability of calcium reaching its sensor, with an important role for the specific spatial organization of calcium channels and synaptic vesicles in the active zone (11 12 13) . However, such models are undermined by the recent finding that there is no change in the probabilistic behavior of vesicular exocytosis when calcium is allowed to bypass the specific organization at the active zone via use of the calcium ionophore, ionomycin (14) . Vesicle release also retains its stochastic nature when flash photolysis of caged calcium is used to rapidly create a uniform elevation of calcium throughout the cytoplasm (15 , 16) . Thus, the basis for stochasticity must lie downstream of the binding of calcium to its sensor. In the light of these recent findings, there presently exists no explanation for the stochasticity of neurotransmitter release, a fundamental property of nerve function. Intriguingly, two recent observations point to a role for SNAREs in influencing release probabilities (15 , 17) . As the contribution of SNAREs to the stochastic elements of synaptic release has not yet been adequately considered, we shall review SNARE properties and explore their possible stochastic behavior.


   HYPOTHESIS OF STOCHASTIC SNARE-MEDIATED VESICLE FUSION
TOP
 ABSTRACT
 INTRODUCTION
 WHERE DOES STOCHASTICITY ARISE...
 HYPOTHESIS OF STOCHASTIC SNARE...
t-SNARE HETERODIMERS AND VESICLE...
 SUMMARY
 APPENDIX 1
 REFERENCES
 
Three SNARE proteins are required for the last step of neurotransmitter release and are members of a highly conserved family that executes membrane fusion in all cellular compartments from yeast to humans (18) . Syntaxin and SNAP-25 are known as t-SNAREs because they are localized in the target plasma membrane (19) whereas synaptobrevin, also known as VAMP, is the synaptic vesicle SNARE (20) . These proteins, though initially split between the opposing vesicular and plasma membranes, can eventually form a fusogenic SNARE complex (21) . Inhibited syntaxin and SNAP-25 in plasma membranes must first be activated to form t-SNARE heterodimers (22 , 23) . Synaptobrevin, on the other hand, remains restricted prior to calcium action on morphologically docked synaptic vesicles by vesicular proteins or the vesicular lipid bilayer (24 , 25) . Synaptic vesicle exocytosis is blocked by botulinum neurotoxins and by soluble fragments of synaptobrevin, which specifically cleave SNAREs not complexed in four-helix bundles (3 , 24) , suggesting that in resting neurons, t-SNARE heterodimer and synaptobrevin are actually apart. Calcium action is strictly required to trigger engagement of synaptobrevin with t-SNARE heterodimer to form fusogenic SNARE complex (25 , 26) , which is a tight four-helix parallel bundle (27) . The time scale of folding of a four-helical bundle protein has been estimated to be only several microseconds (28) . Such a rate may help to satisfy the submillisecond time scale of calcium-evoked neurotransmitter release because structural studies indicate that folding of the SNARE four-helix bundle leads directly to membrane fusion (27) . t-SNARE heterodimer itself, once formed from syntaxin and SNAP-25, exists in a structured {alpha}-helical form (29) . This may act as a structural scaffold that facilitates SNARE complex formation when t-SNARE heterodimer meets synaptobrevin on the calcium signal. Overall, SNAREs are well recognized as the prime mediators of membrane fusion (18) .

We propose here that the assembly of SNAREs into a fusogenic complex occurs probabilistically on stimulation so that these proteins are directly responsible not only for fusion itself, but also for the stochastic nature of neurotransmitter release. This is based on the following. First, the SNARE fusion machinery may be bipartite and inactive prior to nerve stimulation, as discussed above. Second, formation of the fusion-competent SNARE complex is driven by calcium. Third, only a small proportion of the synaptic vesicles docked in a given synapse actually undergo fusion even though all vesicles respond identically to calcium (30 , 31) . Intriguingly, the neuronal calcium sensor synaptotagmin (32 , 33) acts as a calcium/phospholipid binding protein (34) that drives transient apposition of vesicular and target membranes in response to calcium (35) . We assume that on this calcium-triggered membrane apposition, inactive components of the fusion machinery assemble stochastically into fusogenic SNARE complex. In support of this, genetic knockout of synaptotagmin in different organisms results in greatly reduced evoked release probabilities, consistent with impaired engagement of the SNAREs from opposing membranes (3 , 32) .

