Vesicular Glutamate Transporter Expression Level Affects Synaptic Vesicle Release Probability at Hippocampal Synapses in Culture

Herman, Melissa A.; Ackermann, Frauke; Trimbuch, Thorsten; Rosenmund, Christian

doi:10.1523/jneurosci.1444-14.2014

Cited by 77 publications

(87 citation statements)

References 49 publications

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“…SynGCamp6f was generated analogous to synGCamp2 (34) by fusing GCamp6f (35) to the C terminus of the synaptic vesicle protein synaptophysin. Imaging was done as previously described (34).…”

Section: Discussionmentioning

confidence: 99%

RIM-binding protein 2 regulates release probability by fine-tuning calcium channel localization at murine hippocampal synapses

Grauel

Maglione

Reddy-Alla

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

101

178

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The tight spatial coupling of synaptic vesicles and voltage-gated Ca 2+ channels (Ca V s) ensures efficient action potential-triggered neurotransmitter release from presynaptic active zones (AZs). Rab-interacting molecule-binding proteins (RIM-BPs) interact with Ca 2+ channels and via RIM with other components of the release machinery. Although human RIM-BPs have been implicated in autism spectrum disorders, little is known about the role of mammalian RIM-BPs in synaptic transmission. We investigated RIM-BP2-deficient murine hippocampal neurons in cultures and slices. Short-term facilitation is significantly enhanced in both model systems. Detailed analysis in culture revealed a reduction in initial release probability, which presumably underlies the increased shortterm facilitation. Superresolution microscopy revealed an impairment in Ca V 2.1 clustering at AZs, which likely alters Ca 2+ nanodomains at release sites and thereby affects release probability. Additional deletion of RIM-BP1 does not exacerbate the phenotype, indicating that RIM-BP2 is the dominating RIM-BP isoform at these synapses.RIM-BP2 | calcium channel coupling | release probability | short-term plasticity | active zone structure A t the presynapse, coupling between action potentials (APs) and synaptic vesicle fusion is exquisitely precise, ensuring high temporal fidelity of neuron-to-neuron signaling in the nervous system. Two properties are thought to be responsible for this remarkable precision: a highly efficient release apparatus that transduces Ca 2+ signals into vesicle fusion and a tightly organized active zone (AZ), where the release apparatus and voltage-gated Ca 2+ channels (Ca V s) are spatially coupled. Rab-interacting molecules (RIM) are thought to contribute to both properties, because loss of RIM impairs vesicle priming (1) and Ca V localization at the AZ (2). RIM-binding proteins (RIM-BPs) directly interact with RIM (3), the pore-forming subunits of Ca V 1 and Ca V 2 channels (2, 4, 5), and Bassoon (5), and have therefore been suggested to play a role in presynaptic Ca V localization. The Drosophila homolog of RIM-binding proteins (DRBP) is indeed crucial for neurotransmitter release at the AZ of neuromuscular junctions (NMJs) because loss of DRBP reduces Ca V abundance and impairs the integrity of the AZ scaffold (6). DRBP-deficient flies show severe impairment of neurotransmitter release along with increased short-term facilitation (6, 7).Recently, Acuna et al. (8) published a report on the combined loss of RIM-BP1 and RIM-BP2 in mouse synapses. The authors report that although RIM-BPs are not essential for synaptic transmission, AP-triggered neurotransmitter release is more variable and the sensitivity to the Ca 2+ chelator EGTA is increased at the Calyx of Held, suggesting a larger coupling distance of Ca V and the release machinery.In the present study, we further investigated the consequences of constitutive deletion of RIM-BP2 on the structure and function of mouse hippocampal synapses. We show that loss of RIM-BP2 lead...

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“…SynGCamp6f was generated analogous to synGCamp2 (34) by fusing GCamp6f (35) to the C terminus of the synaptic vesicle protein synaptophysin. Imaging was done as previously described (34).…”

Section: Discussionmentioning

confidence: 99%

RIM-binding protein 2 regulates release probability by fine-tuning calcium channel localization at murine hippocampal synapses

Grauel

Maglione

Reddy-Alla

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

101

178

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“…One possible explanation is the presence of SGs with either no catecholamines or almost none, which is not detected by amperometry (42). In addition, the prefilled state of SGs has been recently proposed as a factor that modified the probability of exocytosis either in glutamate- (43) or GABA-neurons (44). It might be also argued that reduced activation of presynaptic purinergic receptors might occur because of the removal of feedback, although the intracellular calcium measurements suggest that purinergic regulation does not contribute to the reduction in spike frequency.…”

