SNARE Function Analyzed in Synaptobrevin/VAMP Knockout Mice

Schoch, Susanne; Deák, F.; Königstorfer, Andreas; Mozhayeva, Marina G.; Sara, Yıldırım; Südhof, Thomas C.; Kavalali, Ege T.

doi:10.1126/science.1064335

Cited by 609 publications

(660 citation statements)

References 42 publications

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“…S1b), were born at the expected Mendelian frequency. In contrast to the embryonically lethal synaptobrevin2 knockout mice 15 they showed no obvious behavioural or morphological defect. Western blot of brain homogenates demonstrated the expected 25-30 kDa shift in migration compared with endogenous Syb2 (Supplementary Fig.…”

Section: Synaptobrevin2 Is the Only V-snare Onmentioning

confidence: 64%

“…This fact might be explained by the essential requirement of neuronal synaptic transmission for survival. Synaptobrevin2 knockout mice die immediately after birth, because they cannot breathe as a result of the loss of synaptic transmission in the Medulla oblongata and the brain stem 15 . Likewise, patients with defects in the synaptobrevin2 gene would die long before immune symptoms associated with FHL would begin to emerge.…”

Section: Discussionmentioning

confidence: 99%

“…To rule out that the mRFP fused to the C-terminus interferes with the function of synaptobrevin2 we performed comprehensive morphological analysis and electrophysiological measurements from neurons and neuroendocrine cells, because in these cell types synaptobrevin2 is the major v-SNARE driving Ca 2 þ -dependent fusion of synaptic vesicles [15][16][17][18] . The obtained results (Supplementary Figs S2-S4) demonstrate that the addition of mRFP does neither alter the morphological and functional characteristics of central synapses in brain nor the hormone release from neuroendocrine cells.…”

Section: Synaptobrevin2 Is the Only V-snare Onmentioning

confidence: 99%

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Synaptobrevin2 is the v-SNARE required for cytotoxic T-lymphocyte lytic granule fusion

et al. 2013

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Cytotoxic T lymphocytes kill virus-infected and tumorigenic target cells through the release of perforin and granzymes via fusion of lytic granules at the contact site, the immunological synapse. It has been postulated that this fusion process is mediated by non-neuronal members of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex protein family. Here, using a synaptobrevin2-monomeric red fluorescence protein knock-in mouse we demonstrate that, surprisingly, the major neuronal v-SNARE synaptobrevin2 is expressed in cytotoxic T lymphocytes and exclusively localized on granzyme B-containing lytic granules. Cleavage of synaptobrevin2 by tetanus toxin or ablation of the synaptobrevin2 gene leads to a complete block of lytic granule exocytosis while leaving upstream events unaffected, identifying synaptobrevin2 as the v-SNARE responsible for the fusion of lytic granules at the immunological synapse.

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Section: Synaptobrevin2 Is the Only V-snare Onmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Section: Synaptobrevin2 Is the Only V-snare Onmentioning

confidence: 99%

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Synaptobrevin2 is the v-SNARE required for cytotoxic T-lymphocyte lytic granule fusion

et al. 2013

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“…In the present study, using double labelling light microscopy immunohistochemistry techniques, we examined the cortical distribution of the co-localization of VAMP or SNAP-25 or syntaxin with markers of glutamatergic or GABAergic synapses. To reveal the SNARE proteins, we used antibodies directed against isoforms considered to be of crucial importance in the CNS synapses, namely VAMP-2 [55,56], SNAP-25A and B [11,34] and syntaxin-1 [32,57]. The glutamatergic terminals were visualized by two different antibodies directed against the glutamate vesicular transporters, vGlutT-1 and vGlutT-2.…”

Section: Introductionmentioning

confidence: 99%

VAMP-2, SNAP-25A/B and syntaxin-1 in glutamatergic and GABAergic synapses of the rat cerebellar cortex

et al. 2011

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BackgroundThe aim of this study was to assess the distribution of key SNARE proteins in glutamatergic and GABAergic synapses of the adult rat cerebellar cortex using light microscopy immunohistochemical techniques. Analysis was made of co-localizations of vGluT-1 and vGluT-2, vesicular transporters of glutamate and markers of glutamatergic synapses, or GAD, the GABA synthetic enzyme and marker of GABAergic synapses, with VAMP-2, SNAP-25A/B and syntaxin-1.ResultsThe examined SNARE proteins were found to be diffusely expressed in glutamatergic synapses, whereas they were rarely observed in GABAergic synapses. However, among glutamatergic synapses, subpopulations which did not contain VAMP-2, SNAP-25A/B and syntaxin-1 were detected. They included virtually all the synapses established by terminals of climbing fibres (immunoreactive for vGluT-2) and some synapses established by terminals of parallel and mossy fibres (immunoreactive for vGluT-1, and for vGluT-1 and 2, respectively). The only GABA synapses expressing the SNARE proteins studied were the synapses established by axon terminals of basket neurons.ConclusionThe present study supplies a detailed morphological description of VAMP-2, SNAP-25A/B and syntaxin-1 in the different types of glutamatergic and GABAergic synapses of the rat cerebellar cortex. The examined SNARE proteins characterize most of glutamatergic synapses and only one type of GABAergic synapses. In the subpopulations of glutamatergic and GABAergic synapses lacking the SNARE protein isoforms examined, alternative mechanisms for regulating trafficking of synaptic vesicles may be hypothesized, possibly mediated by different isoforms or homologous proteins.

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“…Tetanus neurotoxin light chain (TeNT) blocks synaptic transmission through proteolytic cleavage of a synaptic vesicle protein [159][160][161][162]. As the light chain of tetanus neurotoxin blocks synaptic transmission, it is reversible; the heavy chain of tetanus neurotoxin is the element that causes sustained depolarization and cell injury.…”

Section: Inducible Tetanus Neurotoxinmentioning

confidence: 99%

Selective Manipulation of Neural Circuits

Park

Carmel

2016

Neurotherapeutics

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Unraveling the complex network of neural circuits that form the nervous system demands tools that can manipulate specific circuits. The recent evolution of genetic tools to target neural circuits allows an unprecedented precision in elucidating their function. Here we describe two general approaches for achieving circuit specificity. The first uses the genetic identity of a cell, such as a transcription factor unique to a circuit, to drive expression of a molecule that can manipulate cell function. The second uses the spatial connectivity of a circuit to achieve specificity: one genetic element is introduced at the origin of a circuit and the other at its termination. When the two genetic elements combine within a neuron, they can alter its function. These two general approaches can be combined to allow manipulation of neurons with a specific genetic identity by introducing a regulatory gene into the origin or termination of the circuit. We consider the advantages and disadvantages of both these general approaches with regard to specificity and efficacy of the manipulations. We also review the genetic techniques that allow gain-and loss-of-function within specific neural circuits. These approaches introduce light-sensitive channels (optogenetic) or drug sensitive channels (chemogenetic) into neurons that form specific circuits. We compare these tools with others developed for circuit-specific manipulation and describe the advantages of each. Finally, we discuss how these tools might be applied for identification of the neural circuits that mediate behavior and for repair of neural connections.

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SNARE Function Analyzed in Synaptobrevin/VAMP Knockout Mice

Cited by 609 publications

References 42 publications

Synaptobrevin2 is the v-SNARE required for cytotoxic T-lymphocyte lytic granule fusion

Synaptobrevin2 is the v-SNARE required for cytotoxic T-lymphocyte lytic granule fusion

VAMP-2, SNAP-25A/B and syntaxin-1 in glutamatergic and GABAergic synapses of the rat cerebellar cortex

Selective Manipulation of Neural Circuits

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