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Article
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Tomosyns attenuate SNARE assembly and synaptic depression by binding to VAMP2-containing template complexes
SNARE-dependent membrane fusion underlies neurotransmission in the nervous system. Here, the authors demonstrate how, in mammalian neurons, the synaptic protein tomosyn controls secretion by increasing the energy barrier for fusion.
- Marieke Meijer
- , Miriam Öttl
- & Matthijs Verhage
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Article
| Open Access
Synapsin 2a tetramerisation selectively controls the presynaptic nanoscale organisation of reserve synaptic vesicles
How synaptic vesicles (SVs) are clustered at the presynapse is suggestive of anchoring processes counteracting their diffusion. Here, the authors co-track recycling and reserve SVs in live neurons to find that Synapsin 2a tetramerization dynamically immobilizes reserve SVs at the presynapse.
- Shanley F. Longfield
- , Rachel S. Gormal
- & Frédéric A. Meunier
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Article
| Open Access
The juxtamembrane linker of synaptotagmin 1 regulates Ca2+ binding via liquid-liquid phase separation
Synaptotagmin (syt) 1 is a calcium sensor for neuronal exocytosis. Here, the authors show that the juxtamembrane linker of this integral membrane protein negatively regulates its calcium sensing activity by mediating self-association via liquid-liquid phase separation.
- Nikunj Mehta
- , Sayantan Mondal
- & Edwin R. Chapman
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Perspective
| Open Access
Membrane transformations of fusion and budding
Life-crucial membrane fusion and budding were traditionally viewed with electron microscopy. With recent breakthroughs that visualize membrane transformation in real time, Wu and Chan synthesize a new model with mechanistic principles and functions.
- Ling-Gang Wu
- & Chung Yu Chan
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Article
| Open Access
Synaptotagmin-7 outperforms synaptotagmin-1 to promote the formation of large, stable fusion pores via robust membrane penetration
Synaptotagmin-1 and -7 are calcium sensors that distinctly drive vesicular exocytosis. Here, using wild-type proteins but manipulating the composition of the target membranes, the authors show that synaptotagmin-7 is unusually robust at penetrating membranes.
- Kevin C. Courtney
- , Taraknath Mandal
- & Edwin R. Chapman
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Article
| Open Access
Rapid and reversible optogenetic silencing of synaptic transmission by clustering of synaptic vesicles
Existing optogenetic silencing methods affect membrane potential, biochemistry or protein integrity. Here, the authors demonstrate an approach for silencing synaptic transmission that combines fast activation and reversibility, by using nondisruptive, reversible, light-evoked clustering of synaptic vesicles, which they validate in Caenorhabditis elegans, zebrafish, and murine cell culture.
- Dennis Vettkötter
- , Martin Schneider
- & Alexander Gottschalk
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Article
| Open Access
Vesicular release probability sets the strength of individual Schaffer collateral synapses
It is not fully understood if the probability of synaptic vesicle release is homogenous or varies between individual boutons. Here the authors perform optical quantal analyses of individual Schaffer collateral synapses, showing that multivesicular release enables a tenfold increase in glutamate output and that the vesicular release probability is not uniform between synapses.
- Céline D. Dürst
- , J. Simon Wiegert
- & Thomas G. Oertner
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Article
| Open Access
Asynchronous glutamate release is enhanced in low release efficacy synapses and dispersed across the active zone
Neurotransmitters can be released with a delay in relation to action potentials. This work demonstrates how this asynchronous release is related to overall vesicle release probability and short-term plasticity.
- Philipe R. F. Mendonça
- , Erica Tagliatti
- & Kirill E. Volynski
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Article
| Open Access
Diurnal changes in the efficiency of information transmission at a sensory synapse
Neuromodulators can adjust how sensory signals are processed. In this study, the authors demonstrate how time of day affects the way information is transmitted in the zebrafish retina.
- José Moya-Díaz
- , Ben James
- & Leon Lagnado
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Article
| Open Access
PKC-phosphorylation of Liprin-α3 triggers phase separation and controls presynaptic active zone structure
Liquid–liquid phase separation may be a mechanism for organizing the presynaptic nerve terminal. Here, the authors show that PKC-mediated phosphorylation of Liprin-α3 triggers phase separation in cell lines and modulates active zone structure and function in primary hippocampal neurons.
