Faculty Opinions recommendation of A discrete presynaptic vesicle cycle for neuromodulator receptors.

2021 ◽  
Author(s):  
Emmanuel Darcq
Keyword(s):  
Presynaptic Vesicle ◽  
Vesicle Cycle

scholarly journals A Discrete Presynaptic Vesicle Cycle for Neuromodulator Receptors

Neuron ◽  
2020 ◽  
Vol 105 (4) ◽  
pp. 663-677.e8 ◽  
Author(s):  
Damien Jullié ◽  
Miriam Stoeber ◽  
Jean-Baptiste Sibarita ◽  
Hanna L. Zieger ◽  
Thomas M. Bartol ◽  
...  
Keyword(s):  
Presynaptic Vesicle ◽  
Vesicle Cycle

Mutation and Activation of Gαs Similarly Alters Pre- and Postsynaptic Mechanisms Modulating Neurotransmission

2003 ◽  
Vol 89 (5) ◽  
pp. 2620-2638 ◽  
Author(s):  
Robert B. Renden ◽  
Kendal Broadie
Keyword(s):  
Synaptic Vesicle ◽  
Fusion Rate ◽  
Vesicle Fusion ◽  
Synaptic Function ◽  
Loss Of Function ◽  
Receptor Field ◽  
Important Conclusion ◽  
Presynaptic Vesicle ◽  
Vesicle Cycle ◽  
Constitutively Active

Constitutive activation of Gαs in the Drosophilabrain abolishes associative learning, a behavioral disruption far worse than that observed in any single cAMP metabolic mutant, suggesting that Gαs is essential for synaptic plasticity. The intent of this study was to examine the role of Gαs in regulating synaptic function by targeting constitutively active Gαs to either pre- or postsynaptic cells and by examining loss-of-function Gαs mutants ( dgs) at the glutamatergic neuromuscular junction (NMJ) model synapse. Surprisingly, both loss of Gαs and activation of Gαs in either pre- or postsynaptic compartment similarly increased basal neurotransmission, decreased short-term plasticity (facilitation and augmentation), and abolished posttetanic potentiation. Elevated synaptic function was specific to an evoked neurotransmission pathway because both spontaneous synaptic vesicle fusion frequency and amplitude were unaltered in all mutants. In the postsynaptic cell, the glutamate receptor field was regulated by Gαs activity; based on immunocytochemical studies, GluRIIA receptor subunits were dramatically downregulated (>75% decrease) in both loss and constitutive active Gαs genotypes. In the presynaptic cell, the synaptic vesicle cycle was regulated by Gαs activity; based on FM1-43 dye imaging studies, evoked vesicle fusion rate was increased in both loss and constitutively active Gαs genotypes. An important conclusion of this study is that both increased and decreased Gαs activity very similarly alters pre- and postsynaptic mechanisms. A second important conclusion is that Gαs activity induces transynaptic signaling; targeted Gαs activation in the presynapse downregulates postsynaptic GluRIIA receptors, whereas targeted Gαs activation in the postsynapse enhances presynaptic vesicle cycling.

Transmitter Metabolism as a Mechanism of Synaptic Plasticity: A Modeling Study

2004 ◽  
Vol 91 (1) ◽  
pp. 25-39 ◽  
Author(s):  
Nikolai Axmacher ◽  
Martin Stemmler ◽  
Dominique Engel ◽  
Andreas Draguhn ◽  
Raphael Ritz
Keyword(s):  
Nervous System ◽  
Synaptic Plasticity ◽  
Transmitter Release ◽  
A Priori ◽  
Presynaptic Terminal ◽  
Synaptic Efficacy ◽  
Specific Mechanism ◽  
Presynaptic Function ◽  
Presynaptic Vesicle ◽  
Vesicle Cycle

The nervous system adapts to experience by changes in synaptic strength. The mechanisms of synaptic plasticity include changes in the probability of transmitter release and in postsynaptic responsiveness. Experimental and neuropharmacological evidence points toward a third variable in synaptic efficacy: changes in presynaptic transmitter concentration. Several groups, including our own, have reported changes in the amplitude and frequency of postsynaptic (miniature) events indicating that alterations in transmitter content cause alterations in vesicular transmitter content and vesicle dynamics. It is, however, not a priori clear how transmitter metabolism will affect vesicular transmitter content and how this in turn will affect pre- and postsynaptic functions. We therefore have constructed a model of the presynaptic terminal incorporating vesicular transmitter loading and the presynaptic vesicle cycle. We hypothesize that the experimentally observed synaptic plasticity after changes in transmitter metabolism puts predictable restrictions on vesicle loading, cytoplasmic–vesicular transmitter concentration gradient, and on vesicular cycling or release. The results of our model depend on the specific mechanism linking presynaptic transmitter concentration to vesicular dynamics, that is, alteration of vesicle maturation or alteration of release. It also makes a difference whether differentially filled vesicles are detected and differentially processed within the terminal or whether vesicle filling acts back onto the terminal by presynaptic autoreceptors. Therefore, the model allows one to decide, at a given synapse, how transmitter metabolism is linked to presynaptic function and efficacy.

