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  • 1
    Article
    Article
    Language: English
    In: Neuron, 09 December 2010, Vol.68(5), pp.803-6
    Description: Knockout and other perturbations of complexins have provided important insights and elicited controversies about their role in neurotransmitter release. New work by Yang et al. in this issue of Neuron adds important detail and complexity to existing concepts-particularly on the nature of a Ca(2+)-dependent complexin-synaptotagmin switch for the triggering of exocytosis. But it also provokes thoughts about alternative interpretations, which might result in a simpler model of complexin function.
    Keywords: Calcium ; Neurons ; Exocytosis ; Neurotransmitter Release ; Neurobiology;
    ISSN: 08966273
    E-ISSN: 1097-4199
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  • 2
    Language: English
    In: Neuron, 23 September 2015, Vol.87(6), pp.1131-1142
    Description: The concept of a readily releasable pool (RRP) of synaptic vesicles has been used extensively for the analysis of neurotransmitter release. Traditionally the properties of vesicles in such a pool have been assumed to be homogeneous, and techniques have been developed to determine pool parameters, such as the size of the pool and the probability with which a vesicle is released during an action potential. Increasing evidence, however, indicates that vesicles may be quite heterogeneous with respect to their release probability. The question, therefore, arises: what do the estimates of pool parameters mean in view of such heterogeneity? Here, four methods for obtaining pool estimates are reviewed, together with their underlying assumptions. The consequences of violation of these assumptions are discussed, and how apparent pool sizes are influenced by stimulation strength is explored by simulations. Synaptic vesicles are released by action potentials in an all-or-nothing manner. Erwin Neher explores how estimates for the number of release-ready vesicles and their release probability, as obtained by commonly used analysis methods, are influenced by the fact that “pools” of vesicles are not homogeneous.
    Keywords: Biology ; Anatomy & Physiology
    ISSN: 0896-6273
    E-ISSN: 1097-4199
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  • 3
    In: Journal of Physiology, 01 July 2013, Vol.591(13), pp.3189-3195
    Description: Giant nerve terminals offer a unique opportunity to learn about dynamic changes in intracellular global Ca concentration ([Ca]) because this quantity can be measured precisely with indicator dyes and the composition of the intra‐terminal ionic milieu can be controlled. We review here recent literature on [Ca] signalling in the calyx of Held and discuss what these measurements can tell us about endogenous Ca buffers and Ca extrusion mechanisms. We conclude that in spite of the favourable experimental conditions, some unresolved questions still remain regarding absolute values for the Ca‐binding ratio, the affinity of the basic fixed buffer and the Ca affinities of the major endogenous Ca binding proteins. Uncertainties about some of these presynaptic properties, including the roles of Mg and ATP (as a Mg buffer), however, extend to the point that mechanisms controlling the decay of [Ca] signals in unperturbed terminals may have to be reconsidered.
    Keywords: Binding Proteins -- Physiological Aspects ; Protein Binding -- Physiological Aspects;
    ISSN: 0022-3751
    E-ISSN: 1469-7793
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  • 4
    Language: English
    In: Biophysical Journal, 24 January 2017, Vol.112(2), pp.215-223
    Description: The calyx of Held is a giant nerve terminal that forms a glutamatergic synapse in the auditory pathway. Due to its large size, it offers a number of advantages for biophysical studies, including voltage-clamp of both pre- and postsynaptic compartments and the loading with indicator dyes and caged compounds. Three aspects of recent findings on the calyx are reviewed here, each of which seems to have only subtle consequences for nerve-evoked excitatory postsynaptic currents: vesicle heterogeneity, refractoriness of release sites, and superpriming. Together, they determine short-term plasticity features that are superficially similar to those expected for a simple vesicle pool model. However, detailed consideration of these aspects may be required for the correct mechanistic interpretation of data from synapses with normal and perturbed function, as well as for modeling the dynamics of short-term plasticity.
    Keywords: Biology
    ISSN: 0006-3495
    E-ISSN: 1542-0086
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  • 5
    Language: English
    In: Neuron, 19 December 2018, Vol.100(6), pp.1283-1291
    Description: Based on evidence that the docked and primed synaptic vesicle state is very dynamic, we propose a three-step process for the buildup of the molecular machinery that mediates synaptic vesicle fusion: (1) loose tethering and docking of vesicles to release sites, forming the nucleus of SNARE-complex assembly, (2) tightening of the complex by association of additional proteins, and partial SNARE-complex zippering, and (3) Ca -triggered fusion. We argue that the distinction between “phasic synapses” and “tonic synapses” reflects differences in resting occupancy and stability of the loosely and tightly docked states, and we assign corresponding timescales: with high-frequency synaptic activity and concomitantly increased Ca -concentrations, step (1) can proceed within 10–50 ms, step (2) within 1–5 ms, and step (3) within 0.2–1 ms. Synaptic vesicle priming determines synaptic strength and short-term plasticity. Neher and Brose propose a model of loosely and tightly primed vesicle states, which can be interconverted rapidly, and whose occupancy defines the distinction between “phasic” and “tonic” synapses.