- Javier Emperador-Melero
- , Man Yan Wong
- & Pascal S. Kaeser
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Article
| Open Access
Transsynaptic modulation of presynaptic short-term plasticity in hippocampal mossy fiber synapses
Post‐tetanic potentiation (PTP) is a major form of plasticity at hippocampal mossy fiber synapses and is considered an entirely presynaptic phenomenon. The authors show that mossy fiber PTP not only lacks associativity, but rather shows anti‐associative induction properties, implementing a brake on mossy fiber detonation.
- David Vandael
- , Yuji Okamoto
- & Peter Jonas
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Article
| Open Access
The docking of synaptic vesicles on the presynaptic membrane induced by α-synuclein is modulated by lipid composition
α-Synuclein is a presynaptic protein whose aberrant aggregation is associated with Parkinson’s disease. Here, the authors show how αSynuclein-induced docking of synaptic vesicles is modulated by the lipid composition changes typically observed in neurodegeneration using an in vitro system.
- Wing K. Man
- , Bogachan Tahirbegi
- & Giuliana Fusco
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Article
| Open Access
Conserved arginine residues in synaptotagmin 1 regulate fusion pore expansion through membrane contact
Synaptotagmin 1 (Syt1) is the calcium sensor for fast synchronous neurotransmitter release but the mechanism by which it functions is still under debate. Here, the authors combine EPR measurements and functional studies and observe that different faces of the Syt1 C2B domain play different roles in regulating neurotransmitter release and they show that the expansion of the fusion pore is mediated by membrane contact of the C2B arginine apex.
- Sarah B. Nyenhuis
- , Nakul Karandikar
- & David S. Cafiso
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Article
| Open Access
Asynchronous release sites align with NMDA receptors in mouse hippocampal synapses
Action potentials induce synchronous and asynchronous release of neurotransmitters. Here, the authors show that the synchronous and asynchronous release sites are aligned with AMPARs and NMDARs, respectively, in mouse hippocampal synapses. This organization allows efficient activation of NMDARs.
- Shuo Li
- , Sumana Raychaudhuri
- & Shigeki Watanabe
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Article
| Open Access
Cooperative function of synaptophysin and synapsin in the generation of synaptic vesicle-like clusters in non-neuronal cells
Synaptic vesicle clusters were proposed to represent phase separated condensates. Here, the authors show that only two proteins, synapsin and synaptophysin, are sufficient to make vesicle clusters in fibroblasts which are similar to those found at synapses in morphology and liquid-like properties.
- Daehun Park
- , Yumei Wu
- & Sunghoe Chang
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Article
| Open Access
Open syntaxin overcomes exocytosis defects of diverse mutants in C. elegans
Opening of the UNC-64/syntaxin closed conformation by UNC-13/Munc13 to form the neuronal SNARE complex is critical for neurotransmitter release. Here the authors show that facilitating the opening of syntaxin enhances exocytosis not only in unc-13 nulls as well as in diverse C. elegans mutants.
- Chi-Wei Tien
- , Bin Yu
- & Shuzo Sugita
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Article
| Open Access
Resolving kinetic intermediates during the regulated assembly and disassembly of fusion pores
SNAREs mediate the formation of a fusion pore during exocytosis which connects the lumen of a vesicle with the extracellular space. Here, authors use single molecule approaches to define the role of synaptotagmin 1 and NSF in synaptic pore formation and dissolution.
- Debasis Das
- , Huan Bao
- & Edwin R. Chapman
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Article
| Open Access
Synaptotagmin 1 clamps synaptic vesicle fusion in mammalian neurons independent of complexin
The molecular identity of the clamp that arrests the fusion machinery such that synaptic vesicles are docked and primed to release neurotransmitters remains controversial. In this study, the authors use truncation mutants of synaptotagmin (syt) 1 and animal models to demonstrate that the C2B domain of syt1, and not complexin, is solely responsible for the reduction of the spontaneous release at the presynapse
- Nicholas A. Courtney
- , Huan Bao
- & Edwin R. Chapman
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Article
| Open Access
Munc18 and Munc13 serve as a functional template to orchestrate neuronal SNARE complex assembly
Synaptic exocytosis depends on formation of the SNARE complex but its assembly mechanism is still under debate. Here, the authors identify an interaction between Munc13-1 and synaptobrevin-2 that is critical for the transition of the Munc18-1/syntaxin-1 complex to the SNARE complex.
