Regulation of a subset of release-ready vesicles by the presynaptic protein Mover

Neurotransmitter release occurs by regulated exocytosis from synaptic vesicles (SVs). Evolutionarily conserved proteins mediate the essential aspects of this process, including the membrane fusion step and priming steps that make SVs release-competent. Unlike the proteins constituting the core fusion machinery, the SV protein Mover does not occur in all species and all synapses. Its restricted expression suggests that Mover may modulate basic aspects of transmitter release and short-term plasticity. To test this hypothesis, we analyzed synaptic transmission electrophysiologically at the mouse calyx of Held synapse in slices obtained from wild-type mice and mice lacking Mover. Spontaneous transmission was unaffected, indicating that the basic release machinery works in the absence of Mover. Evoked release and vesicular release probability were slightly reduced, and the paired pulse ratio was increased in Mover knockout mice. To explore whether Mover’s role is restricted to certain subpools of SVs, we analyzed our data in terms of two models of priming. A model assuming two SV pools in parallel showed a reduced release probability of so-called “superprimed vesicles” while “normally primed” ones were unaffected. For the second model, which holds that vesicles transit sequentially from a loosely docked state to a tightly docked state before exocytosis, we found that knocking out Mover selectively decreased the release probability of tight state vesicles. These results indicate that Mover regulates a subclass of primed SVs in the mouse calyx of Held.

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Rapid regulation of vesicle priming explains synaptic facilitation despite heterogeneous vesicle:Ca2+ channel distances

eLife ◽

10.7554/elife.51032 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 3

Author(s):

Janus RL Kobbersmed ◽

Andreas T Grasskamp ◽

Meida Jusyte ◽

Mathias A Böhme ◽

Susanne Ditlevsen ◽

...

Keyword(s):

Super Resolution ◽

Release Site ◽

Stochastic Simulations ◽

Short Term ◽

Short Term Plasticity ◽

Release Probability ◽

Vesicular Release ◽

Dependent Inhibition ◽

Super Resolution Microscopy ◽

Activity Dependent

Chemical synaptic transmission relies on the Ca2+-induced fusion of transmitter-laden vesicles whose coupling distance to Ca2+ channels determines synaptic release probability and short-term plasticity, the facilitation or depression of repetitive responses. Here, using electron- and super-resolution microscopy at the Drosophila neuromuscular junction we quantitatively map vesicle:Ca2+ channel coupling distances. These are very heterogeneous, resulting in a broad spectrum of vesicular release probabilities within synapses. Stochastic simulations of transmitter release from vesicles placed according to this distribution revealed strong constraints on short-term plasticity; particularly facilitation was difficult to achieve. We show that postulated facilitation mechanisms operating via activity-dependent changes of vesicular release probability (e.g. by a facilitation fusion sensor) generate too little facilitation and too much variance. In contrast, Ca2+-dependent mechanisms rapidly increasing the number of releasable vesicles reliably reproduce short-term plasticity and variance of synaptic responses. We propose activity-dependent inhibition of vesicle un-priming or release site activation as novel facilitation mechanisms.

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Short-term plasticity at the calyx of held

Nature Reviews Neuroscience ◽

10.1038/nrn705 ◽

2002 ◽

Vol 3 (1) ◽

pp. 53-64 ◽

Cited By ~ 223

Author(s):

Henrique von Gersdorff ◽

J. Gerard G. Borst

Keyword(s):

Short Term ◽

Calyx Of Held ◽

Short Term Plasticity

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A Simple Depletion Model of the Readily Releasable Pool of Synaptic Vesicles Cannot Account for Paired-Pulse Depression

Journal of Neurophysiology ◽

10.1152/jn.00554.2006 ◽

2007 ◽

Vol 97 (1) ◽

pp. 948-950 ◽

Cited By ~ 10

Author(s):

Jane M. Sullivan

Keyword(s):

Synaptic Vesicles ◽

Hippocampal Neurons ◽

Synaptic Activity ◽

Excitatory Synapses ◽

Short Term ◽

Paired Pulse ◽

Short Term Plasticity ◽

Releasable Pool ◽

Readily Releasable Pool ◽

Paired Pulse Depression

Paired-pulse depression (PPD) is a form of short-term plasticity that plays a central role in processing of synaptic activity and is manifest as a decrease in the size of the response to the second of two closely timed stimuli. Despite mounting evidence to the contrary, PPD is still commonly thought to reflect depletion of the pool of synaptic vesicles available for release in response to the second stimulus. Here it is shown that PPD cannot be accounted for by depletion at excitatory synapses made by hippocampal neurons because PPD is unaffected by changes in the fraction of the readily releasable pool (RRP) released by the first of a pair of pulses.

