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At least 1,099 records · Page 61Linked to original sources
PubMed2006

Synaptic vesicles: turning reluctance into action.

Vesicle availability partly determines the efficacy of synaptic communication in the CNS. The authors recently found that some hippocampal glutamate vesicles exhibit reluctance to exocytose during short, high-frequency action potential trains. These same vesicles can be "coaxed" into exocytosis by increased Ca(2+)entry, by direct depolarization of synaptic terminals, or by challenge with hypertonic sucrose, a tool used to cause fusion of the population of release-ready synaptic vesicles. Interestingly, the authors did not find evidence of reluctance at hippocampal GABA synapses, suggesting that vesicle reluctance might be a negative feedback mechanism to prevent runaway excitation. It is also possible that synapses exhibit reluctance to retain a dormant population of readily accessible vesicles, ready to respond to triggers such as enhanced Ca(2+) influx or neuromodulators. Recent work from the calyx of Held synapse suggests that reluctance might arise from inactivation of Ca(2+) channels. The authors review this work, along with several other potential mechanisms of reluctance.

Action Potentials↗
PubMed1996

Functional reconstitution of KCl-evoked, Ca(2+)-dependent acetylcholine release system in Xenopus oocytes microinjected with presynaptic plasma membranes and synaptic vesicles.

We have developed a new method for the generation of functionally active presynaptic chimeras in Xenopus laevis oocytes. Frog oocytes injected with presynaptic subcellular fractions extracted from the electric organ of Torpedo marmorata release acetylcholine in a calcium-dependent manner upon chemical stimulation. Neither oocytes injected without presynaptic plasma membranes nor oocytes injected with ghost erythrocyte plasma membrane instead of presynaptic plasma membrane release acetylcholine. This suggests that specific presynaptic components necessary for KCl-evoked, Ca(2+)-dependent acetylcholine release become functionally integrated in the Xenopus laevis oocytes. Moreover, rhodaminated presynaptic plasma membranes and the synaptic vesicle protein synaptophysin are detected on the oocyte surface by fluorescence or immunofluorescence, respectively, showing that the injected presynaptic components are incorporated into the membrane of the frog oocyte. Furthermore, Botulinum neurotoxin type A, a specific blocker of acetylcholine release in the neuromuscular junction, inhibits the neurotransmitter release from the chimerical oocytes. This suggests that targets for toxin action are also functionally incorporated in the oocyte upon injection of membranous presynaptic components. Our results show that oocytes injected with presynaptic components behave as cholinergic nerve ending chimeras, at least in terms of neurotransmitter release and toxin targets. The system bypasses some problems associated with messenger RNA expression because not only proteins, but native presynaptic components are incorporated. This new technique may provide a useful approach for electrophysiological and pharmacological studies in order to characterize the synaptic transmission.

Acetylcholine↗
PubMed1999

Phenotypic interaction between temperature-sensitive paralytic mutants comatose and paralytic suggests a role for N-ethylmaleimide-sensitive fusion factor in synaptic vesicle cycling in Drosophila.

The temperature-induced paralysis of comatose (comt) mutants of Drosophila is suggestive of a function for N-ethylmaleimide-sensitive fusion factor (NSF) in the CNS. Mutations in the para gene encoding the subunit of the voltage-gated sodium channel also result in a similar phenotype. We show that paralysis in comt flies is activity-dependent, and in the doubly mutant comt para flies comt-like paralysis does not set in until the effects of para are reversed by shifting to permissive temperatures. During recording from the thoracic flight muscles, we observed that comt flies showed a burst of spontaneous activity at restrictive temperature. This has been reported earlier as a unique characteristic of comt paralysis. The comt para double mutant showed this burst of activity not at restrictive but only on shifting back to permissive temperature. The unusual behavior and electrophysiology of the doubly mutant flies reported here indicates a role for NSF in synaptic vesicle cycling.

Animals↗
PubMed1997

Ultrastructural localization of zinc transporter-3 (ZnT-3) to synaptic vesicle membranes within mossy fiber boutons in the hippocampus of mouse and monkey.

Zinc transporter-3 (ZnT-3), a member of a growing family of mammalian zinc transporters, is expressed in regions of the brain that are rich in histochemically reactive zinc (as revealed by the Timm's stain), including entorhinal cortex, amygdala, and hippocampus. ZnT-3 protein is most abundant in the zinc-enriched mossy fibers that project from the dentate granule cells to hilar and CA3 pyramidal neurons. We show here by electron microscopy that ZnT-3 decorates the membranes of all clear, small, round synaptic vesicles (SVs) in the mossy fiber boutons of both mouse and monkey. Furthermore, up to 60-80% of these SVs contain Timm's-stainable zinc. The coincidence of ZnT-3 on the membranes of SVs that accumulate zinc, and its homology with known zinc transporters, suggest that ZnT-3 is responsible for the transport of zinc into SVs, and hence for the ability of these neurons to release zinc upon excitation.