Hence, we can consider a minimal system for fusion in which a synaptic vesicle that carries synaptobrevin faces a target membrane carrying t-SNARE heterodimers composed of syntaxin and SNAP-25. On calcium entry, the vesicular and target membranes become apposed, but vesicular synaptobrevin may fail to meet a t-SNARE heterodimer in the target membrane, so fusion does not occur. Alternatively, SNAREs in the two apposed membranes do engage, resulting in assembly of the SNARE complex and fusion. In the case of multiple synaptic vesicles docked in the active zone, calcium induces apposition of all of them, but this still results in probabilistic SNARE complex formation and the release of only a proportion of the vesicles. Since this stochastic model permits quantitative predictions to be made about the stochastic behavior of the synapse, we tested its validity by comparing its predictions against known synaptic properties.

We considered the probability, P, of at least one vesicle fusing in a given synapse when n synaptic vesicles are apposed to the target membrane containing d t-SNARE heterodimers (see Appendix). Figure 1 shows the predicted relationships between the number of synaptic vesicles and the number of t-SNARE heterodimers on the one hand and synaptic release probability on the other. We plot two limiting cases of synaptic release probability P: the probability of exactly one vesicle being released in response to stimulation, P=1, and the probability of more than one vesicle being released in response to stimulation, Pmulti. Note that we looked only at the cumulative response of the synapse, which may have one or more active zones. We have assumed that the number of synaptobrevins on each synaptic vesicle is constant and equal over the period of stimulation. Thus, the number of synaptobrevins is a function solely of the number of synaptic vesicles, which is independent of the number of t-SNAREs on the plasma membrane.



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  		Figure 1. Release probabilities in a bipartite SNARE-driven membrane fusion system. Probability of synaptic release, P (open triangles), probability of uniquantal release, P=1 (solid circles), and probability of release of more than one vesicle, Pmulti (open squares), are plotted as functions of the number of synaptic vesicles, n (A–C) and the number of t-SNARE heterodimers, d (D–F). Note that Pmulti = P - P=1 (see Appendix).

We find that the relationships between the synaptic release probability, P, and the number of synaptic vesicles (Fig. 1A-C ) are generally consistent with the established relationships between synaptic strength and active zone size (which is proportional to the maximum number of docked synaptic vesicles) (30 , 36 , 37) . The model yields a quantitative relationship between the synaptic release probability, P, and the fusion probability of an individual vesicle within the synapse, Pves:

This formula is, in fact, identical to that derived by del Castillo and Katz in their classical binomial model (1 , 10) . This formula has recently been confirmed to hold experimentally for central synapses (5 , 6) .

To further validate our hypothesis, we analyzed another numerical relationship between the number of synaptic vesicles, n, and synaptic release probability, P, obtained in electrophysiological experiments on central synapses (7) :

Our model again yields a similar relationship:

in which d is the number of t-SNARE heterodimers and f is a fusion parameter (see Appendix).

We investigated the probability of exactly one vesicle being released, P=1, and we find that it is predicted to peak at ~ 0.4 for all combinations of n and d (Fig. 1) . Crucially, at low synaptic release probabilities P, most successful transmissions will be due to the release of a single vesicle. As P rises, the fraction of multivesicular events becomes more significant (Fig. 1) . These predictions are corroborated in vivo by the behavior of central synapses, known to display mainly uniquantal release at low P (38 39 40) . Our predictions also accord with the observations that central synapses can exhibit occasional multiquantal release (41) and that the fraction of multivesicular events increases when synaptic release probability P rises (40) . Furthermore, consistent with our hypothesis, large high-probability synapses such as the calyx of Held and the neuromuscular junction normally exhibit multiquantal release (2) .


   t-SNARE HETERODIMERS AND VESICLE PRIMING
TOP
 ABSTRACT
 INTRODUCTION
 WHERE DOES STOCHASTICITY ARISE...
 HYPOTHESIS OF STOCHASTIC SNARE...
 t-SNARE HETERODIMERS AND VESICLE...
SUMMARY
 APPENDIX 1
 REFERENCES
 