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Presynaptic mitochondrial regulation of microdomain calcium and short-term plasticity at the calyx of Held

IBRO Reports ◽

10.1016/j.ibror.2019.07.474 ◽

2019 ◽

Vol 6 ◽

pp. S149

Author(s):

Cheho Yang ◽

Won Kyung Ho ◽

Suk Ho Lee

Keyword(s):

Short Term ◽

Calyx Of Held ◽

Short Term Plasticity ◽

Mitochondrial Regulation

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Interactions between multiple sources of short-term plasticity during evoked and spontaneous activity at the rat calyx of Held

The Journal of Physiology ◽

10.1113/jphysiol.2008.152124 ◽

2008 ◽

Vol 586 (13) ◽

pp. 3129-3146 ◽

Cited By ~ 14

Author(s):

Matthias H. Hennig ◽

Michael Postlethwaite ◽

Ian D. Forsythe ◽

Bruce P. Graham

Keyword(s):

Spontaneous Activity ◽

Multiple Sources ◽

Short Term ◽

Calyx Of Held ◽

Short Term Plasticity

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Synaptic transmission and short-term plasticity at the calyx of Held synapse revealed by multielectrode array recordings

Journal of Neuroscience Methods ◽

10.1016/j.jneumeth.2008.07.015 ◽

2008 ◽

Vol 174 (2) ◽

pp. 227-236 ◽

Cited By ~ 9

Author(s):

Martin D. Haustein ◽

Thomas Reinert ◽

Annika Warnatsch ◽

Bernhard Englitz ◽

Beatrice Dietz ◽

...

Keyword(s):

Synaptic Transmission ◽

Multielectrode Array ◽

Short Term ◽

Calyx Of Held ◽

Short Term Plasticity ◽

Array Recordings

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Presynaptic Endoplasmic Reticulum Contributes Crucially to Short-term Plasticity in Small Hippocampal Synapses

10.1101/431866 ◽

2018 ◽

Cited By ~ 1

Author(s):

Nishant Singh ◽

Thomas Bartol ◽

Herbert Levine ◽

Terrence Sejnowski ◽

Suhita Nadkarni

Keyword(s):

Endoplasmic Reticulum ◽

Calcium Influx ◽

Critical Role ◽

Presynaptic Terminal ◽

Calcium Stores ◽

Pathological State ◽

Calcium Dynamics ◽

Short Term ◽

Short Term Plasticity ◽

Release Probability

Short-term plasticity (STP) of the presynaptic terminal maintains a brief history of activity experienced by the synapse that may otherwise remain unseen by the postsynaptic neuron. These synaptic changes are primarily regulated by calcium dynamics in the presynaptic terminal. A rapid increase in intracellular calcium is initiated by the opening of voltage-dependent calcium channels in response to depolarization, the main source of calcium required for vesicle fusion. Separately, electron-microscopic studies of hippocampal CA3-CA1 synapses reveal the strong presence of endoplasmic reticulum (ER) in all presynaptic terminals. However, the precise role of the ER in modifying STP at the presynaptic terminal remains unexplored. To investigate the contribution of ER in modulating calcium dynamics in small hippocampal boutons, we performed in silico experiments in a physiologically-realistic canonical synaptic geometry based on reconstructions of CA3-CA1 Schaffer collaterals in the rat hippocampus. The model predicts that presynaptic calcium stores are critical in generating the observed paired-pulse ratio (PPR) of normal CA3-CA1 synapses. In control synapses with intact ER, SERCA pumps act as additional calcium buffers, lowering the intrinsic release probability of vesicle release and increasing PPR. In addition, the presence of ER allows ongoing activity to trigger calcium influx from the presynaptic ER via ryanodine receptors (RyRs) and inositol trisphosphate receptors (IP3Rs). Intracellular stores and their associated machinery also allows a synapse with a low release probability to operate more reliably due to attenuation of calcium fluctuations. Finally, blocking ER activity in the presynaptic terminal mimics the pathological state of a low facilitating synapse characterized in animal models of Alzheimer’s disease, and underscores the critical role played by presynaptic stores in normal function.

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Reexamination of N-terminal domains of Syntaxin-1 in vesicle fusion from central murine synapses

eLife ◽

10.7554/elife.69498 ◽

2021 ◽

Vol 10 ◽

Author(s):

Gülçin Vardar ◽

Andrea Salazar-Lázaro ◽

Marisa M Brockmann ◽

Marion Weber-Boyvat ◽

Sina Zobel ◽

...

Keyword(s):

Synaptic Transmission ◽

Neurotransmitter Release ◽

Null Mouse ◽

General View ◽

Binding Modes ◽

Short Term ◽

Short Term Plasticity ◽

Open Conformation ◽

Vesicular Release ◽

Mouse Model System

Syntaxin-1 (STX1) and Munc18-1 are two requisite components of synaptic vesicular release machinery, so much so synaptic transmission cannot proceed in their absence. They form a tight complex through two major binding modes: through STX1's N-peptide and through STX's closed conformation driven by its Habc- domain. However, physiological roles of these two reportedly different binding modes in synapses are still controversial. Here we characterized the roles of STX1's N-peptide, Habc-domain, and open conformation with and without N-peptide deletion using our STX1-null mouse model system and exogenous reintroduction of STX1A mutants. We show, on the contrary to the general view, that the Habc-domain is absolutely required and N-peptide is dispensable for synaptic transmission. However, STX1A's N-peptide plays a regulatory role, particularly in the Ca2+-sensitivity and the short-term plasticity of vesicular release, whereas STX1's open-conformation governs the vesicle fusogenicity. Strikingly, we also show neurotransmitter release still proceeds when the two interaction modes between STX1A and Munc18-1 are presumably intervened, necessitating a refinement of the conceptualization of STX1A-Munc18-1 interaction.

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