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PubMed1987

Synaptophysin identified in metastases of neuroendocrine tumors by immunocytochemistry and immunoblotting.

Synaptophysin, an Mr 38,000 integral membrane glycoprotein of neurotransmitter vesicles, has been identified in diverse primary neuroendocrine (NE) tumors of both neural and epithelial origin (Wiedenmann and co-workers, Proc Natl Acad Sci USA 1986; 83: 3500-3504). In the present study, metastases of several types of NE tumors, including medullary thyroid carcinoma, gastrinoma, insulinoma, small (oat) cell carcinoma of the lung, gastrointestinal carcinoid, and neuroblastoma, were examined for the presence of synaptophysin by immunocytochemistry, with the use of tissue sections as well as centrifuged cell suspensions and by immunoblotting of tumor proteins. The results show that expression of synaptophysin can be maintained during formation of metastases. Therefore, the authors propose that synaptophysin antibodies be used for the positive identification of metastatic NE tumors, notably in differential diagnosis. The possible implications of these findings for tumor diagnosis are discussed.

Endocrine System Diseases↗

PubMed1996

Developmental profiles of synaptophysin in granule cells of rat cerebellum: an immunohistocytochemical study.

The expression of synaptophysin was immunohistocytochemically examined at the protein level in the cerebellar cortex of the neonatal rat with special reference to the development of granule cells. In the premigratory zone of the external granular layer, these cells expressed synaptophysin at an early stage of development, where it was localized in the trans-side cisterns of the Golgi apparatus and in nearby small vesicles. When the granule cells began to horizontally extend their axons in the upper molecular layer, the growth cones and expansions of parallel fibers already contained many small vesicles similar in shape and size to synaptic vesicles. These small vesicles were labeled with antibody against synaptophysin. Tubular structures were often found among the accumulations of synaptic vesicles, and their membranes were also labeled with synaptophysin. Both growth cones and expansions of parallel fibers were often observed to approach and to contact with the small process of Purkinje cell dendrites. The contact between the two components formed a junction with the characteristics of a synapse. The profiles of synaptogenesis began to be observed in the deeper molecular layer during a period from the 7th to the 9th days after birth.

Age Factors↗

PubMed1994

Striatal synaptophysin expression and haloperidol-induced synaptic plasticity.

Synaptophysin is a presynaptic vesicle protein and a marker of synaptic density. We have studied the expression of its encoding mRNA in the brains of rats treated with haloperidol (2 mg kg-1 d-1) for two weeks. A significant increase in synaptophysin mRNA content was observed in the dorsolateral striatum but not in other brain areas compared with control animals. A similar trend was observed for synaptophysin immunoreactivity. Quantification of synaptophysin mRNA per cell showed that the increase was pronounced in large putatively cholinergic, striatal neurones. These data provide further evidence that localized synaptic plasticity occurs after neuroleptic treatment and indicate that such alterations are manifested in terms of expression of a synaptic protein gene by striatal neurones.

Animals↗

PubMed1998

Evidence for a role for synaptophysin in expression of long-term potentiation in rat dentate gyrus.

Maintenance of long-term potentiation in perforant path-granule cell synapses is accompanied by increased glutamate release. Here we investigate the role of synaptophysin in release and in expression of long-term potentiation in dentate gyrus. We report that long-term potentiation was accompanied by increased endogenous glutamate release and increased tyrosine phosphorylation of synaptophysin, but these changes were attenuated when long-term potentiation was inhibited by the tyrosine kinase inhibitor tyrphostin AG879 or by the NMDA antagonist D-aminophosphonovalerate. In vitro analysis revealed that KCl-induced glutamate release was abolished in synaptosomes prepared in the presence of antisynaptophysin. The data suggest a role for synaptophysin in release and indicate that activation of tyrosine kinase and synaptophysin phosphorylation contribute to long-term potentiation perhaps by modulating glutamate release.

