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PubMed1993

What do the synaptic vesicles contain?

The intersynaptic membranes of the rat brain cortex were found to remain firmly attached to one another after perfusion of strongly anisotonic solutions. Brains perfused with depolarizing and excitotoxic agents showed abundant, apparent intermingling of mitochondria and synaptic vesicles. The results suggest (i) that the intersynaptic membranes are not separated from one another by an essentially fluid intersynaptic medium as it is commonly assumed, but rather firmly attached to one another by a layer of faintly osmiophilic yet remarkably stable, water-insoluble material; and (ii) that the synaptic vesicles may be involved in adenosine triphosphate carriage. Well established multidisciplinary data are presented which appear to be in line with both possibilities.

2,4-Dinitrophenol↗

PubMed2006

Pharmacology meets vesicular trafficking at a central nervous system synapse: pregabalin effects on synaptic vesicle cycling in hippocampal neurons.

The contribution by Micheva et al. in this issue of Molecular Pharmacology adds to our understanding of the action of pregabalin, a drug used for treatment of partial seizures and neuropathic pain. The authors examine the effects of pregabalin on presynaptic function of cultured hippocampal neurons using a powerful technique to follow the trafficking of synaptic vesicles in individual boutons. The study revealed that pregabalin reduces the readily releasable pool of synaptic vesicles in an N-methyl-d-aspartate receptor-dependent manner.

Animals↗

PubMed2002

Synphilin-1 is developmentally localized to synaptic terminals, and its association with synaptic vesicles is modulated by alpha-synuclein.

Alpha-synuclein is the major component of Lewy bodies in patients with Parkinson's disease, and mutations in the alpha-synuclein gene are responsible for some familial forms of the disease. alpha-Synuclein is enriched in the presynapse, but its synaptic targets are unknown. Synphilin-1 associates in vivo with alpha-synuclein promoting the formation of intracellular inclusions. Additionally synphilin-1 has been found to be an intrinsic component of Lewy bodies in patients with Parkinson's disease. To understand the role of synphilin-1 in Parkinson's disease, we sought to define its localization and function in the brain. We now report that, like alpha-synuclein, synphilin-1 was enriched in neurons. In young rats, synphilin-1 was prominent in neuronal cell bodies but gradually migrated to neuropil during development. Immunoelectron microscopy of adult rat cerebral cortex demonstrated that synphilin-1 was highly enriched in presynaptic nerve terminals. Synphilin-1 co-immunoprecipitated with synaptic vesicles, indicating a strong association with these structures. In vitro binding experiments demonstrated that the N terminus of synphilin-1 robustly associated with synaptic vesicles and that this association was resistant to high salt washing but was abolished by inclusion of alpha-synuclein in the incubation medium. Our data indicated that synphilin-1 is a synaptic partner of alpha-synuclein, and it may mediate synaptic roles attributed to alpha-synuclein.

Animals↗

PubMed1987

Synaptic vesicles in electromotoneurones. I. Axonal transport, site of transmitter uptake and processing of a core proteoglycan during maturation.

We were able by using an in vivo pulse-label technique to trace part of the life cycle of a secretory organelle, the acetylcholine-storing synaptic vesicle from electromotoneurones of Torpedo marmorata. This technique uses [35S]sulphate incorporation into the cell bodies of the electromotoneurones which results in radioactive labelling of a synaptic vesicle heparansulphate proteoglycan--a major core component. Vesicles are anterogradely transported in the axons at a fast rate as 'empty' organelles (VP0 population). In the nerve terminal, maturation of the granule to a population (VP1) fully charged with acetylcholine and ATP occurs. Finally after a longer time interval a change to a third population (VP2) is observed. This population is reduced in diameter as compared to VP0 and VP1 suggesting, in agreement with earlier reports, that it has undergone exo-endocytosis. The changes from VP0 to VP1 and VP2 are accompanied by a degradation of the core proteoglycan as measured by gel filtration of the 35S-labelled compound. The results show that vesicles are axonally transported as preformed organelles, exist in the neurone at least in three different populations and that the nerve terminal is the major site of transmitter uptake.

Acetylcholine↗

PubMed2001

Spring, a novel RING finger protein that regulates synaptic vesicle exocytosis.

The synaptosome-associated protein of 25 kDa (SNAP-25) interacts with syntaxin 1 and vesicle-associated membrane protein 2 (VAMP2) to form a ternary soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor (SNARE) complex that is essential for synaptic vesicle exocytosis. We report a novel RING finger protein, Spring, that specifically interacts with SNAP-25. Spring is exclusively expressed in brain and is concentrated at synapses. The association of Spring with SNAP-25 abolishes the ability of SNAP-25 to interact with syntaxin 1 and VAMP2 and prevents the assembly of the SNARE complex. Overexpression of Spring or its SNAP-25-interacting domain reduces Ca(2+)-dependent exocytosis from PC12 cells. These results indicate that Spring may act as a regulator of synaptic vesicle exocytosis by controlling the availability of SNAP-25 for the SNARE complex formation.