- Shen Wang
- , Yun Li
- & Cong Ma
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Article
| Open Access
Focused clamping of a single neuronal SNARE complex by complexin under high mechanical tension
The SNARE complex enables the fusion of synaptic vesicles with presynaptic membrane via a zippering process that is modulated by the protein complexin, though the precise mechanism remains unclear. Here, the authors used magnetic tweezers to show how complexin prepares a SNARE complex for fusion under mechanical tension.
- Min Ju Shon
- , Haesoo Kim
- & Tae-Young Yoon
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Article
| Open Access
Vti1a/b regulate synaptic vesicle and dense core vesicle secretion via protein sorting at the Golgi
Vti1a and Vti1b are SNARE proteins implicated in regulated secretion. Here the authors show that Vti1a and Vti1b control protein sorting at the Golgi, and targeting to the axon, and thereby indirectly control regulated secretion at the synapse.
- Javier Emperador-Melero
- , Vincent Huson
- & Matthijs Verhage
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Article
| Open Access
Membrane cholesterol mediates the cellular effects of monolayer graphene substrates
Understanding the biological role of graphene in eukaryotic cells is essential for future biomedicine applications. Here, the authors investigate the interaction of neurons and fibroblasts with graphene substrates, which increase cell membrane cholesterol and potentiate neurotransmitter release and receptor signaling.
- Kristina E. Kitko
- , Tu Hong
- & Qi Zhang
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Article
| Open Access
Dysbindin links presynaptic proteasome function to homeostatic recruitment of low release probability vesicles
At the fly neuromuscular junction, postsynaptic receptor perturbation induces homeostatic enhancement of neurotransmitter release. Here, the authors show that the presynaptic proteasome controls a vesicle pool required for homeostatic plasticity and that dysbindin is required to access this pool.
- Corinna Wentzel
- , Igor Delvendahl
- & Martin Müller
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Article
| Open Access
Semisynthetic fluorescent pH sensors for imaging exocytosis and endocytosis
Existing pH-sensitive red fluorescent protein probes don’t perform well in monitoring exocytosis and endocytosis. Here, the authors combine organic dyes with self-labeling tags or antibodies to develop semisynthetic protein conjugates that can image synaptic vesicle fusion events in living cells.
- Magalie Martineau
- , Agila Somasundaram
- & David Perrais
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Article
| Open Access
AIP limits neurotransmitter release by inhibiting calcium bursts from the ryanodine receptor
In this work the authors show that AIP (aryl hydrocarbon receptor-interacting protein), a gene frequently mutated in association with pituitary tumors, regulates neurotransmitter release by inhibiting calcium release from ryanodine receptors.
- Bojun Chen
- , Ping Liu
- & Zhao-Wen Wang
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Article
| Open Access
Munc13-1 and Munc18-1 together prevent NSF-dependent de-priming of synaptic vesicles
The molecular mechanism underlying the generation and maintenance of the readily releasable pool composed of primed synaptic vesicles is only partially known. Here the authors show that in mouse primary neurons, Munc13-1 and Munc18-1 stabilize primed synaptic vesicles by preventing NSF-dependent de-priming.
- Enqi He
- , Keimpe Wierda
- & Matthijs Verhage
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Article
| Open Access
TRPV1 channels are critical brain inflammation detectors and neuropathic pain biomarkers in mice
TRPV1 is known to be expressed in peripheral structures and the spinal cord, especially for pain processing. Here the authors show that in the brain, in particular the anterior cingulate cortex, TRPV1 is functionally expressed in microglia; stimulation of TRPV1 activates microglia, which in turn affects glutamatergic neurotransmission.