Animals↗

PubMed2003

Cellular expression and specific intragranular localization of chromogranin A, chromogranin B, and synaptophysin during ontogeny of pancreatic islet cells: an ultrastructural study.

INTRODUCTION AND AIMS: To get more insight into the differentiation patterns of pancreatic islet neuroendocrine cells and granules during ontogeny, the expression and localization of chromogranin A (CgA), chromogranin B (CgB), synaptophysin, and insulin were ultrastructurally studied with the immunogold technique in porcine and human pancreatic islet neuroendocrine cells. METHODOLOGY AND RESULTS: In porcine pancreas at early fetal stage, CgA was visualized throughout the immature granules in all neuroendocrine cells. Later, CgB also was expressed with the same pattern in most granules in all types of cells. In neonatal islets, CgA was localized in the periphery of immature alpha- and beta-cell granules and throughout the matrix of delta-cell granules; CgB was distributed throughout the matrix of these granules. In adult islets, alpha-cell granules stored CgA in the halo and CgB in both the core and the halo, beta-cell granules stored both CgA and CgB in their cores, and in delta-cell granules, both substances were mixed throughout the matrix. In all ontogenetic stages, synaptophysin was demonstrated in all cell types and granules. Insulin was expressed in early fetal cells of both pigs and humans, and colocalization with CgA, CgB, and synaptophysin was demonstrated. CONCLUSION: The early expression of CgA and synaptophysin may reflect a role at early fetal stages, and the individual localization of CgA and CgB upon differentiation indicates individual functions.

Animals↗

PubMed2002

Quantitative immunocytochemistry of GABA and synaptophysin in the cerebellar cortex of old ethanol-fed rats.

BACKGROUND: Ethanol-related synaptic loss, Purkinje neuron dendritic regression, and parallel fiber degeneration have been reported in the molecular layer of the adult cerebellar cortex. The known plasticity of the cerebellar cortex suggests that this region may respond to ethanol-related losses by compensatory remodeling of cerebellar circuitry. Stellate and basket interneurons may play an essential role in the remodeling process. Little is known about ethanol-related effects on cerebellar interneurons or on the GABAergic synapses that they form despite the fact that ethanol-related alterations in these components may contribute to the sensitivity of the cerebellum to ethanol. The paucity of data on GABAergic synapses extends to other synaptic components as well including synaptophysin, a glycoprotein component of synaptic vesicles and a synaptic marker. METHODS: Thirty 12-month-old F344 rats were divided into ethanol-fed, pair-fed, and chow-fed groups (10/group). Ethanol rats were treated for 40 weeks with a liquid diet in which 35% of the calories were derived from ethanol. At the end of treatment, rats were perfused, and tissue processed for quantitative immunohistochemistry of GABA and synaptophysin labels. RESULTS: Levels of GABA within inhibitory synapses formed by stellate and basket neurons and levels of synaptophysin were not altered by long-term ethanol treatment. CONCLUSIONS: Stable levels of GABA within GABAergic basket and stellate interneuron synapses suggest that interneurons in the molecular layer of the cerebellar cortex may not play a major role in remodeling of cerebellar circuitry following long-term ethanol consumption. The lack of ethanol-related alterations in synaptophysin levels reported here suggests that synaptic vesicles may be relatively insensitive to ethanol and that known ethanol-related effects on synapse number are due to other mechanisms.

Aging↗

PubMed1986

Expression of synaptophysin during postnatal development of the mouse brain.

The expression of the synaptic vesicle membrane protein, synaptophysin, was analyzed during postnatal development of the mouse cerebrum using a quantitative immunoblotting procedure. From birth to adulthood, the relative contents of synaptophysin increased 80-fold, reaching a final level of 3.5 micrograms/mg of total protein. The time course of accumulation suggests that synaptophysin expression is correlated with synaptogenesis. Thus synaptophysin may be used as a reliable marker of nerve terminal differentiation.