Amino Acid Sequence↗

PubMed1988

The synaptic vesicle proteins synapsin I and synaptophysin (protein P38) are concentrated both in efferent and afferent nerve endings of the skeletal muscle.

Synapsin I and synaptophysin (protein p38) are 2 major protein components of the membranes of small synaptic vesicles of virtually all presynaptic nerve endings. Synapsin I, a phosphoprotein regulated by both Ca2+ and cAMP, is a peripheral protein of the cytoplasmic surface of the vesicle membrane. It is thought to anchor the vesicle surface to the cytoskeleton of the terminal and to play a regulatory role in neurotransmitter release. Synaptophysin is an intrinsic transmembrane glycoprotein. We report here that both proteins are present and concentrated also in afferent nerve endings, which provide the sensory innervation of the skeletal muscle and of the tendon. The distribution of both antigens in sensory nerve endings is consistent with their localization on the microvesicles that have been described in such endings. Thus, our results suggest the existence of important biochemical, and possibly functional, similarities between small synaptic vesicles of presynaptic nerve endings and microvesicles of sensory endings. Such findings provide new clues to the understanding of the physiology of sensory endings.

Afferent Pathways↗

PubMed2003

Defects in expression of genes related to synaptic vesicle trafficking in frontal cortex of Alzheimer's disease.

Loss of synapses correlates with cognitive decline in Alzheimer's disease (AD). However, molecular mechanisms underlying the synaptic dysfunction and loss are not well understood. In this study, microarray analysis of brain tissues from five AD cases revealed a reduced expression of a group of related genes, all of which are involved in synaptic vesicle (SV) trafficking. By contrast, several synaptic genes with functions other than vesicle trafficking remained unchanged. Quantitative RT-PCR confirmed and expanded the microarray findings. Furthermore, immunoblotting showed that the protein level of at least one of these gene products, dynamin I, correlated with its reduced transcript. Immunhistochemical analysis exhibited an altered distribution of dynamin I immunolabeling in AD neurons. Microarray analysis of transgenic mice with mutated amyloid precursor protein showed that although the transcript levels for some of the SV trafficking-related genes are also decreased, the change in dynamin did not replicate the AD pattern. The results suggest a link among SV vesicle-trafficking pathways, synaptic malfunction, and AD pathogenesis.

Aged↗

PubMed1995

Dynamic imaging of purified individual synaptic vesicles.

The atomic force microscope (AFM) was used to directly image purified synaptic vesicles. Individual secretory vesicles (approximately 50 nm diameter) were resolved with the AFM when imaged either dry or in solution. Vesicles were observed repeatedly for periods of greater than 2 h. To ask whether the AFM can detect structural change of vesicles the osmolarity of the bathing medium was reduced from 330 to 110 mOsm. Hypo-osmotic treatment caused an expansion and flattening of the vesicles. Thus, using the AFM it is possible to resolve individual vesicles and follow changes in vesicular structure. This opens the possibility that the secretory event can be reconstituted and visualized in vitro in order to elucidate the roles of synaptic proteins in synaptic transmission.

Animals↗

PubMed2006

Effects of restraint stress on the expression of proteins involved in synaptic vesicle exocytosis in the hippocampus.

Chronic restraint stress has been associated with induction of morphological changes in the hippocampus. Postsynaptically, these changes include decreased length and branching of apical dendrites from CA3 pyramidal neurons, while presynaptically, depletion and clustering of synaptic vesicles have been observed. However, the molecular correlates of these changes remain poorly defined; while some studies have identified changes in the levels of some presynaptic proteins, none have assessed the coordinate expression of components of the membrane fusion complex, including synaptobrevin, syntaxin, and synaptosomal-associated protein 25 kDa, and their major regulatory molecules synaptotagmin, synaptophysin, and synapsin. Therefore, we undertook to assess the immunoreactivity of these proteins in hippocampal slices obtained from rats subjected to either acute (one 6 h session) or chronic (21 days at 6 h per day) of restraint stress. Specifically, we observed a significant increase in synaptobrevin immunoreactivity in the inner molecular layer of the dentate gyrus (54.2%; P=0.005), the stratum radiatum in the CA1 subfield (55.5%; P=0.007), and a region including the stratum lucidum and the proximal portion of the stratum radiatum in the CA3 subfield (52.7%; P=0.002); we also observed a trend toward increased synaptophysin levels in the stratum lucidum/radiatum of the CA3 subfield (8.0%; P=0.051) following chronic, but not acute, restraint stress. In that synaptobrevin has been associated with replenishment of the "readily-releasable" pool of synaptic vesicles and the efficiency of neurotransmitter release, the present results suggest that stress-induced changes in synaptobrevin may at least in part underlie the previously observed changes in synaptic and neuronal morphology.