Synapses can exhibit significant differences in release probability despite similarity in size and in average number of docked vesicles, as evidenced by climbing fiber synapses and parallel fiber synapses on cerebellar Purkinje cells (42) . As structural features cannot fully account for differences in synaptic strength, molecular differences superimposed on synaptic morphology must contribute to regulation of release probability (43) . What is the nature of these molecular differences? Analysis of our stochastic mechanism demonstrates the quantitative importance of t-SNARE heterodimers for release probability (Fig. 1D-F ). This may account for differences between synapses of similar morphology and explains why disruption of t-SNARE heterodimer supply, either by direct cleavage using botulinum toxins or by injecting synaptobrevin peptides, can cause reduction in neurotransmitter release even though synaptic vesicles accumulate (3 , 24) . Overall, it is possible that availability of t-SNARE heterodimers in the active zone is (along with the number of docked synaptic vesicles) an important and independent point for control of release probability. This is further emphasized when we examine Pves, the fusion probability of an individual vesicle within the synapse.

Recent electrophysiological studies (5 , 6) have highlighted the important question of the underlying nature of the variable, Pves. This may, in principle, depend on either the properties of the docked vesicle itself or other factors needed for fusion. According to our analysis (see Eq. 1 in Appendix), the fusion probability of an individual docked vesicle, Pves, actually reflects t-SNARE heterodimer availability in the plasma membrane. If t-SNARE heterodimer availability indeed determines the release probability of individual vesicles, we are led to the startling conclusion that priming of vesicle release probabilities may be a property not of the synaptic vesicle itself but of the plasma membrane of the active zone at which it is docked. We propose that this previously unsuspected role for t-SNARE heterodimers may be an important component in the regulation of synaptic release probabilities. This may explain the long-standing puzzle of why synaptic release probability and the number of morphologically docked vesicles show incomplete correlation (42 , 43) .


   SUMMARY
TOP
 ABSTRACT
 INTRODUCTION
 WHERE DOES STOCHASTICITY ARISE...
 HYPOTHESIS OF STOCHASTIC SNARE...
 t-SNARE HETERODIMERS AND VESICLE...
 SUMMARY
APPENDIX 1
 REFERENCES
 
This study advances the novel hypothesis that calcium-triggered assembly of the bipartite SNARE fusion machinery is sufficient to account for the stochastic nature of neurotransmitter release. Our hypothesis embraces both a substantial body of molecular data and many well-known stochastic properties of the synapse. Our analysis does have certain limitations, such as an assumption of equal distribution of synaptobrevin among all vesicles. Nevertheless, it reveals that the sophisticated binomial behavior of stochastic synaptic responses may actually have rather simple origins, namely, separation of the components of the SNARE fusion machinery prior to calcium action.

Although it is well known that the number of morphologically docked synaptic vesicles influences synaptic release probability, imperfect correlations between the two have so far defied explanation (43) . We have shown here that the availability of t-SNARE heterodimers in the target membrane may be a novel regulator of the probability of fusion of synaptic vesicles (Fig. 2 ). Recognition of this important regulator permits a better description of the basis of stochastic synaptic behaviors. Evidently, regulation of stochasticity at the level of t-SNAREs is likely to be physiologically relevant only if molecules exist in vivo to regulate t-SNARE heterodimer formation. In fact, formation of t-SNARE heterodimers is governed by the action of Munc18, Munc13, and other presynaptic factors, genetic disruption of any of which leads to profound changes in release probabilities (2 , 3) . Moreover, NSF ATPase is essential for disassembly of postfusion SNARE complexes into monomeric components, resupplying SNAREs for further rounds of fusion (3) . Another merit of our analysis is that it provides a framework for understanding the roles of these disparate molecules in modulating synaptic strength.



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  		Figure 2. Supply of synaptic vesicles and formation of fusion-ready t-SNARE heterodimers in the presynaptic membrane as determinants of probability of calcium-triggered membrane fusion. 1) Synaptic vesicles are recruited from a reserve pool for docking at the active zone. During priming, SNAP-25 forms fusion-ready t-SNARE heterodimers with syntaxin (Syx), which normally is inhibited (49) . 2) On calcium entry, vesicular synaptobrevin (Syb) probabilistically engages presynaptic t-SNARE heterodimer, leading to fusion of a proportion of docked vesicles and release of neurotransmitter quanta.