Animals↗

PubMed1989

Most synaptic vesicles isolated from rat brain carry three membrane proteins, SV2, synaptophysin, and p65.

We have prepared highly purified synaptic vesicles from rat brain by subjecting vesicles purified by our previous method to a further fractionation step, i.e., equilibrium centrifugation on a Ficoll gradient. Monoclonal antibodies to three membrane proteins enriched in synaptic vesicles--SV2, synaptophysin, and p65--each were able to immunoprecipitate specifically approximately 90% of the total membrane protein from Ficoll-purified synaptic vesicle preparations. Anti-SV2 precipitated 96% of protein, anti-synaptophysin 92%, and anti-p65 83%. These results demonstrate two points: (1) Ficoll-purified synaptic vesicles appear to be greater than 90% pure, i.e., less than 10% of membranes in the preparation do not carry synaptic vesicle-associated proteins. These very pure synaptic vesicles may be useful for direct biochemical analyses of mammalian synaptic vesicle composition and function. (2) SV2, synaptophysin, and p65 coexist on most rat brain synaptic vesicles. This result suggests that the functions of these proteins are common to most brain synaptic vesicles. However, if SV2, synaptophysin, or p65 is involved in synaptic vesicle dynamics, e.g., in vesicle trafficking or exocytosis, separate cellular systems are very likely required to modulate the activity of such proteins in a temporally or spatially specific manner.

Animals↗

PubMed2006

GLT-1 down-regulation induced by clozapine in rat frontal cortex is associated with synaptophysin up-regulation.

In rat frontal cortex, extracellular levels of glutamate are raised by the anti-psychotic drug clozapine. We have recently shown that a significant reduction in the levels of the glutamate transporter GLT-1 may be one of the mechanisms responsible for this elevation. Here we studied whether GLT-1 down-regulation induced by chronic clozapine treatment is associated with changes in the expression of synaptophysin, synaptosome-associated protein of 25 kDa (SNAP-25) and vesicular glutamate transporter 1 (VGLUT1), three major presynaptic proteins involved in neurotransmitter release. Quantitative high-resolution confocal microscopy studies in vivo showed that GLT-1 down-regulation is closely associated with a significant increase in synaptophysin, but not SNAP-25 and VGLUT1, expression. This was confirmed in vitro studies, and in western blotting studies of synaptophysin, SNAP-25 and VGLUT1. In addition, our results show that, following clozapine treatment, synaptophysin expression increases in the very cortical regions in which GLT-1 expression is down-regulated. These findings suggest that part of the effects of clozapine may be exerted via an action on the presynaptic machinery involved in neurotransmitter release.

Animals↗

PubMed1987

Synaptophysin--an immuno-histochemical marker for childhood neuroblastoma.

Synaptophysin, an integral membrane glycoprotein of presynaptic vesicles, was tested as an immuno-histochemical marker for childhood neuroblastoma. Synaptophysin immuno-reactivity was found in all neuroblastomas (6/6), but not in the other small round-cell tumors to be considered in its differential diagnosis. Thus, rhabdomyosarcomas (0/5), lymphomas (0/4), or Ewing's sarcomas (0/2) were negative for synaptophysin. The results suggest that synaptophysin is a useful marker for neuroblastoma, and it should belong to the marker panel used for the differential diagnosis of small round-cell tumors of childhood.

Adult↗

PubMed1992

Calcium-dependent transmitter secretion reconstituted in Xenopus oocytes: requirement for synaptophysin.

Calcium-dependent glutamate secretion was reconstituted in Xenopus oocytes by injecting the oocyte with total rat cerebellar messenger RNA (mRNA). Co-injection of total mRNA with antisense oligonucleotides to synaptophysin message decreased the expression of synaptophysin in the oocyte and reduced the calcium-dependent secretion. A similar effect on secretion was observed for oocytes injected with total mRNA together with an antibody to rat synaptophysin. These results indicate that synaptophysin is necessary for transmitter secretion and that the oocyte expression system may be useful for dissecting the molecular events associated with the secretory process.

