Size of Vesicle Pools, Rates of Mobilization, and Recycling at Neuromuscular Synapses of a Drosophila mutant, shibire

Delgado, Ricardo; Maureira, Carlos; Oliva, Carolina A.; Kidokoro, Yoshiaki; Labarca, Pedro

doi:10.1016/s0896-6273(00)00165-3

Cited by 187 publications

(202 citation statements)

References 28 publications

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“…Kuromi and Kidokoro (1998) demonstrated that fast cycling synaptic vesicles generally form a pool located near the bouton periphery at the Drosophila NMJ, while reserve pool vesicle are typically found at the center of the synaptic boutons. This fast cycling pool is presumably vastly overlapping with the readily releasable pool (Kuromi and Kidokoro, 2003), which has been electrophysiologically defined in this preparation (Delgado et al, 2000). For stn-vl hypomorphs, our ultrastructural data reconfirms the integrity of this vesicle pool, as vesicle density near the active zone is normal (Fig.…”

Section: Severe Stnb Hypomorphic Mutants Exhibit Only Minor Ultrastrusupporting

confidence: 72%

“…Strikingly, the ultrastructural analysis of stn-vl synapses showed that clustered and docked vesicle pools at the presynaptic active zone were completely unaffected in this hypomorphic condition, although there is a slight reduction in overall vesicle density. At the Drosophila NMJ, Kidokoro (1998, 2003) previously distinguished an "exo/endo cycling vesicle pool" (ECP) at the bouton periphery, which probably corresponds to the electrophysiologically defined readily releasable pool (RRP; Delgado et al, 2000), and a reserve pool (RP) at the bouton center. According to this study the ECP/RRP alone is sufficient to allow for full-scale basal synaptic transmission after pharmacological depletion of the RP, and a loss of RP vesicles mainly affects synaptic fatigue during HFS.…”

Section: Discussionmentioning

confidence: 99%

“…A simplistic model of synaptic depression (Zucker and Regehr, 2002) could be satisfied by a progressive depletion of fusion-ready synaptic vesicles during phases of increased activity. Using shibire mutants to study depression in the absence of compensating endocytosis, Delgado et al (2000) previously demonstrated that short trains (5-20Hz) that selectively deplete the RRP caused a depression profile whose shape is reminiscent of the de-staining kinetics of FM1-43 labeled RRP in presynaptic boutons. Hence, the initial phase of depression at NMJ synapses presumably reflects the depletion of the RRP.…”

Section: Discussionmentioning

confidence: 99%

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Stoned B mediates sorting of integral synaptic vesicle proteins

Mohrmann¹,

Matthies²,

Woodruff³

et al. 2008

Neuroscience

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A continuous supply of fusion-competent synaptic vesicles is essential for sustainable neurotransmission. Drosophila mutations of the dicistronic stoned locus disrupt normal vesicle cycling and cause functional deficits in synaptic transmission. Although both Stoned A and B proteins putatively participate in reconstituting synaptic vesicles, their precise function is still unclear. Here we investigate the effects of progressive depletion of Stoned B (STNB) on the release properties of neuromuscular synapses using a novel set of synthetic STNB hypomorphic alleles. Decreasing neuronal STNB expression to ≤35% of wildtype level causes a strong reduction in EJC amplitude at low stimulation frequencies and a marked slowing in synaptic depression during high-frequency stimulation, suggesting vesicle depletion is attenuated by decreased release probability. Recovery from synaptic depression after prolonged stimulation is also decelerated in mutants, indicating a delayed recovery of fusion-ready vesicles. These phenotypes appear not to be due to a diminished vesicle population, since the docked vesicle pool is ultrastructurally unaffected, and the total number of vesicles is only slightly reduced in these hypomorphs, unlike lethal stoned mutants. Therefore, we conclude that STNB not only functions as an essential component of the endocytic complex for vesicle reconstitution, as previously proposed, but also regulates the competence of recycled vesicles to undergo fusion. In support of such role of STNB, synaptic levels of the vesicular glutamate transporter (vGLUT) and synaptotagmin-1 are strongly reduced with diminishing STNB function, while other synaptic proteins are largely unaffected. We conclude that STNB organizes the endocytic sorting of a subset of integral synaptic vesicle proteins thereby regulating the fusion-competence of the recycled vesicle.