Regulation of synaptic release probability may also involve factors originating outside the nerve terminal, including exogenous drugs and various endogenous molecules such as neurotrophic factors, nitric oxide, or arachidonic acid (44 45 46) . We propose that these may all affect either mobilization of vesicles to the active zone or up-regulation of the t-SNARE machinery. To investigate the exact point of control by factors affecting presynaptic function, it will be important to develop new methods to quantitatively estimate the numbers of not only syntaxin and SNAP-25 but also their fusion-ready heterodimers in individual synapses. Future studies will refine the presented stochastic hypothesis, but the simple molecular strategies that have been considered here undoubtedly are essential for sophisticated modulation of neurotransmitter release and neuronal information transfer.


   APPENDIX 1
TOP
 ABSTRACT
 INTRODUCTION
 WHERE DOES STOCHASTICITY ARISE...
 HYPOTHESIS OF STOCHASTIC SNARE...
 t-SNARE HETERODIMERS AND VESICLE...
 SUMMARY
 APPENDIX 1
REFERENCES
 
Stochastic modeling
In a simple system for fusion, a docked synaptic vesicle that carries multiple copies of synaptobrevin (47) must face a target membrane carrying a t-SNARE heterodimer composed of syntaxin and SNAP-25. In response to calcium, vesicular synaptobrevin may fail to engage the t-SNARE heterodimer in the target membrane, with characteristic probability f, so fusion does not occur. Alternatively, SNAREs in the two apposed membranes engage with probability 1-f, resulting in fusion.

The probability of fusion for the vesicle, Pves, in the case of d t-SNARE heterodimers in the membrane facing the synaptic vesicle is given by:

because probability of fusion failure is fd.

In the general case of n synaptic vesicles facing a target membrane, the probability that none of the n vesicles fuses on apposition is fnd. Thus, release probability P, the probability of at least one vesicle in a synapse fusing in response to stimulation, is:

By substitution using Eq. 1 , we can rewrite Eq. 2 as:

The probability of R successes in N trials is (N!/(R!(N-R)!))·pR(1-p)N-R, where p is the proportion of successes (48) . Therefore, the probability, P=1, of exactly one out of n vesicles being released is given by:

We can express this in terms of n, d, and f by substituting for Pves from Eq. 1 :

The probability of multiquantal release, Pmulti, is the difference between P (see Eq. 2 ) and P=1 (see Eq. 5 ):

For graph plotting, Eqs. 2 , 5 , and 6 were evaluated numerically in Excel (Microsoft) and plotted using Prism (GraphPad).

Estimation and meaning of f
In the hippocampal synapses studied (7) : ln (1-P) = (-0.09) · n. Transformation of Eq. 2 yields: ln (1-P) = (d ln f) · n, and thus (d ln f) equals -0.09. As d must lie between 1 and some, possibly large number, the value of the parameter f lies between 0.914 and a value close to 1. The mean value of these limits, 0.957 [that is, ((1+0.914)/2)], is an estimate of f for the synapses studied. Exact values for f will be determined by studies of single synapses using a combination of electrophysiological (P), morphological (n), and molecular (d) measurements.

The parameter f is by definition the probability of fusion failure on apposition of a synaptic vesicle to a target membrane carrying a single t-SNARE heterodimer. How else could f be interpreted? In general, the probability of success in a trial may be defined as the number of successful trials divided by the total number of trials in a long series. Therefore, for one success in a number of trials, an average of (1/probability of success) trials is needed. Because the probability of a vesicle fusing on a single apposition to a target membrane bearing one t-SNARE heterodimer is 1-f, each synaptic vesicle requires an average of 1/(1-f) appositions to fuse with this target membrane. Thus, the estimate f = 0.957 implies that 23 appositions of a synaptic vesicle to a target membrane bearing one t-SNARE heterodimer are required for fusion.


   ACKNOWLEDGMENTS
 
K.H. was supported by a MRC Postgraduate Studentship and in part by the University of Cambridge M.B./Ph.D. Program.

Received for publication July 26, 2002. Accepted for publication October 16, 2002.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 WHERE DOES STOCHASTICITY ARISE...
 HYPOTHESIS OF STOCHASTIC SNARE...
 t-SNARE HETERODIMERS AND VESICLE...
 SUMMARY
 APPENDIX 1
 REFERENCES
 

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