Perturbation of synaptic vesicle delivery during neurotransmitter release triggered independently of calcium influx

Homeostatic signaling stabilizes synaptic transmission at the neuromuscular junction (NMJ) of Drosophila, mice, and human. It is believed that homeostatic signaling at the NMJ is bi-directional and considerable progress has been made identifying mechanisms underlying the homeostatic potentiation of neurotransmitter release. However, very little is understood mechanistically about the opposing process, homeostatic depression, and how bi-directional plasticity is achieved. Here, we show that homeostatic potentiation and depression can be simultaneously induced, demonstrating true bi-directional plasticity. Next, we show that mutations that block homeostatic potentiation do not alter homeostatic depression, demonstrating that these are genetically separable processes. Finally, we show that homeostatic depression is achieved by decreased presynaptic calcium channel abundance and calcium influx, changes that are independent of the presynaptic action potential waveform. Thus, we identify a novel mechanism of homeostatic synaptic plasticity and propose a model that can account for the observed bi-directional, homeostatic control of presynaptic neurotransmitter release.

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Synaptic vesicle pool-specific modification of neurotransmitter release by intravesicular free radical generation

The Journal of Physiology ◽

10.1113/jp273115 ◽

2016 ◽

Vol 595 (4) ◽

pp. 1223-1238 ◽

Cited By ~ 8

Author(s):

Olusoji A. T. Afuwape ◽

Catherine R. Wasser ◽

Thomas Schikorski ◽

Ege T. Kavalali

Keyword(s):

Free Radical ◽

Synaptic Vesicle ◽

Neurotransmitter Release ◽

Free Radical Generation ◽

Specific Modification ◽

Radical Generation ◽

Vesicle Pool

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Recent Breakthroughs in Neurotransmitter Release: Paradigm for Regulated Exocytosis?

Physiology ◽

10.1152/physiologyonline.1995.10.1.42 ◽

1995 ◽

Vol 10 (1) ◽

pp. 42-46

Author(s):

G Thiel

Keyword(s):

Synaptic Vesicle ◽

Brain Function ◽

Neurotransmitter Release ◽

Synaptic Vesicles ◽

Vesicle Trafficking ◽

Regulated Exocytosis ◽

Intracellular Vesicle ◽

Vesicle Cycle ◽

Synaptic Vesicle Cycle

Synaptic vesicles play a fundamental role in brain function by mediating the release of neurotransmitters. Neurons do not use an entirely unique secretion apparatus but rather a modification of the general secretion machinery. Moreover, the synaptic vesicle cycle has many similarities with intracellular vesicle trafficking pathways.

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Neurotransmitter Release

10.1093/med/9780190237493.003.0011 ◽

2017 ◽

Author(s):

Peggy Mason

Keyword(s):

Plasma Membrane ◽

Synaptic Vesicle ◽

Active Zone ◽

Neurotransmitter Release ◽

Synaptic Vesicles ◽

Synaptic Cleft ◽

Fusion Pore ◽

Synaptic Membrane ◽

Specialized Region ◽

Synaptic Vesicle Fusion

The biochemical and physiological processes of neurotransmitter release from an active zone, a specialized region of synaptic membrane, are examined. Synaptic vesicles containing neurotransmitters are docked at the active zone and then primed for release by SNARE complexes that bring them into extreme proximity to the plasma membrane. Entry of calcium ions through voltage-gated calcium channels triggers synaptic vesicle fusion with the synaptic terminal membrane and the consequent diffusion of neurotransmitter into the synaptic cleft. Release results when the fusion pore bridging the synaptic vesicle and plasma membrane widens and neurotransmitter from the inside of the synaptic vesicle diffuses into the synaptic cleft. Membrane from the active zone membrane is endocytosed, and synaptic vesicle proteins are then reassembled into recycled synaptic vesicles, allowing for more rounds of neurotransmitter release.

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Botulinum Neurotoxin a Blocks Synaptic Vesicle Exocytosis but Not Endocytosis at the Nerve Terminal

The Journal of Cell Biology ◽

10.1083/jcb.147.6.1249 ◽

1999 ◽

Vol 147 (6) ◽

pp. 1249-1260 ◽

Cited By ~ 59

Author(s):

Elaine A. Neale ◽

Linda M. Bowers ◽

Min Jia ◽

Karen E. Bateman ◽

Lura C. Williamson

Keyword(s):