Animals↗
PubMed1996

A role of amphiphysin in synaptic vesicle endocytosis suggested by its binding to dynamin in nerve terminals.

Amphiphysin, a major autoantigen in paraneoplastic Stiff-Man syndrome, is an SH3 domain-containing neuronal protein, concentrated in nerve terminals. Here, we demonstrate a specific, SH3 domain-mediated, interaction between amphiphysin and dynamin by gel overlay and affinity chromatography. In addition, we show that the two proteins are colocalized in nerve terminals and are coprecipitated from brain extracts consistent with their interactions in situ. We also report that a region of amphiphysin distinct from its SH3 domain mediates its binding to the alpha c subunit of AP2 adaptin, which is also concentrated in nerve terminals. These findings support a role of amphiphysin in synaptic vesicle endocytosis.

Adaptor Protein Complex 2↗
PubMed1994

Light and electron microscopic analysis of synaptic development in Macaca monkey retina as detected by immunocytochemical labeling for the synaptic vesicle protein, SV2.

The development of synapses has been followed in Macaca monkey fetal and infant retina using immunocytochemical labeling for the transmembrane synaptic vesicle glycoprotein, SV2. Electron microscopy (EM) was used to verify the presence of morphological synapses at selected ages. EM immunocytochemical labeling in adult retina showed that all synaptic types contained SV2 in inner (IPL) and outer (OPL) plexiform layers. In fetal retina, SV2 expression and the appearance of morphological synapses were closely related in time, demonstrating that SV2 is a reliable marker for synaptogenesis. SV2 expression appears along a foveal to peripheral gradient. Both SV2 and synapses appear in the foveal IPL at Fd50-55, and reach the retinal edge by Fd90-103. Cone ribbon synapses and SV2 labeling are not present in the foveal OPL until Fd60. Photoreceptors in the far periphery contain SV2 by Fd119-125. This pattern demonstrates an "inner to outer" direction of synaptogenesis. Cones show SV2 labeling before rods at the same retinal eccentricity. In the cone-dominated fovea, SV2 labeling and bipolar cell ribbon-containing terminals are present at Fd55 when amacrine cell conventional terminals are very scarce, indicating that bipolar synapses precede amacrine synapses in monkey foveal IPL. SV2 labeling and bipolar terminals appear first in the outer IPL which contains "OFF" ganglion and bipolar processes in the adult, suggesting that "OFF" midget bipolar cells may form the first synapses. Both SV2 immunocytochemical labeling and EM morphology find that monkey retina follows a generalized inner before outer, and cone before rod synaptic developmental pattern, similar to that in other mammals. The cone-dominated fovea initiates synaptogenesis, and shows a different synaptic sequence from rod-dominated peripheral retina.

Animals↗
PubMed2006

Drosophila homologue of Eps15 is essential for synaptic vesicle recycling.

The mammalian protein Eps15 is phosphorylated by EGF receptor tyrosine kinase and has been shown to interact with several components of the endocytic machinery. We have identified a hypomorphic Eps15 mutant in Drosophila which shows reversible paralysis and an altered physiology at restrictive temperatures. In addition, the temperature-sensitive paralytic defect of shibire mutant is enhanced by this mutant. Eps15 is enriched in the larval neuromuscular junction in endocytic 'hot spots' in a pattern similar to Dynamin. Eps15 mutants show a decrease in the alpha-Adaptin levels at the larval neuromuscular junction synapse. Genetic and biochemical studies of interactions with components of the endocytic machinery suggest that Eps15 has an important role in synaptic vesicle recycling and regulates recruitment of alpha-Adaptin.

Adaptor Protein Complex alpha Subunits↗
PubMed1998

Reduced O-glycosylated clathrin assembly protein AP180: implication for synaptic vesicle recycling dysfunction in Alzheimer's disease.

Synapse loss is one of the neuropathologies in Alzheimer's disease (AD) that may play a crucial role in the mechanism of its distinct cognitive impairment and dementia. In a previous study [18], a significant reduction of O-glycosylated clathrin assembly protein AP180 was observed in neocortex of AD. The reduction correlated with the density of neurofibrillary tangles. In this study we further determine that the O-GlcNAc/AP180 ratio is not changed, but the level of AP180 protein decreases in AD. Furthermore, whereas the level of neurofilament (NF-M) remains relatively unchanged, another clathrin assembly protein, AP-2, is also reduced in AD along with a small loss of synaptophysin. Our findings suggest that synaptic vesicle recycling dysfunction may be involved in the pathology of synapse loss in AD.

