Vti1a Identifies a Vesicle Pool that Preferentially Recycles at Rest and Maintains Spontaneous Neurotransmission

Ramirez, Denise M.O.; Khvotchev, Mikhail; Trauterman, Brent; Kavalali, Ege T.

doi:10.1016/j.neuron.2011.10.034

Cited by 150 publications

(240 citation statements)

References 67 publications

(108 reference statements)

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“…54 Vit1a is known to interact with the lysosomal R-SNARE VAMP7 and regulate spontaneous neurotransmission as well as stimulated secretion. 55,56 Lysosomal exocytosis facilitates ATP secretion by astrocytes and mechanical injury triggers ATP release from astrocytes. 20,57 ATP released by astrocytes activates AKT and ERK signaling, resulting in gliosis following traumatic brain injury.…”

Section: Discussionmentioning

confidence: 99%

Injured astrocytes are repaired by Synaptotagmin XI-regulated lysosome exocytosis

et al. 2015

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Astrocytes are known to facilitate repair following brain injury; however, little is known about how injured astrocytes repair themselves. Repair of cell membrane injury requires Ca 2+ -triggered vesicle exocytosis. In astrocytes, lysosomes are the main Ca 2+ -regulated exocytic vesicles. Here we show that astrocyte cell membrane injury results in a large and rapid calcium increase. This triggers robust lysosome exocytosis where the fusing lysosomes release all luminal contents and merge fully with the plasma membrane. In contrast to this, receptor stimulation produces a small sustained calcium increase, which is associated with partial release of the lysosomal luminal content, and the lysosome membrane does not merge into the plasma membrane. In most cells, lysosomes express the synaptotagmin (Syt) isoform Syt VII; however, this isoform is not present on astrocyte lysosomes and exogenous expression of Syt VII on lysosome inhibits their exocytosis. Deletion of one of the most abundant Syt isoform in astrocyte -Syt XI -suppresses astrocyte lysosome exocytosis. This identifies lysosome as Syt XI-regulated exocytic vesicle in astrocytes. Further, inhibition of lysosome exocytosis (by Syt XI depletion or Syt VII expression) prevents repair of injured astrocytes. These results identify the lysosomes and Syt XI as the sub-cellular and molecular regulators, respectively of astrocyte cell membrane repair.

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Section: Discussionmentioning

confidence: 99%

Injured astrocytes are repaired by Synaptotagmin XI-regulated lysosome exocytosis

et al. 2015

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“…It is conceivable that spontaneous fusion at this low rate can still be maintained with the reduced RRP that we saw in the syb1 knockdown. Alternatively, spontaneously fusing vesicles may originate from a different pool than the RRP (Ramirez et al 2012;Sara et al 2005). In the scenario in which syb2 is absent, syb1 drives fusion of the RRP whereas an additional v-SNARE may exclusively drive spontaneous fusion.…”

Section: Discussionmentioning

confidence: 99%

“…In the scenario in which syb2 is absent, syb1 drives fusion of the RRP whereas an additional v-SNARE may exclusively drive spontaneous fusion. A possible candidate could be the noncanonical SNARE Vps10p-tail-interactor-1a (vti1a), which has been shown to promote spontaneous release in the absence of syb2 (Ramirez et al 2012). Similarly, in Drosophila Ca 2ϩ -evoked release is thought to be driven by the v-SNARE n-syb, whereas spontaneous release persists even in the absence of n-syb (Deitcher et al 1998;Yoshihara et al 1999).…”

Section: Discussionmentioning

confidence: 99%

Synaptobrevin 1 mediates vesicle priming and evoked release in a subpopulation of hippocampal neurons