Synaptic Vesicle ◽

Nerve Terminal ◽

Neurotransmitter Release ◽

Synaptic Vesicles ◽

Botulinum Neurotoxin ◽

Vesicle Membrane ◽

Botulinum Neurotoxin A ◽

Synaptic Vesicle Exocytosis ◽

Vesicle Exocytosis ◽

Botulinum Neurotoxins

The supply of synaptic vesicles in the nerve terminal is maintained by a temporally linked balance of exo- and endocytosis. Tetanus and botulinum neurotoxins block neurotransmitter release by the enzymatic cleavage of proteins identified as critical for synaptic vesicle exocytosis. We show here that botulinum neurotoxin A is unique in that the toxin-induced block in exocytosis does not arrest vesicle membrane endocytosis. In the murine spinal cord, cell cultures exposed to botulinum neurotoxin A, neither K+-evoked neurotransmitter release nor synaptic currents can be detected, twice the ordinary number of synaptic vesicles are docked at the synaptic active zone, and its protein substrate is cleaved, which is similar to observations with tetanus and other botulinal neurotoxins. In marked contrast, K+ depolarization, in the presence of Ca2+, triggers the endocytosis of the vesicle membrane in botulinum neurotoxin A–blocked cultures as evidenced by FM1-43 staining of synaptic terminals and uptake of HRP into synaptic vesicles. These experiments are the first demonstration that botulinum neurotoxin A uncouples vesicle exo- from endocytosis, and provide evidence that Ca2+ is required for synaptic vesicle membrane retrieval.

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Molecular Mechanisms of Fast Neurotransmitter Release

Annual Review of Biophysics ◽

10.1146/annurev-biophys-070816-034117 ◽

2018 ◽

Vol 47 (1) ◽

pp. 469-497 ◽

Cited By ~ 47

Author(s):

Axel T. Brunger ◽

Ucheor B. Choi ◽

Ying Lai ◽

Jeremy Leitz ◽

Qiangjun Zhou

Keyword(s):

Synaptic Vesicle ◽

Neurotransmitter Release ◽

High Speed ◽

Molecular Mechanisms ◽

Current Knowledge ◽

Vesicle Fusion ◽

Synaptic Proteins ◽

Functional Studies ◽

Protein Receptors ◽

Synaptic Vesicle Fusion

This review summarizes current knowledge of synaptic proteins that are central to synaptic vesicle fusion in presynaptic active zones, including SNAREs (soluble N-ethylmaleimide sensitive factor attachment protein receptors), synaptotagmin, complexin, Munc18 (mammalian uncoordinated-18), and Munc13 (mammalian uncoordinated-13), and highlights recent insights in the cooperation of these proteins for neurotransmitter release. Structural and functional studies of the synaptic fusion machinery suggest new molecular models of synaptic vesicle priming and Ca2+-triggered fusion. These studies will be a stepping-stone toward answering the question of how the synaptic vesicle fusion machinery achieves such high speed and sensitivity.

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The Nature of Surround-Induced Depolarizing Responses in Goldfish Cones

The Journal of General Physiology ◽

10.1085/jgp.115.1.3 ◽

1999 ◽

Vol 115 (1) ◽

pp. 3-16 ◽

Cited By ~ 23

Author(s):

D.A. Kraaij ◽

H. Spekreijse ◽

M. Kamermans

Keyword(s):

Membrane Potential ◽

Neurotransmitter Release ◽

Calcium Current ◽

Calcium Influx ◽

Horizontal Cell ◽

Activation Function ◽

Bipolar Cells ◽

Horizontal Cells ◽

Calcium Dependent ◽

Postsynaptic Cell

Cones in the vertebrate retina project to horizontal and bipolar cells and the horizontal cells feedback negatively to cones. This organization forms the basis for the center/surround organization of the bipolar cells, a fundamental step in the visual signal processing. Although the surround responses of bipolar cells have been recorded on many occasions, surprisingly, the underlying surround-induced responses in cones are not easily detected. In this paper, the nature of the surround-induced responses in cones is studied. Horizontal cells feed back to cones by shifting the activation function of the calcium current in cones to more negative potentials. This shift increases the calcium influx, which increases the neurotransmitter release of the cone. In this paper, we will show that under certain conditions, in addition to this increase of neurotransmitter release, a calcium-dependent chloride current will be activated, which polarizes the cone membrane potential. The question is, whether the modulation of the calcium current or the polarization of the cone membrane potential is the major determinant for feedback-mediated responses in second-order neurons. Depolarizing light responses of biphasic horizontal cells are generated by feedback from monophasic horizontal cells to cones. It was found that niflumic acid blocks the feedback-induced depolarizing responses in cones, while the shift of the calcium current activation function and the depolarizing biphasic horizontal cell responses remain intact. This shows that horizontal cells can feed back to cones, without inducing major changes in the cone membrane potential. This makes the feedback synapse from horizontal cells to cones a unique synapse. Polarization of the presynaptic (horizontal) cell leads to calcium influx in the postsynaptic cell (cone), but due to the combined activity of the calcium current and the calcium-dependent chloride current, the membrane potential of the postsynaptic cell will be hardly modulated, whereas the output of the postsynaptic cell will be strongly modulated. Since no polarization of the postsynaptic cell is needed for these feedback-mediated responses, this mechanism of synaptic transmission can modulate the neurotransmitter release in single synaptic terminals without affecting the membrane potential of the entire cell.

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