Animals↗

PubMed1988

Identification of synaptophysin as a hexameric channel protein of the synaptic vesicle membrane.

The quaternary structure and functional properties of synaptophysin, a major integral membrane protein of small presynaptic vesicles, were investigated. Cross-linking and sedimentation studies indicate that synaptophysin is a hexameric homo-oligomer, which in electron micrographs exhibits structural features common to channel-forming proteins. On reconstitution into planar lipid bilayers, purified synaptophysin displays voltage-sensitive channel activity with an average conductance of about 150 picosiemens. Because specific channels and fusion pores have been implicated in vesicular uptake and release of secretory compounds, synaptophysin may have a role in these processes.

Animals↗

PubMed1998

Frontal cortical synaptophysin in Lewy body diseases: relation to Alzheimer's disease and dementia.

OBJECTIVES: Dementia in Alzheimer's disease correlates closely with loss of neocortical synapses. Similar synaptic loss has been shown in patients whose Alzheimer's disease is also associated with neocortical and brain stem Lewy bodies. The aim was to determine if dementia in Lewy body disease was associated with diminished concentrations of midfrontal cortex synaptophysin. METHODS: An immunobinding assay was used to measure synaptophysin in postmortem samples of midfrontal cortex from 89 patients with Alzheimer's disease (ages 59-100, mean 79), 22 with combined Lewy body disease and Alzheimer's disease (ages 69-103, mean 79), 15 demented patients with "pure" Lewy body disease (ages 57-80, mean 74), nine with neocortical and brain stem Lewy bodies who had Parkinson's disease but were not demented (ages 68-85, mean 79), and 20 neurologically normal controls (ages 58-89, mean 75). The diagnosis was confirmed in all cases by detailed neuropathological examination of the contralateral hemibrain. Seven of the patients in the pure Lewy body disease with dementia group had initially presented with parkinsonism and eight with dementia. RESULTS: Synaptophysin concentrations (arbitrary units (AU)/microg) in patients with Alzheimer's disease (mean 79 (SD 28)) or combined Lewy body disease and Alzheimer's disease (mean 83 (SD 33)) were significantly lower than in controls (mean 115 (SD 29)) (p=0.002). Synaptophysin concentrations in demented patients with pure Lewy body disease (mean 106 SD 39) and patients with Lewy body disease who were not demented (mean 101 (SD 18)) did not differ significantly from control values or from each other. CONCLUSION: Loss of midfrontal cortex synapses probably contributes to dementia in Lewy body disease when Alzheimer's disease is also present but not to the dementia of pure Lewy body disease.

Aged↗

PubMed2001

Changes in vesicular monoamine transporter (VMAT2) and synaptophysin in rat Substantia nigra and prefrontal cortex induced by psychotropic drugs.

We investigated the regulatory effect of the dopaminergic agent L-dopa, the mood stabilizer lithium and the nonselective monoamine oxidase inhibitor phenelzine on brain vesicular monoamine transporter (VMAT2) expression. Rats were treated chronically (21 days) with the three psychoactive drugs. VMAT2 gene expression at the protein level was assessed in the prefrontal cortex and striatum by autoradiography with high-affinity [(3)H]dihydrotetrabenazine ([(3)H]TBZOH) binding and at the mRNA level in the substantia nigra pars compacta by in situ hybridization. In addition, the effect of various treatments on the synaptophysin mRNA level was determined in the substantia nigra by in situ hybridization. Chronic administration of L-dopa resulted in a significant decrease (28%, p < 0.05) in the density of [(3)H]TBZOH binding in the prefrontal cortex but had no effect on VMAT2 and synaptophysin mRNA levels in the substantia nigra. Lithium treatment increased [(3)H]TBZOH-specific binding in the prefrontal cortex (23%, p < 0.05) but had no effect on VMAT2 and synaptophysin mRNA levels. Phenelzine did not modulate VMAT2 gene expression but reduced the synaptophysin mRNA level (19%, p < 0.05). The modulatory activities of these drugs, although relatively weak, may be relevant to the drug-induced synaptic and neuronal plasticity as well as to the molecular and cellular pathophysiology of monoamine-related neuropsychiatric disorders.

