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SYMPOSIUM REPORT |
1 Department of Neurobiology and Anatomy and the Graduate School of Biomedical Sciences, University of Texas Medical School at Houston, 6431 Fannin Street, Houston, TX 77030, USA
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Abstract |
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 Top Abstract IntroductionMechanisms contributing to...Mechanisms contributing to...Concluding remarksReferences |
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(Received 3 June 2007;
accepted after revision 19 June 2007;
first published online 21 June 2007)
Corresponding author R. Heidelberger: Department of Neurobiology and Anatomy and the Graduate School of Biomedical Sciences, University of Texas Medical School at Houston, 6431 Fannin Street, Houston, TX 77030, USA. Email: ruth.heidelberger{at}uth.tmc.edu
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Introduction |
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TopAbstractIntroductionMechanisms contributing to...Mechanisms contributing to...Concluding remarksReferences |
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Mechanisms contributing to sustained release |
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TopAbstractIntroductionMechanisms contributing to...Mechanisms contributing to...Concluding remarksReferences |
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1000 (B. Innocenti and R. Heidelberger, unpublished observations) to possibly a few thousand, depending upon experimental conditions (Rabl et al. 2005). Assuming approximately 10–15 ribbons per cone terminal (S. M. Wu, personal communication), this would suggest a cone releasable pool of 75–500 vesicles per AZ, with the lower estimate in keeping with anatomical data. The number of vesicles available for release at a photoreceptor ribbon-style active zone exceeds that of a typical conventional synapse by at least an order of magnitude (Stevens & Tsujimoto, 1995; Satzler et al. 2002; Taschenberger et al. 2002; Hallermann et al. 2003; Fernandez-Alfonso & Ryan, 2006) and thus, could more easily support the sustained release of neurotransmitter. However, it is worth noting that cerebellar mossy fibres, which exhibit long periods of high-frequency spiking, employ a physiologically defined releasable pool of about 300 vesicles per AZ (Saviane & Silver, 2006). Thus, the utilization of a large releasable pool is not a feature peculiar to ribbon synapses or graded release, but represents a general strategy for maintaining release at synapses with high synaptic demand.
Even though large, the releasable pool is not infinite. To maintain a release rate of 20–80 vesicles per AZ per second during the course of a 10 h night, the releasable pool would need to be replenished about 2000 times. Ultimately, it is the interplay between the rate of pool depletion and the rate of pool refilling that determines the ability to maintain release. In both rods and cones, recovery from paired-pulse depression, used as an assay of pool depletion and replenishment, is complete within a few seconds (DeVries, 2000; Innocenti & Heidelberger, 2005; Rabl et al. 2006). The shortest estimates (
100–300 ms) may represent replenishment of a subset of vesicles rather than the entire releasable pool (DeVries, 2000; Heidelberger & Innocenti, 2006) or perhaps calcium-accelerated refilling of the pool (von Ruden & Neher, 1993; Sakaba et al. 1997; von Gersdorff & Matthews, 1997; Gomis et al. 1999). Careful depletion of a well-defined releasable pool in cells in which calcium measurements were simultaneously performed, yielded the longer estimate ( 1 s). Although, the exact time constant of recovery is not yet clear, the range of values suggests a significantly more rapid time course than reported for other neurons, where refilling of the releasable pool typically takes 15–20 s (Stevens & Tsujimoto, 1995; von Gersdorff & Matthews, 1997; von Gersdorff et al. 1997). An exception to this generalization is the hair cell; this graded primary sensory neuron also appears to have an unusually rapid refilling rate (Edmonds et al. 2004; Spassova et al. 2004).
What is the source of new vesicles? At conventional synapses, refilling is tightly coupled to endocytosis (De Camilli et al. 1995; Shupliakov et al. 1997; Daly et al. 2000), but this is not necessarily the case at ribbon synapses, where the releasable pool can be refilled multiple times in the absence of complete membrane retrieval (Parsons et al. 1994; von Gersdorff & Matthews, 1997; Heidelberger et al. 2002; Holt et al. 2004). In photoreceptors, both early tracer studies and recent studies using FM dyes have shown that retrieved vesicles are dispersed throughout the cytosolic pool (Fig. 1B) rather than being preferentially localized to synaptic ribbons (Schacher et al. 1974; Schaeffer & Raviola, 1978; Townes-Anderson et al. 1985; Rea et al. 2004). In addition, photoreceptor membrane retrieval may begin following a delay of half a second or more (Rieke & Schwartz, 1996) and can take a second, if not tens of seconds, to reach completion depending upon experimental conditions (Rabl et al. 2005; B. Innocenti and R. Heidelberger, unpublished observations), similar to other neurons. Thus, it seems unlikely that refilling from newly retrieved vesicles can be the sole mechanism by which the photoreceptor releasable pool is maintained. To avoid an empty fusion site that would erroneously signal an increase in illumination, replenishment of the releasable pool from the large cytoplasmic reserve (Fig. 1) emerges as an attractive alternative. Reserve vesicles in photoreceptors are significantly more mobile than those of conventional synapses, suggestive of the potential to rapidly refill an empty vesicle docking site (Rea et al. 2004; see also discussion in Heidelberger & Innocenti, 2006). A question for the future is whether all vesicles in the cytoplasmic pool are equally able to replenish the releasable pool or whether there is heterogeneity within this large pool.
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Mechanisms contributing to graded release |
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TopAbstractIntroductionMechanisms contributing to...Mechanisms contributing to...Concluding remarksReferences |
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The underlying modecular mechanism for this profound difference in functionality is not known. One possibility is that the rod uses a novel calcium sensor, as has been suggested for the cochlear hair cell (Safieddine & Wenthold, 1999; Roux et al. 2006). However, mammalian photoreceptors, and possibly those of the salamander, contain synaptotagmin I, the putative low-affinity calcium sensor for fast neurotransmitter release (reviewed in Heidelberger et al. 2005; Fox & Sanes, 2007). In addition, they may contain synaptotagmin III, which binds calcium with an affinity that is better matched to the high calcium sensitivity of the rod sensor (Fig. 2B). Possibly, these proteins work together and with additional proteins to refine the calcium sensitivity of exocytosis. However, this would not necessarily account for the relatively shallow relationship that generates the linearity (Goda & Stevens, 1994).
An interesting explanation for linearity at the level of the secretory machinery is suggested by recent work in the calyx of Held, where an allosteric model was found to describe the relationship between release rate and calcium better than traditional models (Lou et al. 2005). With the allosteric model, release not only occurs from the fully occupied state of the calcium sensor, as in traditional models, but from all states, albeit at slower rates. An attractive feature of this modification is that the relationship between the rate of release and calcium reflects the number of occupied calcium binding sites. Thus, any neuron might release in a graded manner if the local calcium concentration were sufficiently low relative to the affinity for calcium of the binding sites. Given that rod exocytosis is exquisitely sensitive to small increases in calcium (Fig. 2B), this hypothesis is quite attractive. The model relationship grows steeper as more binding sites on the sensor become occupied, predicting that even a photoreceptor might release a burst of neurotransmitter given the right stimulus, and there are hints that this may indeed happen (Kreft et al. 2003; Xu et al. 2005). Honing in on whether such a single-sensor model could quantitatively account for all the features of release at the rod photoreceptor is one of the challenges for the future.
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Concluding remarks |
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Footnotes |
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References |
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). The voltage dependence of the magnitude of exocytosis mirrors that of ICa (grey curve). Reproduced with permission from