    Keywords: Synaptic Vesicles ; Exocytosis ; Snare-Complex ; Tethering ; Phasic Synapses ; Tonic Synapses ; Facilitation ; Biology ; Anatomy & Physiology
    ISSN: 0896-6273
    E-ISSN: 1097-4199
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  • 6
    Language: English
    In: Biophysical Journal, 31 January 2012, Vol.102(3), pp.318a-318a
    Keywords: Biology
    ISSN: 0006-3495
    E-ISSN: 1542-0086
    Source: ScienceDirect Journals (Elsevier)
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  • 7
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 02 August 2016, Vol.113(31), pp.E4548-57
    Description: Glutamatergic synapses show large variations in strength and short-term plasticity (STP). We show here that synapses displaying an increased strength either after posttetanic potentiation (PTP) or through activation of the phospholipase-C-diacylglycerol pathway share characteristic properties with intrinsically strong synapses, such as (i) pronounced short-term depression (STD) during high-frequency stimulation; (ii) a conversion of that STD into a sequence of facilitation followed by STD after a few conditioning stimuli at low frequency; (iii) an equalizing effect of such conditioning stimulation, which reduces differences among synapses and abolishes potentiation; and (iv) a requirement of long periods of rest for reconstitution of the original STP pattern. These phenomena are quantitatively described by assuming that a small fraction of "superprimed" synaptic vesicles are in a state of elevated release probability (p ∼ 0.5). This fraction is variable in size among synapses (typically about 30%), but increases after application of phorbol ester or during PTP. The majority of vesicles, released during repetitive stimulation, have low release probability (p ∼ 0.1), are relatively uniform in number across synapses, and are rapidly recruited. In contrast, superprimed vesicles need several seconds to be regenerated. They mediate enhanced synaptic strength at the onset of burst-like activity, the impact of which is subject to modulation by slow modulatory transmitter systems.
    Keywords: Munc13 ; Calyx of Held ; Phorbol Ester ; Posttetanic Potentiation ; Short-Term Plasticity ; Excitatory Postsynaptic Potentials -- Physiology ; Synapses -- Physiology ; Synaptic Transmission -- Physiology ; Synaptic Vesicles -- Physiology
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 8
    Language: English
    In: Science (New York, N.Y.), 09 February 2018, Vol.359(6376), pp.633-634
    Description: Neurons can be modified with light-gated ion channels, which cause them to become excited upon illumination (1, 2). This discovery has given rise to the field of optogenetics, with impressive examples such as triggering the beat of a heart with light (3). There is, however, one technical limitation:...
    Keywords: Brain
    ISSN: 00368075
    E-ISSN: 1095-9203
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  • 9
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 10 September 2013, Vol.110(37), pp.15079-84
    Description: Recruitment of release-competent vesicles during sustained synaptic activity is one of the major factors governing short-term plasticity. During bursts of synaptic activity, vesicles are recruited to a fast-releasing pool from a reluctant vesicle pool through an actin-dependent mechanism. We now show that newly recruited vesicles in the fast-releasing pool do not respond at full speed to a strong Ca(2+) stimulus, but require approximately 4 s to mature to a "superprimed" state. Superpriming was found to be altered by agents that modulate the function of unc13 homolog proteins (Munc13s), but not by calmodulin inhibitors or actin-disrupting agents. These findings indicate that recruitment and superpriming of vesicles are regulated by separate mechanisms, which require integrity of the cytoskeleton and activation of Munc13s, respectively. We propose that refilling of the fast-releasing vesicle pool proceeds in two steps, rapid actin-dependent "positional priming," which brings vesicles closer to Ca(2+) sources, followed by slower superpriming, which enhances the Ca(2+) sensitivity of primed vesicles.
    Keywords: Calyx of Held ; Diacylglycerol ; Phospholipase C ; Presynaptic ; Vesicle Release Rate Constant ; Synaptic Vesicles -- Physiology
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 10
    Language: English
    In: Science (New York, N.Y.), 22 October 2010, Vol.330(6003), pp.502-5
    Description: Exocytosis requires formation of SNARE [soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptor] complexes between vesicle and target membranes. Recent assessments in reduced model systems have produced divergent estimates of the number of SNARE complexes needed for fusion. Here, we used a titration approach to answer this question in intact, cultured chromaffin cells. Simultaneous expression of wild-type SNAP-25 and a mutant unable to support exocytosis progressively altered fusion kinetics and fusion-pore opening, indicating that both proteins assemble into heteromeric fusion complexes. Expressing different wild-type:mutant ratios revealed a third-power relation for fast (synchronous) fusion and a near-linear relation for overall release. Thus, fast fusion typically observed in synapses and neurosecretory cells requires at least three functional SNARE complexes, whereas slower release might occur with fewer complexes. Heterogeneity in SNARE-complex number may explain heterogeneity in vesicular release probability.
    Keywords: Exocytosis -- Physiology ; Membrane Fusion -- Physiology ; Synaptosomal-Associated Protein 25 -- Physiology
    ISSN: 00368075
    E-ISSN: 1095-9203
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