Zimmermann

Trimbuch

Rosenmund

2014

Journal of Neurophysiology

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Zimmermann J, Trimbuch T, Rosenmund C. Synaptobrevin 1 mediates vesicle priming and evoked release in a subpopulation of hippocampal neurons. J Neurophysiol 112: 1559 -1565, 2014. First published June 18, 2014 doi:10.1152/jn.00340.2014.-The core machinery of synaptic vesicle fusion consists of three soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) proteins, the two t-SNAREs at the plasma membrane (SNAP-25, Syntaxin 1) and the vesicle-bound v-SNARE synaptobrevin 2 (VAMP2). Formation of the trans-oriented four-␣-helix bundle between these SNAREs brings vesicle and plasma membrane in close proximity and prepares the vesicle for fusion. The t-SNAREs are thought to be necessary for vesicle fusion. Whether the v-SNAREs are required for fusion is still unclear, as substantial vesicle priming and spontaneous release activity remain in mammalian mass-cultured synaptobrevin/cellubrevindeficient neurons. Using the autaptic culture system from synaptobrevin 2 knockout neurons of mouse hippocampus, we found that the majority of cells were devoid of any evoked or spontaneous release and had no measurable readily releasable pool. A small subpopulation of neurons, however, displayed release, and their release activity correlated with the presence and amount of v-SNARE synaptobrevin 1 expressed. Comparison of synaptobrevin 1 and 2 in rescue experiments demonstrates that synaptobrevin 1 can substitute for the other v-SNARE, but with a lower efficiency in neurotransmitter release probability. Release activity in synaptobrevin 2-deficient mass-cultured neurons was massively reduced by a knockdown of synaptobrevin 1, demonstrating that synaptobrevin 1 is responsible for the remaining release activity. These data support the hypothesis that both t-and v-SNAREs are absolutely required for vesicle priming and evoked release and that differential expression of SNARE paralogs can contribute to differential synaptic coding in the brain. SNARE; neurotransmitter release; spontaneous release; release probability; short-term plasticity RELEASE OF NEUROTRANSMITTERS in the mammalian brain is mediated by fusion of synaptic vesicles (SVs) with the neuronal plasma membrane. This process has to be both fast and reliable and is performed by evolutionarily conserved protein machinery (Rizo and Rosenmund 2008;Sudhof 2013). Three proteins from the soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) family are considered to bring the two membranes in close proximity and carry out membrane fusion (Sollner et al. 1993;Weber et al. 1998). A v-SNARE (anchored in the SV membrane) and the t-SNAREs syntaxin (Bennett et al. 1992) and synaptosomal-associated protein 25 (SNAP-25) (Oyler et al. 1989) (both anchored in the plasma membrane) zipper up from their NH 2 to COOH terminus and thus form a four-␣-helix bundle called the trans-SNARE complex (Poirier et al. 1998;Sorensen et al. 2006;Sutton et al. 1998). Whether fusion of SVs is possible without SNARE proteins is still an open question. The major v-SNARE paralog on SVs i...

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“…To relate ex.E 2 GFP-positive puncta to active synapses, we co-infected hippocampal neurons with lentiviruses expressing ex.E 2 GFP and synaptobrevinpHluorin-mOrange2 (Syb2O), a marker of synaptic vesicle (SV) exo-endocytosis at active synaptic sites that has an emission spectrum that does not overlap with that of ex.E 2 GFP (Ramirez et al, 2012). Upon electrical stimulation with 1200 APs at 10 Hz, ex.E 2 GFP fluorescence and Syb2O fluorescence overlapped by approximately 60%, confirming the localization of the probe to active synapses (Fig.…”

Section: Hyperactivity-induced Ph Shifts Occur At Synaptic Sitesmentioning

confidence: 99%

“…For multi-electrode array experiments, neurons were infected at 10 DIV, and recordings performed at 17-18 DIV. For pHluorin experiments, neurons were co-infected with synaptobrevin-pHluorin-m-Orange2 (Syb2O) (Ramirez et al, 2012) and ex.E 2 GFP lentiviruses at 13 DIV, and optical recordings were performed at 17-18 DIV. Subcellular fractionation of transduced 17 DIV neurons was performed as previously described (Huttner et al, 1983).…”

Section: Viral Transduction Proceduresmentioning

confidence: 99%

Neuronal hyperactivity causes Na+/H+ exchanger-induced extracellular acidification at active synapses

Chiacchiaretta

Latifi

Bramini

et al. 2017

Journal of Cell Science

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Extracellular pH impacts on neuronal activity, which is in turn an important determinant of extracellular H + concentration. The aim of this study was to describe the spatio-temporal dynamics of extracellular pH at synaptic sites during neuronal hyperexcitability. To address this issue we created ex.E 2 GFP, a membrane-targeted extracellular ratiometric pH indicator that is exquisitely sensitive to acidic shifts. By monitoring ex.E 2 GFP fluorescence in real time in primary cortical neurons, we were able to quantify pH fluctuations during network hyperexcitability induced by convulsant drugs or highfrequency electrical stimulation. Sustained hyperactivity caused a pH decrease that was reversible upon silencing of neuronal activity and located at active synapses. This acidic shift was not attributable to the outflow of synaptic vesicle H + into the cleft nor to the activity of membrane-exposed H + V-ATPase, but rather to the activity of the Na + /H + -exchanger. Our data demonstrate that extracellular synaptic pH shifts take place during epileptic-like activity of neural cultures, emphasizing the strict links existing between synaptic activity and synaptic pH. This evidence may contribute to the understanding of the physio-pathological mechanisms associated with hyperexcitability in the epileptic brain.

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Vti1a Identifies a Vesicle Pool that Preferentially Recycles at Rest and Maintains Spontaneous Neurotransmission

Cited by 150 publications

References 67 publications

Injured astrocytes are repaired by Synaptotagmin XI-regulated lysosome exocytosis

Injured astrocytes are repaired by Synaptotagmin XI-regulated lysosome exocytosis

Synaptobrevin 1 mediates vesicle priming and evoked release in a subpopulation of hippocampal neurons

Neuronal hyperactivity causes Na+/H+ exchanger-induced extracellular acidification at active synapses

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