Interplay between VGLUT Isoforms and Endophilin A1 Regulates Neurotransmitter Release and Short-Term Plasticity

Synaptic vesicle (SV) release, recycling, and plastic changes of release probability co-occur side by side within nerve terminals and rely on local Ca2+ signals with different temporal and spatial profiles. The mechanisms that guarantee separate regulation of these vital presynaptic functions during action potential (AP)–triggered presynaptic Ca2+ entry remain unclear. Combining Drosophila genetics with electrophysiology and imaging reveals the localization of two different voltage-gated calcium channels at the presynaptic terminals of glutamatergic neuromuscular synapses (the Drosophila Cav2 homolog, Dmca1A or cacophony, and the Cav1 homolog, Dmca1D) but with spatial and functional separation. Cav2 within active zones is required for AP-triggered neurotransmitter release. By contrast, Cav1 localizes predominantly around active zones and contributes substantially to AP-evoked Ca2+ influx but has a small impact on release. Instead, L-type calcium currents through Cav1 fine-tune short-term plasticity and facilitate SV recycling. Separate control of SV exo- and endocytosis by AP-triggered presynaptic Ca2+ influx through different channels demands efficient measures to protect the neurotransmitter release machinery against Cav1-mediated Ca2+ influx. We show that the plasma membrane Ca2+ ATPase (PMCA) resides in between active zones and isolates Cav2-triggered release from Cav1-mediated dynamic regulation of recycling and short-term plasticity, two processes which Cav2 may also contribute to. As L-type Cav1 channels also localize next to PQ-type Cav2 channels within axon terminals of some central mammalian synapses, we propose that Cav2, Cav1, and PMCA act as a conserved functional triad that enables separate control of SV release and recycling rates in presynaptic terminals.

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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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Augmentation Controls the Fast Rebound From Depression at Excitatory Hippocampal Synapses

Journal of Neurophysiology ◽

10.1152/jn.01348.2007 ◽

2008 ◽

Vol 99 (4) ◽

pp. 1770-1786 ◽

Cited By ~ 17

Author(s):

Elizabeth Garcia-Perez ◽

John F. Wesseling

Keyword(s):

Neurotransmitter Release ◽

Single Pulse ◽

Maximal Level ◽

Short Term ◽

Paired Pulse ◽

Short Term Plasticity ◽

Readily Releasable Pool ◽

Hippocampal Synapses ◽

Low Probability ◽

Chemical Synapses

Short-term plasticity occurs at most central chemical synapses and includes both positive and negative components, but the principles governing interaction between components are largely unknown. The residual Ca2+ that persists in presynaptic terminals for several seconds after repetitive use is known to enhance neurotransmitter release under artificial, low probability of release conditions where depression is absent; this is termed augmentation. However, the full impact of augmentation under standard conditions at synapses where depression dominates is not known because of possibly complicated convolution with a variety of potential depression mechanisms. This report shows that residual Ca2+ continues to have a large enhancing impact on release at excitatory hippocampal synapses recovering from depression, including when only recently recruited vesicles are available for release. No evidence was found for gradual vesicle priming or for fast refilling of a highly releasable subdivision of the readily releasable pool (RRP). And decay of enhancement matched the clearance of residual Ca2+, thus matching the behavior of augmentation when studied in isolation. Because of incomplete RRP replenishment, synaptic strength was not typically increased above baseline when residual Ca2+ levels were highest. Instead residual Ca2+ caused single pulse release probability to rebound quickly from depression and then depress quickly during subsequent bursts of activity. Together, these observations can help resolve discrepancies in recent timing estimates of recovery from depression. Additionally, in contrast to results obtained under reduced release conditions, augmentation could be driven to a maximal level, occluding paired-pulse facilitation and other mechanisms that increase release efficiency.

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Neurotransmitter Release Site Replenishment and Presynaptic Plasticity

International Journal of Molecular Sciences ◽

10.3390/ijms22010327 ◽

2020 ◽

Vol 22 (1) ◽

pp. 327

Author(s):

Sumiko Mochida

Keyword(s):

Neurotransmitter Release ◽

Synaptic Vesicles ◽

High Speed ◽

Release Site ◽

Short Term ◽

Short Term Plasticity ◽

Multiple Protein ◽

Presynaptic Plasticity ◽

Presynaptic Plasma Membrane ◽

Ca2 Channels

An action potential (AP) triggers neurotransmitter release from synaptic vesicles (SVs) docking to a specialized release site of presynaptic plasma membrane, the active zone (AZ). The AP simultaneously controls the release site replenishment with SV for sustainable synaptic transmission in response to incoming neuronal signals. Although many studies have suggested that the replenishment time is relatively slow, recent studies exploring high speed resolution have revealed SV dynamics with milliseconds timescale after an AP. Accurate regulation is conferred by proteins sensing Ca2+ entering through voltage-gated Ca2+ channels opened by an AP. This review summarizes how millisecond Ca2+ dynamics activate multiple protein cascades for control of the release site replenishment with release-ready SVs that underlie presynaptic short-term plasticity.

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