Analysis of Variance↗

PubMed1980

Number of synaptic vesicles in the rat somatosensory cortex after repetitive electrical stimulation prolonging self-sustained after-discharges.

The sensorimotor area of the cerebral cortex of rats was repetitively electrically stimulated (8 Hz for sec) at 10-min intervals, inducing a gradual prolongation of self-sustained after-discharges (SSADs). At 10 min after termination of the third SSAD, the animals were perfused with a fixation solution. The homotopic area of the contralateral hemisphere was examined in the electron microscope. In the II cortical layer, the agranular synaptic vesicles in type I synapses (after Gray) were counted close to the synaptic cleft. The number of synaptic vesicles was significantly increased in the experimental animals.

Animals↗

PubMed1991

Detection with monoclonal antibodies of a 15-kDa proteolipid in both presynaptic plasma membranes and synaptic vesicles in Torpedo electric organ.

A protein, the mediatophore, has been purified from Torpedo electric organ presynaptic plasma membranes. This protein mediates the release of acetylcholine through artificial membranes when activated by calcium and is made up of 15-kDa proteolipid subunits. After immunization with purified delipidated mediatophore, monoclonal antibodies binding to the 15-kDa proteolipid band on Western blots of purified mediatophore were selected. A 15-kDa proteolipid antigen was also detected in cholinergic synaptic vesicles. Using an immunological assay, it was estimated that presynaptic plasma membranes and synaptic vesicles contain similar proportions of 15-kDa proteolipid antigen. Detection by immunofluorescence in the electric organ showed that only nerve endings were labeled. In electric lobes, the staining was associated with intracellular membranes of the electroneuron cell bodies and in axons. Nerve endings at Torpedo neuromuscular junctions were also labeled with anti-15-kDa proteolipid monoclonal antibodies.

Animals↗

PubMed2001

Disruption of ClC-3, a chloride channel expressed on synaptic vesicles, leads to a loss of the hippocampus.

Several plasma membrane chloride channels are well characterized, but much less is known about the molecular identity and function of intracellular Cl- channels. ClC-3 is thought to mediate swelling-activated plasma membrane currents, but we now show that this broadly expressed chloride channel is present in endosomal compartments and synaptic vesicles of neurons. While swelling-activated currents are unchanged in mice with disrupted ClC-3, acidification of synaptic vesicles is impaired and there is severe postnatal degeneration of the retina and the hippocampus. Electrophysiological analysis of juvenile hippocampal slices revealed no major functional abnormalities despite slightly increased amplitudes of miniature excitatory postsynaptic currents. Mice almost lacking the hippocampus survive and show several behavioral abnormalities but are still able to acquire motor skills.

Acids↗

PubMed1998

Synaptic vesicle size and number are regulated by a clathrin adaptor protein required for endocytosis.

Clathrin-mediated endocytosis is thought to involve the activity of the clathrin adaptor protein AP180. However, the role of this protein in endocytosis in vivo remains unknown. Here, we show that a mutation that eliminates an AP180 homolog (LAP) in Drosophila severely impairs the efficiency of synaptic vesicle endocytosis and alters the normal localization of clathrin in nerve terminals. Most importantly, the size of both synaptic vesicles and quanta is significantly increased in lap mutants. These results provide novel insights into the molecular mechanism of endocytosis and reveal a role for AP180 in regulating vesicle size through a clathrin-dependent reassembly process.

Adaptor Proteins, Vesicular Transport↗

PubMed1984

Localization of vasopressin in synaptic vesicles of extra-hypothalamic rat brain.

The subcellular localization of vasopressin (VP) from extra-hypothalamic areas of rat brain was investigated by measuring its distribution (a) along a continuous sucrose gradient; (b) during the preparation of isolated nerve endings (synaptosomes) and (c) during the preparation of synaptic vesicles. Quite large amounts of vasopressin are isolated in the same fractions as mitochondria, as well as synaptosomes. Osmotic rupture of membrane bound organelles in the homogenate results in the vasopressin being measured largely in the fraction containing synaptic vesicles. These results would suggest that vasopressin could be released by nerve terminals which is consistent with the hypothesis that it may have a neurotransmitter/neuromodulator function in the CNS.

Animals↗

PubMed1979

Stimulation by subsynaptosomal fractions of transmitter efflux from plain synaptic vesicle fraction.