Acetylglucosamine↗
PubMed1986

CNS distribution of a novel pituitary protein '7B2': localization in secretory and synaptic vesicles.

A detailed study of the immunoreactivity distribution of a novel pituitary protein, '7B2', within specific brain regions and in spinal cord revealed a complex network of neurons and fibers. Immunoreactive cell bodies were found exclusively in the hypothalamus. Stained fibers were more widely distributed and encompassed nearly 100 structures, including several limbic and autonomic nuclei. Biogenic amine centers such as substantia nigra, raphe nuclei and locus coeruleus have also contained immunoreactive 7B2. Subcellular fractionation using differential centrifugation and Percoll gradient revealed the preferential localization of this protein within granule-enriched fractions of rat neurointermediate lobe of the hypophysis. In agreement, ultrastructural studies revealed the presence of 7B2 within secretory-like granules in the median eminence and within synaptic vesicles of selected extrahypothalamic nuclei. Based upon migration on SDS-PAGE, the apparent molecular weight of the major form of 7B2 extracted from different brain regions was found to be 22,000, identical to that of the pituitary form.

Animals↗
PubMed1982

Varicose axons bearing "synaptic" vesicles on the basal lamina of the human seminiferous tubules.

Normal (infant and adult) and pathological testes were examined by electron microscopy in order to study testicular innervation. Nerves composed of non-myelinated fibres were abundant in the tunica vasculosa of the tunica albuginea. These nerves penetrated into the testicular septa reaching the interstitial tissue. This showed numerous non-myelinated nerve fibres running among the Leydig cells and blood vessels. Single axons or small groups of them, partially surrounded by Schwann cells, approached: 1) the Leydig cells, 2) the interstitial blood vessels, and 3) the seminiferous tubules. Single naked axons were also observed primarily in the proximity of the seminiferous tubules. These axons showed varicosities containing both small and large "synaptic" vesicles. The latter were less numerous and contained a central dense core. Small vesicles were agranular. Some varicose axons ran across the myofibroblast layer of the tunica propria reaching the basal lamina of the seminiferous tubules at the level of the Sertoli cells but not at the level of the spermatogonia. The intercellular space between Sertoli cell and axon membrane was about 150-200 nm.

Adolescent↗
PubMed1984

Calmodulin binding proteins of the cholinergic electromotor synapse: synaptosomes, synaptic vesicles, receptor-enriched membranes, and cytoskeleton.

Calmodulin binding proteins (CBPs) have been identified using a gel overlay technique for fractions isolated from Torpedo electromotor nerve endings. Different fractions possessed characteristic patterns of CBPs. Synaptosomes showed five major CBPs--Mr 220,000, 160,000, 125,000, 55,000, and 51,000. Polypeptides of Mr 55,000 and 51,000 were found in the cytoplasm and the others are membrane-associated. The Triton X-100-insoluble cytoskeleton of synaptosomes was isolated in the presence or absence of calcium. The major CBPs had Mr of 19,000, 18,000, and 16,000. In the presence of calcium, no other CBPs were seen. In the absence of calcium, an Mr 160,000 polypeptide was present in the Triton cytoskeleton. Synaptic vesicles showed CBPs of Mr 160,000, 25,000, and 20,000. Membrane fragments enriched in acetylcholine receptors contained two major CBPs, Mr 160,000 and 125,000, together with a less prominent protein at Mr 26,000. A protein of Mr similar to that of fodrin was present in synaptosomes and acetylcholine receptor membrane fragments, but only in small amounts relative to the other polypeptides observed. The heavy and light chains of clathrin-coated vesicles from pig brain did not bind calmodulin, although strong labelling of an Mr 47,000 polypeptide was found. Results showed that calelectrin does not bind calmodulin. The possible identity of the calmodulin binding proteins is discussed.

Animals↗
PubMed2005

Synaptic vesicle chips to assay botulinum neurotoxins.