- Maria Cristina Marrone
- , Annunziato Morabito
- & Silvia Marinelli
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Article
| Open Access
Heterodimerization of Munc13 C2A domain with RIM regulates synaptic vesicle docking and priming
The interaction between RIM and the C2A domain of Munc13 is known to be required for synaptic vesicle priming. Here the authors show new implications of the C2A domain of Munc13, through its dynamic interaction with RIM, in orchestrating a wide range of modulatory operations that shape vesicle docking, priming and neurotransmitter release.
- Marcial Camacho
- , Jayeeta Basu
- & Christian Rosenmund
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Article
| Open Access
Selective molecular impairment of spontaneous neurotransmission modulates synaptic efficacy
Emerging evidence suggests that spontaneous neurotransmitter release contributes to the maintenance of synaptic efficacy. Here the authors selectively reduce spontaneous glutamatergic transmission while leaving the stimulus-evoked responses intact and show that this leads to homeostatic scaling at the postsynaptic side in cultured neurons and alters synaptic plasticity in acute brain slices.
- Devon C. Crawford
- , Denise M. O. Ramirez
- & Ege T. Kavalali
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Article
| Open Access
In vivo single-molecule imaging of syntaxin1A reveals polyphosphoinositide- and activity-dependent trapping in presynaptic nanoclusters
Syntaxin1A (Sx1A) is organized in nanoclusters in neurosecretory cells but how these nanoclusters are affected by neurotransmitter release in a living organism is unknown. Here the authors perform single molecule imaging analysis in live fly larvae and show that the lateral diffusion and trapping of Sx1A in nanoclusters are altered by synaptic activity.
- Adekunle T. Bademosi
- , Elsa Lauwers
- & Frédéric A. Meunier
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Article
| Open Access
Actin dynamics provides membrane tension to merge fusing vesicles into the plasma membrane
As vesicles fuse to the plasma membrane, they form intermediate Ω-shaped structures followed by either closure of the pore or full merging with the plasma membrane. Here Wen et al. show that dynamic actin assembly provides membrane tension to promote Ω merging in neuroendocrine cells and synapses.
- Peter J. Wen
- , Staffan Grenklo
- & Ling-Gang Wu
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The trans-SNARE-regulating function of Munc18-1 is essential to synaptic exocytosis
Munc18-1 binds trans-SNARE complexes and promotes membrane fusion in vitro. Here the authors provide genetic evidence that this trans-SNARE-regulating function plays an essential role in synaptic releases in neurons, and show that this function is disrupted by a disease-causing Munc18-1 mutation.
- Chong Shen
- , Shailendra S. Rathore
- & Jingshi Shen
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Article
| Open Access
Diffusional spread and confinement of newly exocytosed synaptic vesicle proteins
Neurotransmission is mediated by synaptic vesicles (SVs) fusion with the plasma membrane near active zones. Here, Gimber et al.observe that rapid diffusional spread and confinement is followed by slow reclustering of SV proteins at the periactive endocytic zone through SV protein association with the clathrin-based machinery.
- Niclas Gimber
- , Georgi Tadeus
- & Volker Haucke
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Activity-driven relaxation of the cortical actomyosin II network synchronizes Munc18-1-dependent neurosecretory vesicle docking
Secretory vesicles must cross a dense cortical actin network to dock and fuse with the plasma membrane. Papadopulos et al. reveal that, in neurosecretory cells, relaxation of this network acts as a 'casting net', driving tethered vesicles towards the plasma membrane.
- Andreas Papadopulos
- , Guillermo A. Gomez
- & Frederic A. Meunier
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Phosphatidylinositol(4,5)bisphosphate coordinates actin-mediated mobilization and translocation of secretory vesicles to the plasma membrane of chromaffin cells
The role of phosphatidylinositol(4,5)bisphosphate in exocytosis is unclear. This study shows that inhibition of the p110δ isoform of PI3-kinase promotes a transient increase in phosphatidylinositol(4,5)bisphosphate, leading to a potentiation of exocytosis in chromaffin cells.
- Peter J. Wen
- , Shona L. Osborne
- & Frédéric A. Meunier
Differential SNARE chaperoning by Munc13-1 and Munc18-1 dictates fusion pore fate at the release site