Section: Discussionmentioning

confidence: 99%

ATP: The crucial component of secretory vesicles

Estévez-Herrera

Domínguez

Pardo

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The colligative properties of ATP and catecholamines demonstrated in vitro are thought to be responsible for the extraordinary accumulation of solutes inside chromaffin cell secretory vesicles, although this has yet to be demonstrated in living cells. Because functional cells cannot be deprived of ATP, we have knocked down the expression of the vesicular nucleotide carrier, the VNUT, to show that a reduction in vesicular ATP is accompanied by a drastic fall in the quantal release of catecholamines. This phenomenon is particularly evident in newly synthesized vesicles, which we show are the first to be released. Surprisingly, we find that inhibiting VNUT expression also reduces the frequency of exocytosis, whereas the overexpression of VNUT drastically increases the quantal size of exocytotic events. To our knowledge, our data provide the first demonstration that ATP, in addition to serving as an energy source and purinergic transmitter, is an essential element in the concentration of catecholamines in secretory vesicles. In this way, cells can use ATP to accumulate neurotransmitters and other secreted substances at high concentrations, supporting quantal transmission.exocytosis | purines | quantum size | secretory vesicles | VNUT V irtually most, and possibly all, types of secretory vesicles found in cells contain ATP, which often accumulates at high concentrations and, commonly, in conjunction with different types of neurotransmitters. However, the reason for this widespread distribution of ATP remains a mystery. Although ATP is present in all animal species, including primitive life forms like Giardia lamblia that lack Golgi complexes and mitochondria, the detection of ATP in the secretory vesicles of sympathetic neurons was considered to be the first example of cotransmission (1). However, given the ubiquitous accumulation of ATP in secretory vesicles, it might instead be considered that it is the other neurotransmitters that coincide with ATP, rather than the other way around (2). Indeed, perhaps ATP should be considered as the first molecule used as a transmitter in primitive forms of life.Astonishingly high concentrations of releasable species are stored inside secretory vesicles, far exceeding those in the cytosol (3, 4). For example, the catecholamine content of adrenal secretory granules (SGs), a type of large dense core secretory vesicles also known as chromaffin granules, was 0.8-1 M when measured directly in adrenal chromaffin cells using patch amperometry (5, 6). In addition, SGs from chromaffin cells contain ATP at ∼150 mM (7), calcium ∼40 mM (8), about 2 mM of granins, ascorbate, peptides, and other nucleotides, all in an acidic pH ∼5.5 environment.ATP possesses intrinsic chemical characteristics that make it relevant to the accumulation of soluble substances in secretory vesicles. The formation of weak complexes between monoamines and ATP, the two main soluble compounds in chromaffin granules, has been demonstrated in vitro by NMR (9), ultracentrifugation (10), infrared spectroscopy, and calorime...

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“…These observations suggest their involvement in different synaptic functions. VGLUT1 has been suggested to have a role in modulating transmitter release probability and synaptic plasticity, as well as in the reserved pool of vesicles [57, 60, 86,87,99,100]. Colocalization of VGLUT 3 and vesicular acetylcholine and monoamine transporters has been implicated in motor control, reward behavior, and neuropsychiatric disease [84].…”

Section: Mechanism Of Bimodal Modulation By CL 2 Of Vesicular Glutamamentioning

confidence: 99%

“…Analysis of the frequency dependence of the presynaptic parameters n (number of quanta capable of responding to a nerve impulse) and P (average probability of responding) has revealed the physiological basis underlying facilitation. Recent evidence suggests that the amount of glutamate per vesicle could alter P [211]. Since both n and P increase as a function of frequency, facilitation has been described in terms of the rates of quantal mobilization and demobilization [212,213].…”

Section: Short Term Synaptic Plasticitymentioning

confidence: 99%

Glutamate Release

Hackett

Ueda

2015

Neurochem Res

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Our aim was to review the processes of glutamate release from both biochemical and neurophysiological points of view. A large body of evidence now indicates that glutamate is specifically accumulated into synaptic vesicles, which provides strong support for the concept that glutamate is released from synaptic vesicles and is the major excitatory neurotransmitter. Evidence suggests the notion that synaptic vesicles, in order to sustain the neurotransmitter pool of glutamate, are endowed with an efficient mechanism for vesicular filling of glutamate. Glutamate-loaded vesicles undergo removal of Synapsin I by CaM kinase II-mediated phosphorylation, transforming to the release-ready pool. Vesicle docking to and fusion with the presynaptic plasma membrane are thought to be mediated by the SNARE complex. The Ca(2+)-dependent step in exocytosis is proposed to be mediated by synaptotagmin.

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Vesicular Glutamate Transporter Expression Level Affects Synaptic Vesicle Release Probability at Hippocampal Synapses in Culture

Cited by 77 publications

References 49 publications

RIM-binding protein 2 regulates release probability by fine-tuning calcium channel localization at murine hippocampal synapses

RIM-binding protein 2 regulates release probability by fine-tuning calcium channel localization at murine hippocampal synapses

ATP: The crucial component of secretory vesicles

Glutamate Release

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