BoNTs (botulinum neurotoxins), considered to be the most toxic of all biological substances, inhibit neurotransmission through proteolytic cleavage of SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins [VAMP (vesicle-associated membrane protein, or synaptobrevin), SNAP-25 (25 kDa synaptosome-associated protein) or syntaxin]. Expansion in the use of BoNTs as therapeutic and cosmetic agents, and the potential threat they constitute as biological weapons, underlines the need for rapid and sensitive in vitro assays. Here, we present new automatized bioassays to detect VAMP cleavage by BoNT/B and F. Western blotting and SPR (surface plasmon resonance) methods revealed that BoNT/B and F totally cleave their substrate on immunoisolated SVs (synaptic vesicles). Real-time monitoring of the immunocapture of native SVs from crude lysates on SPR sensor chips enabled the detection of picogram amounts of different SV proteins. Pre-incubation of a membrane fraction containing SVs with BoNT specifically inhibited capture by anti-VAMP antibodies, and amounts as low as 0.1 pg of BoNT/B were detected. This automated SPR assay is approx. 200 times more sensitive, and 25 times more rapid, than the in vivo BoNT/B test currently used. Moreover, the method can be performed using a few thousand cultured neurons and constitutes a new screening assay for inhibitors. Our data indicate that native VAMP is an optimal substrate for in vitro BoNT assays that can be monitored by SPR.

Animals↗
PubMed1976

Evidence that the rapid binding of newly accumulated noradrenaline within synaptosomes involves synaptic vesicles.

When rat brain synaptosomes were incubated with [3H]noradrenaline for 1 min and then exposed to osmotic shock, only about 20% of the newly accumulated [3H]noradrenaline was released. It would appear that most, but possibly not all of the newly accumulated [3H]noradrenaline is rapidly bound to some particulate cytoplasmic constituent within the synaptosome. [3H]Dopamine and [3H]5-hydroxytryptamine were also rapidly bound within synaptosomes but [3H]glycine and [3H]gamma-aminobutyric acid were not. Reserpinization (5 mg/kg, i.p., 24 h before preparation) only slightly reduced the initial rate of [3H]noradrenaline uptake by synaptosomes. However, when reserpinized synaptosomes were osmotically shocked, most of the newly accumulated radioactivity was released; this radioactivity was identified chromatographically as [3H]noradrenaline. On the basis of the findings with reserpinized preparations, it seems likely that (1) the rapid intrasynaptosomal binding involves synaptic vesicles and (2) the neuronal membrane transport system itself may be capable of driving the uptake of noradrenaline by nerve-terminals. The rapid vesicular binding observed may not be essential for the accumulation of the amine by presynaptic terminals during brief exposures.

Animals↗
PubMed1999

Adult-generated neurons in the dentate gyrus send axonal projections to field CA3 and are surrounded by synaptic vesicles.

The subgranule zone of the dentate gyrus in rats has been shown to be proliferative into adulthood and senescence. However, the connectivity of newly generated, identified neurons in the adult has not been definitively described. In the present study, 9 weeks after a series of intraperitoneal injections of 5-bromo-2'-deoxyuridine (BrdU), animals received stereotaxic iontophoretic injections of Fluoro-Gold (FG) into field CA3. Three weeks after FG injections, sections were analyzed for BrdU immunoreactivity (proliferative label), FG retrograde label, and either calbindin-D28k or synaptophysin immunohistochemistry. A large proportion (up to 44%) of BrdU-labeled cells in the dentate gyrus within regions of FG retrograde label incorporated FG. All of the doubly labeled (BrdU-FG) neurons also immunolabeled with the antibody to calbindin-D28k. Many doubly labeled (BrdU-FG) cells were also surrounded in three planes by synaptophysin immunoreactivity. We conclude that newly generated neurons in the dentate gyrus have the correct immunohistochemical profile, send appropriate axonal projections to field CA3, and are surrounded by profiles containing synaptic vesicle proteins.

Animals↗
PubMed2003

Removal of polysialic acid induces aberrant pathways, synaptic vesicle distribution, and terminal arborization of retinotectal axons.

Developing chick retinotectal projections extend rostrally in the superficial stratum opticum of the tectum until they reach their appropriate target zone. They then penetrate, arborize, and form synapses within distinct tectal retinorecipient layers. In this study, we show that the polysialylated neural cell adhesion molecule is expressed both on the membrane of these developing projections and in the stratum opticum and retinorecipient layers during the period of optic innervation. On this basis, the role of polysialic acid was analyzed with respect to both trajectory and arborization in the tectum, using confocal imaging of DiI-labeled retinotectal fibers in whole-mount tecta of embryos pretreated with a polysialic acid-specific degrading enzyme, endoneuraminidase N. The removal of polysialic acid caused several distinct abnormalities, including random dorsal/ventral meandering of fibers in the stratum opticum, a distorted branching and extension of arbors in the retinorecipient layers, and inappropriate synaptic vesicle accumulation in pretarget areas. These findings indicate that the unique ability of polysialic acid to regulate different types of cell interactions is an essential component of axon behavior during multiple steps of tectal target innervation.