Zn7Metallothionein-3 and the Synaptic Vesicle Cycle:  Interaction of Metallothionein-3 with the Small GTPase Rab3A†

Biochemistry ◽  
2005 ◽  
Vol 44 (9) ◽  
pp. 3159-3165 ◽  
Author(s):  
Markus Knipp ◽  
Gabriele Meloni ◽  
Bernd Roschitzki ◽  
Milan Vašák
Keyword(s):  
Synaptic Vesicle ◽  
Small Gtpase ◽  
Vesicle Cycle ◽  
Synaptic Vesicle Cycle

scholarly journals Human autoantibodies to amphiphysin induce defective presynaptic vesicle dynamics and composition

Brain ◽  
2015 ◽  
Vol 139 (2) ◽  
pp. 365-379 ◽  
Author(s):  
Christian Werner ◽  
Martin Pauli ◽  
Sören Doose ◽  
Andreas Weishaupt ◽  
Holger Haselmann ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Ex Vivo ◽  
Super Resolution ◽  
Synaptic Activity ◽  
Stiff Person Syndrome ◽  
Specific Patient ◽  
Presynaptic Boutons ◽  
Presynaptic Vesicle

Abstract See Irani (doi:10.1093/awv364) for a scientific commentary on this article.  Stiff-person syndrome is the prototype of a central nervous system disorder with autoantibodies targeting presynaptic antigens. Patients with paraneoplastic stiff-person syndrome may harbour autoantibodies to the BAR (Bin/Amphiphysin/Rvs) domain protein amphiphysin, which target its SH3 domain. These patients have neurophysiological signs of compromised central inhibition and respond to symptomatic treatment with medication enhancing GABAergic transmission. High frequency neurotransmission as observed in tonic GABAergic interneurons relies on fast exocytosis of neurotransmitters based on compensatory endocytosis. As amphiphysin is involved in clathrin-mediated endocytosis, patient autoantibodies are supposed to interfere with this function, leading to disinhibition by reduction of GABAergic neurotransmission. We here investigated the effects of human anti-amphiphysin autoantibodies on structural components of presynaptic boutons ex vivo and in vitro using electron microscopy and super-resolution direct stochastic optical reconstruction microscopy. Ultrastructural analysis of spinal cord presynaptic boutons was performed after in vivo intrathecal passive transfer of affinity-purified human anti-amphiphysin autoantibodies in rats and revealed signs of markedly disabled clathrin-mediated endocytosis. This was unmasked at high synaptic activity and characterized by a reduction of the presynaptic vesicle pool, clathrin coated intermediates, and endosome-like structures. Super-resolution microscopy of inhibitory GABAergic presynaptic boutons in primary neurons revealed that specific human anti-amphiphysin immunoglobulin G induced an increase of the essential vesicular protein synaptobrevin 2 and a reduction of synaptobrevin 7. This constellation suggests depletion of resting pool vesicles and trapping of releasable pool vesicular proteins at the plasma membrane. Similar effects were found in amphiphysin-deficient neurons from knockout mice. Application of specific patient antibodies did not show additional effects. Blocking alternative pathways of clathrin-independent endocytosis with brefeldin A reversed the autoantibody induced effects on molecular vesicle composition. Endophilin as an interaction partner of amphiphysin showed reduced clustering within presynaptic terminals. Collectively, these results point towards an autoantibody-induced structural disorganization in GABAergic synapses with profound changes in presynaptic vesicle pools, activation of alternative endocytic pathways, and potentially compensatory rearrangement of proteins involved in clathrin-mediated endocytosis. Our findings provide novel insights into synaptic pathomechanisms in a prototypic antibody-mediated central nervous system disease, which may serve as a proof-of-principle example in this evolving group of autoimmune disorders associated with autoantibodies to synaptic antigens.

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