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The Mechanisms and Functions of Spontaneous Neurotransmitter Release

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The Mechanisms and Functions of Spontaneous Neurotransmitter Release REVIEWS The mechanisms and functions of spontaneous neurotransmitter release Ege T. Kavalali Abstract | Fast synaptic communication in the brain requires synchronous vesicle fusion that is evoked by action potential-induced Ca2+ influx. However, synaptic terminals also release neurotransmitters by spontaneous vesicle fusion, which is independent of presynaptic action potentials. A functional role for spontaneous neurotransmitter release events in the regulation of synaptic plasticity and homeostasis, as well as the regulation of certain behaviours, has been reported. In addition, there is evidence that the presynaptic mechanisms underlying spontaneous release of neurotransmitters and their postsynaptic targets are segregated from those of evoked neurotransmission. These findings challenge current assumptions about neuronal signalling and neurotransmission, as they indicate that spontaneous neurotransmission has an autonomous role in interneuronal communication that is distinct from that of evoked release. 10–13 Docked vesicles Our current insights into the mechanisms under­lying relatively intact . Thus, although these experiments Synaptic vesicles that are synaptic transmission originate from experiments that proved the vesicular hypothesis of neurotransmitter tethered to the presynaptic were conducted in the 1950s by Bernard Katz and col- release, they raised the question of whether spontane- membrane or the active zone leagues1–3 (FIG. 1). A key aspect of these studies was the ous release events originate from the same vesicular traf- structure. According to current discovery of spontaneous neurotransmitter release ficking pathway as evoked neurotransmission14. Recent views, not all docked vesicles are fully primed for fusion and events, which seemed to occur in discrete ‘quantal’ advances in our understanding support the autonomous release of neurotransmitter. packets (FIG. 2). This fundamental observation enabled nature of spontaneous neurotransmission and indicate its the complex and seemingly intractable nature of action key role in the signalling that leads to synaptic maturation potential-evoked neurotransmission to be analysed and and homeostasis. This Review presents an overview of the understood on the basis of its unitary components2–4. experimental results and conceptual developments that Although the original work solely relied on electrophysi- have given rise to this revised outlook on the mechanisms ological analysis, later studies that used electron micros- and functions of spontaneous neurotransmitter release. copy provided visual validation of the hypothesis that neurotransmission occurs through fusion of discrete Spontaneous release mechanisms synaptic vesicles that contain neurotransmitters with Specific synaptic vesicle fusion machinery. The tradi- the presynaptic plasma membrane5,6. tional view of spontaneous neurotransmitter release The quantal hypothesis of neurotransmission now posits that these spontaneous events occur randomly has overwhelming experimental support, and we are in the absence of stimuli owing to low-probability con- beginning to understand the exquisite molecular mecha- formational changes in the vesicle fusion machinery15. nisms involved7. However, the discovery of the molecular Random fluctuations of the vesicle fusion machinery can machinery that enables presynaptic vesicle fusion to occur be augmented in response to subthreshold elevations in also uncovered some unexpected distinctions between the presynaptic Ca2+ levels, which facilitate neurotransmit- 16,17 Department of Neuroscience, processes that lead to spontaneous and action potential- ter release when the neuron is at rest . Spontaneous University of Texas evoked neurotransmitter release. Early studies that used events were initially thought to arise from fusion of the Southwestern Medical Center, clostridial toxins to impair presynaptic machinery com- same docked vesicles and primed vesicles that mediate 5323 Harry Hines Blvd., ponents8,9 and later work that used genetic manipula- release after the arrival of a presynaptic action potential Dallas, Texas 75390–9111, tions to selectively knock out the function of individual (called the readily releasable pool (RRP)). Indeed, sev- USA. e-mail: Ege.Kavalali@ fusion proteins showed varying degrees of presynaptic eral electrophysiological and presynaptic optical imag- UTSouthwestern.edu release impairment; however, in most circumstances, the ing experiments have documented a correlation between doi:10.1038/nrn3875 process of spontaneous neurotransmitter release was left the responsiveness of evoked release events and that of NATURE REVIEWS | NEUROSCIENCE VOLUME 16 | JANUARY 2015 | 5 © 2014 Macmillan Publishers Limited. All rights reserved REVIEWS a b 1 2 1 2 Microelectrode Motor fibre Nature Reviews | Neuroscience Figure 1 | The earliest recordings of spontaneous synaptic activity. a | The neuromuscular junction preparation used by Bernard Katz and colleagues, in which they initially described spontaneous cholinergic neurotransmitter release events, is shown. b | Intracellular recordings near the sites of nerve innervation (1), but not recordings at distal regions (2), showed random spontaneous voltage fluctuations that were sensitive to cholinergic agents, nerve denervation and osmotic pressure2. Part b reproduced from Fatt, P. & Katz, B. Spontaneous subthreshold activity at motor nerve endings. J. Physiol. 117, 109–128 (1952). John Wiley & Sons. spontaneous release to presynaptic Ca2+ concentrations and comprise distinct populations. Furthermore, these at the macroscopic level, which provides quantitative SNAREs may be involved in the formation of alternative justification for their emergence from the same pro- fusion complexes with specialized functional properties cess18,19. However, an increasing number of molecular that enable them to selectively mediate spontaneous or studies have identified mechanisms that either promote asynchronous neurotransmission29 (BOX 1). or suppress spontaneous release that are dissociable from Recent studies have examined the synaptic function of their impact on evoked release20,21. these alternative SNAREs and have uncovered their com- In the brain, the canonical synaptic vesicular SNARE plementary roles to synaptobrevin 2 in synaptic transmis- (soluble N‑ethylmaleimide-sensitive factor (NSF) attach- sion. In neurons, VTI1A is localized to cell bodies, where ment protein receptor) protein synaptobrevin 2 (also known it is involved in the endosome and trans-Golgi network, as vesicle-associated membrane protein 2 (VAMP2)) as well as to presynaptic terminals, where a splice vari- forms a complex with the plasma membrane SNARE ant of VTI1A is enriched in purified synaptic vesicles30. synaptosomal-associated protein 25 (SNAP25) and syn- VAMP7 is expressed throughout the adult brain. It is taxin 1 to drive rapid action potential-evoked synaptic typically found in the cell body and dendrites of neurons vesicle fusion22. Therefore, loss of synaptobrevin 2 in but has also been shown to be present in presynaptic ter- mice results in near-complete loss of the Ca2+-dependent minals in certain brain areas, such as the hippocampal release that is evoked in tight synchrony with presynap- dentate gyrus31,32. Simultaneous optical imaging of syn- tic action potentials. By contrast, a sizeable proportion aptobrevin 2 and VTI1A or VAMP7, as well as electro- of spontaneous neurotransmission and asynchronous physiological experiments, have shown that although both release (which is loosely coupled to stimulation) are left VTI1A and VAMP7 could be slowly mobilized in response intact in these mice11,23. This observation suggests that to strong stimulation, VTI1A was preferentially trafficked there may be a specialized role for alternative vesicu- under resting conditions27. Further experiments showed Primed vesicles lar SNAREs in the maintenance of spontaneous and that gain or loss of function of VTI1A alters the regula- Vesicles that are docked and asynchronous neurotransmission. tion of a high-frequency spontaneous release event. These that have advanced through all Several additional SNAREs with structures similar results support the hypothesis that VTI1A selectively the necessary molecular to that of synaptobrevin 2 are expressed at low levels on maintains spontaneous neurotransmitter release27. rearrangements of the SNARE synaptic vesicles. These include VAMP4, VAMP7 (also Recent evidence also indicates a key role for VAMP7 (soluble N‑ethylmaleimide- sensitive factor (NSF) known as tetanus-insensitive VAMP) and VTI1A (vesi- in the regulation of spontaneous release. Earlier stud- attachment protein receptor) cle transport through interaction with t-SNAREs homo- ies showed that VAMP7‑containing synaptic vesicles fusion machinery; that is, logue 1A)24. These vesicular SNAREs typically function are responsive to strong stimulation and may therefore vesicles waiting for the influx of in the fusion and trafficking of subcellular organelles perform asynchronous neurotransmission and spon- 2+ Ca ions to trigger fusion. 28,31 According to the current view, within the neuron and possibly guide the biogenesis taneous release . A newer study demonstrated that 25,26 vesicle priming requires partial of synaptic vesicles through the secretory pathway . although VAMP7 in its native form did not show much or full assembly of the SNARE However, there is also evidence that these alternative trafficking under resting conditions, VAMP7‑enriched complex, as well as interaction
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