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Section: Severe Stnb Hypomorphic Mutants Exhibit Only Minor Ultrastrusupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Stoned B mediates sorting of integral synaptic vesicle proteins

Mohrmann¹,

Matthies²,

Woodruff³

et al. 2008

Neuroscience

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“…The role of dynamin 1 in synaptic vesicle endocytosis has been well documented in Drosophila. In the absence of dynamin 1, synapses lose their ability to successively transmit signals under stimulation due to incomplete endocytosis of the synaptic vesicles (Delgado et al 2000). Our results provide evidence suggesting that Aβ-induced dynamin 1 depletion caused similar deficiency in synaptic vesicle recycling in mammalian hippocampal neurons.…”

Section: Discussionmentioning

confidence: 58%

Beta-amyloid disrupted synaptic vesicle endocytosis in cultured hippocampal neurons

Kelly¹,

Ferreira²

2007

Neuroscience

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Neuronal death leading to gross brain atrophy is commonly seen in Alzheimer's disease (AD) patients. Yet, it is becoming increasingly apparent that the pathogenesis of AD involves early and more discrete synaptic changes in affected brain areas. However, the molecular mechanisms that underlie such synaptic dysfunction remain largely unknown. Recently, we have identified dynamin 1, a protein that plays a critical role in synaptic vesicle endocytosis, and hence, in the signaling properties of the synapse, as a potential molecular determinant of such dysfunction in AD. In the present study, we analyzed beta-amyloid (Aβ)-induced changes in synaptic vesicle recycling in cultured hippocampal neurons. Our results showed that Aβ, the main component of senile plaques, caused ultrastructural changes indicative of impaired synaptic vesicle endocytosis in cultured hippocampal neurons that have been stimulated by depolarization with high potassium. In addition, Aβ led to the accumulation of amphiphysin in membrane fractions from stimulated hippocampal neurons. Moreover, experiments using FM1-43 showed reduced dye uptake in stimulated hippocampal neurons treated with Aβ when compared to untreated stimulated controls. Similar results were obtained using a dynamin 1 inhibitory peptide suggesting that dynamin 1 depletion caused deficiency in synaptic vesicle recycling not only in Drosophila but also in mammalian neurons. Collectively, these results showed that Aβ caused a disruption of synaptic vesicle endocytosis in cultured hippocampal neurons. Furthermore, we provided evidence suggesting that Aβ-induced dynamin 1 depletion might play an important role in this process. Keywords synaptic dysfunction; amphiphysin; beta-amyloid; endocytosis; FM1-43 Alzheimer disease (AD) is a debilitating disorder that leads to significant cognitive deficits. Pathologically, AD is characterized by the presence of extracellular senile plaques, composed of the amyloid-beta protein (Aβ), and intraneuronal neurofibrillary tangles, composed of the tau protein (Glenner and Wong 1984;Grundke-Iqbal et al. 1986). In addition, significant atrophy due to the loss of neurons in the cholinergic and glutamatergic areas of the brain have been detected in this disease (Teipel et al. 2005;van de Pol et al. 2006). While neuronal death is important and could contribute to the decline in cognition, synapse loss is the best correlate with the severity of dementia in AD (Davies et al. 1987;Terry et al. 1991). However, this loss Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (Koenig and Ikeda 1989). Collectively, these...

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“…Synapses are highly specialized cellular components whose function is closely tied to their unique structure. Of particular interest is the relationship between the presynaptic organization of neurotransmitter-filled vesicles and their release in response to activity (Delgado et al, 2000;Schikorski and Stevens, 2001;Rizzoli and Betz, 2004). One of the best studied systems for examining this relationship is the mammalian neuromuscular junction, the synapse between motor neurons and skeletal muscle fibers.…”

Section: Introductionmentioning

confidence: 99%

Heterogeneity in Synaptic Vesicle Release at Neuromuscular Synapses of Mice Expressing SynaptopHluorin

Wyatt

Balice-Gordon²

2008

J. Neurosci.

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Mammalian neuromuscular junctions are useful model synapses to study the relationship between synaptic structure and function, although these have rarely been studied together at the same synapses. To do this, we generated transgenic lines of mice in which the thy1.2 promoter drives expression of synaptopHluorin (spH) as a means of optically measuring synaptic vesicle distribution and release. SpH is colocalized with other synaptic vesicle proteins in presynaptic terminals and does not alter normal synaptic function. Nerve stimulation leads to readily detectable and reproducible fluorescence changes in motor axon terminals that vary with stimulus frequency and, when compared with electrophysiological recordings, are reliable indicators of neurotransmitter release. Measurements of fluorescence intensity changes reveal a surprising amount of heterogeneity in synaptic vesicle release throughout individual presynaptic motor axon terminals. Some discrete terminal regions consistently displayed a greater rate and extent of release than others, regardless of stimulation frequency. The amount of release at a particular site is highly correlated to the relative abundance of synaptic vesicles there, indicating that a relatively constant fraction of the total vesicular pool, ϳ30%, is released in response to activity. These studies reveal previously unknown relationships between synaptic structure and function at mammalian neuromuscular junctions and demonstrate the usefulness of spH expressing mice as a tool for studying neuromuscular synapses in adults, as well as during development and diseases that affect neuromuscular synaptic function.

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Size of Vesicle Pools, Rates of Mobilization, and Recycling at Neuromuscular Synapses of a Drosophila mutant, shibire

Cited by 187 publications

References 28 publications

Stoned B mediates sorting of integral synaptic vesicle proteins

Stoned B mediates sorting of integral synaptic vesicle proteins

Beta-amyloid disrupted synaptic vesicle endocytosis in cultured hippocampal neurons

Heterogeneity in Synaptic Vesicle Release at Neuromuscular Synapses of Mice Expressing SynaptopHluorin

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