The effects were investigated of purified subsynaptic fractions on the efflux of radioactivity from a plain synaptic vesicle fraction which had incorporated [3H]dopamine. About 50% of the radioactivity incorporated into the plain vesicles (120 microgram protein) was liberated on exposure to purified synaptic membranes (30 microgram protein). The synaptic membrane-dependent efflux appeared to depend on both adenosine triphosphate and divalent cations, especially Ca2+. Of the sub-cellular fractions used, the heavy microsomal fraction showed the same effects as the synaptic membrane fraction. Purified synaptic junctions exhibited the strongest stimulating effects: the efflux was 2 times greater than that observed with synaptic membranes. The stimulating effects of myelin were less than one-seventh of those of synaptic junctional fraction. These observations may indicate that the transmitters are liberated by interaction of vesicle membrane with synaptic membrane in the presence of ATP and divalent cations.

Adenylyl Imidodiphosphate↗

PubMed1995

Distinct pools of synaptic vesicles in neurotransmitter release.

Nerve terminals are unique among cellular secretory systems in that they can sustain vesicular release at a high rate. Although little is known about the mechanisms that account for the distinctive features of neurotransmitter release, it can be assumed that neuron-specific proteins are involved. One such protein family, the synapsins, are believed to regulate neurotransmitter release through phosphorylation-dependent interactions with synaptic vesicles and cytoskeletal elements. Here we show that clusters of vesicles at synaptic release sites are composed of two pools, a distal pool containing synapsin and a proximal pool devoid of synapsin and located adjacent to the presynaptic membrane. Presynaptic injection of synapsin antibodies resulted in the loss of the distal pool, without any apparent effect on the proximal pool. Depletion of this distal pool was associated with a marked depression of neurotransmitter release evoked by high-frequency (18-20 Hz) but not by low-frequency (0.2 Hz) stimulation. Thus the availability of the synapsin-associated pool of vesicles seems to be required to sustain release of neurotransmitter in response to high-frequency bursts of impulses.

Animals↗

PubMed1998

Glutamate transport and storage in synaptic vesicles.

Glutamate plays an important metabolic role in virtually every vertebrate cell. In particular, glutamate is the most common excitatory neurotransmitter in the vertebrate central nervous system. As such, the mechanism by which glutamate is diverted from its normal metabolic activities toward its role as a neurotransmitter has, in recent years, been systematically investigated. In glutamatergic nerve endings, synaptic vesicles accumulate and store a proportion of the cellular glutamate pool and, in response to appropriate signals, release glutamate into the synaptic cleft by exocytosis. Glutamate accumulation is accomplished by virtue of a glutamate uptake system present in the synaptic vesicle membrane. The uptake system consists of a transport protein, remarkably specific for glutamate, and a vacuolar-type H+-ATPase, which provides the coupling between ATP hydrolysis and glutamate transport. The precise manner in which the glutamate transporter and H+-ATPase operate is currently the subject of debate. Recent data relevant to this debate are reviewed in this article. Additionally, pharmacological agents thought to specifically interact with the vesicular glutamate transporter are discussed. Finally, a newly discovered, endogenous inhibitor of vesicular uptake, inhibitory protein factor (IPF), is discussed with some speculations as to its potential role as a presynaptic modulator of neurotransmission.

ATP-Binding Cassette Transporters↗

PubMed2000

Synaptic vesicle protein 2, A new neuroendocrine cell marker.

Synaptic vesicle protein 2 (SV2) is a glycoprotein identified in the nervous system of several species, including man, but its occurrence in the human neuroendocrine (NE) cell system has not been investigated. By using a monoclonal antibody to SV2, immunoreactivities were demonstrated in NE cell types in human gastrointestinal tract, pancreas, anterior pituitary gland, thyroid, parathyroid, and adrenal medulla, and also in chief cells of gastric oxyntic mucosa. Immunoelectron microscopy of pancreatic islets revealed SV2 immunoreactivity in secretory granules. Comparison of SV2, synaptophysin, and chromogranin A immunoreactivity showed more SV2- and synaptophysin- than chromogranin A-immunoreactive cells in the antrum and pancreas. In the other gastrointestinal regions and in the other endocrine organs more SV2- than synaptophysin-immunoreactive cells were seen. More chromogranin A- than SV2-immunoreactive cells were observed in duodenum, colon, and parathyroid. Various NE tumors were examined and all contained SV2-immunoreactive cells. The staining patterns with the three markers agreed well, except in hindgut carcinoids, which showed strong SV2 immunoreactivity, weak synaptophysin but no chromogranin A immunostaining. In pituitary adenomas more cells were immunoreactive to SV2 than to the other two antibodies. In conclusion, SV2 is recognized as a further broad marker for NE cells and widens the arsenal of diagnostic tools for NE tumors. It is of special importance for identifying hindgut carcinoids.

Biomarkers↗