Animals↗
PubMed1998

Physical link and functional coupling of presynaptic calcium channels and the synaptic vesicle docking/fusion machinery.

N- and P/Q-type calcium channels are localized in high density in presynaptic nerve terminals and are crucial elements in neuronal excitation-secretion coupling. In addition to mediating Ca2+ entry to initiate transmitter release, they are thought to interact directly with proteins of the synaptic vesicle docking/fusion machinery. As outlined in the preceding article, these calcium channels can be purified from brain as a complex with SNARE proteins which are involved in exocytosis. In addition, N-type and P/Q-type calcium channels are co-localized with syntaxin in high-density clusters in nerve terminals. Here we review the role of the synaptic protein interaction (synprint) sites in the intracellular loop II-III (L(II-III)) of both alpha1B and alpha1A subunits of N-type and P/Q-type calcium channels, which bind to syntaxin, SNAP-25, and synaptotagmin. Calcium has a biphasic effect on the interactions of N-type calcium channels with SNARE complexes, stimulating optimal binding in the range of 10-20 microM. PKC or CaM KII phosphorylation of the N-type synprint peptide inhibits interactions with native brain SNARE complexes containing syntaxin and SNAP-25. Introduction of the synprint peptides into presynaptic superior cervical ganglion neurons reversibly inhibits EPSPs from synchronous transmitter release by 42%. At physiological Ca2+ concentrations, synprint peptides cause an approximate 25% reduction in transmitter release of injected frog neuromuscular junction in cultures, consistent with detachment of 70% of the docked vesicles from calcium channels based on a theoretical model. Together, these studies suggest that presynaptic calcium channels not only provide the calcium signal required by the exocytotic machinery, but also contain structural elements that are integral to vesicle docking, priming, and fusion processes.

Action Potentials↗
PubMed2000

Kappa opioid receptor immunoreactivity in the nucleus accumbens and caudate-putamen is primarily associated with synaptic vesicles in axons.

A rabbit polyclonal antiserum, raised against a C-terminal oligopeptide of the mouse kappa opioid receptor, was used to localize the cellular distribution of kappa receptors in the dorsal and ventral striatum of rats with light and electron microscopic immunocytochemistry. Prominent, diffuse kappa receptor immunoreactivity was present in the nucleus accumbens, particularly in the shell, ventral caudate-putamen and olfactory tubercle. The density of receptor immunoreactivity decreased in more dorsal areas of the caudate-putamen. In contrast, neuronal cell bodies stained clearly in the dorsal endopiriform nucleus, claustrum and layer VI of the adjacent cerebral cortex. Observations at the electron microscopic level in the dorsomedial shell of the nucleus accumbens and caudate-putamen revealed that the kappa receptor immunoreactivity was predominantly located in axons, often associated with synaptic vesicles, remote from the terminal or preterminal area. The few terminals which were labeled made slightly more asymmetrical than symmetrical contacts and the percentage of asymmetrical contacts observed was greater in the caudate than in the accumbens. A small number of postsynaptic spines was labeled; most of them were contacted by asymmetrical terminals. No labeling was observed in dendritic shafts.Thus, the predominant localization of kappa receptor immunoreactivity in axons is consistent with its role as a major inhibitor of glutamate and dopamine release in the dorsal and ventral striatum.

Animals↗
PubMed2001

Nicotinic acid adenine dinucleotide phosphate enhances quantal neurosecretion at the frog neuromuscular junction: possible action on synaptic vesicles in the releasable pool.

Inositol 1,4,5-trisphosphate (IP(3)) and cyclic adenosine diphosphate-ribose (cADPR) are second messengers that enhance neurosecretion by inducing Ca(2+) release from smooth endoplasmic reticulum (SER). The putative intracellular messenger, nicotinic acid adenine dinucleotide phosphate (NAADP), releases Ca(2+) from stores that are distinct from SER. Evidence is presented here that NAADP causes a concentration-dependent increase in quantal output that is associated with an increase in probability of transmitter release at the frog neuromuscular junction. This effect is mimicked by A23187, a Ca ionophore that promotes Ca(2+) entry at the plasmalemma. The response to NAADP is potentiated by IP(3) but antagonized by cADPR. Thapsigargin completely blocks IP(3) and cADPR responses and decreases but does not prevent the response to NAADP. We conclude that NAADP, whose receptors are widely distributed in the brain, enhances neurosecretion by releasing Ca(2+) from an internal store near the plasmalemma, possibly from synaptic vesicles in the releasable pool. These data also support the hypothesis of a two-pool model for Ca(2+) oscillations at the presynaptic site.

Adenosine Diphosphate Ribose↗