Animals↗

PubMedDate not supplied

Synaptophysin immunoreactivity in Pick's disease: comparison with Alzheimer's disease and dementia with Lewy bodies.

Frontotemporal lobe atrophy is a hallmark of Pick's disease (PiD), however, the underlying pathobiology of the neuronal losses is unknown. Synaptic losses have been described in Alzheimer's disease (AD) and correlate with the severity of dementia, however few studies of synaptic integrity have been done to determine whether synaptic loss also contributes to symptoms in non-AD dementias. To begin to assess synaptic integrity in other types of dementia, we examined the site of termination of the hippocampal perforant pathway, the major source of afferent tracts to the hippocampus. We determined immunoreactivity for the synaptic-terminal specific protein synaptophysin in the outer molecular layer of the hippocampal dentate gyrus (OMDG) in eight PiD, nine AD, nine dementia with Lewy bodies (DLB), and seven control cases. Quantitative data were obtained using an Image-Pro automated image analysis system. In AD and PiD, synaptophysin immunoreactivity was visibly reduced in the OMDG Densitometric analysis confirmed that there were statistically significant differences among groups in synaptophysin immunoreactivity when comparing the OMDG to the adjacent inner molecular layer of the hippocampal dentate gyrus (IMDG) (p = 0.002). These differences were present between PiD and both the control and DLB groups. The AD group also showed a reduction in synaptophysin immunoreactivity compared with DLB and control groups. In contrast, perforant pathway synaptic losses in DLB were minimal. Our data supports the hypothesis that focal synaptic losses occur in PiD and AD and may contribute to the cognitive deficits in both conditions.

Aged↗

PubMed1995

The topogenic fate of the polytopic transmembrane proteins, synaptophysin and connexin, is determined by their membrane-spanning domains.

The synaptophysins and connexins are polytopic transmembrane proteins of similar secondary structure that accumulate as multiple homo-oligomers in specialized membrane regions, the presynaptic transmitter vesicles or gap junctions. Transfection and expression of the respective genes in cultured epithelial cells results in the de novo formation of either small cytoplasmic, synaptophysin-rich vesicles, or functional gap junctions consisting of clustered connexin molecules. To examine the molecular requirements for the specific enrichment and topogenesis of both types of molecule, chimeric cDNAs were constructed composed of different parts of the rat synaptophysin and rat liver connexin32 genes. Expression of the encoded chimeric polypeptides in hepatocellular carcinoma-derived cells showed that only chimeras with all four transmembrane domains from either parent molecule were delivered to their specific destination. In contrast, chimeras with transmembrane domains from both connexin32 and synaptophysin were always retained in the endoplasmic reticulum. The topogenic nature of the transmembrane domains was further demonstrated by deletion mutagenesis, indicating that removal of cytoplasmic end domains or intravesicular loops does not abolish targeting. On the other hand, excision of individual transmembrane domains or introduction of point mutations in transmembrane segments resulted in retention in the endoplasmic reticulum.

Animals↗

PubMed1994

Redistribution of synapsin I and synaptophysin in response to electrical stimulation in the rat neurohypophysial nerve endings.

To understand the dynamics of synaptic vesicles and synapsin I, we have studied the localization of synapsin I and synaptophysin in resting and stimulated nerve endings by ultracryomicrotomy and colloidal gold-immunocytochemistry. First, we characterized microvesicles in resting nerve endings of the rat neurohypophysis, which was chosen as the model of nerve ending in this study. Synaptophysin was localized in microvesicles that were clustered beneath the plasma membrane. Quick-freeze deep-etching electron microscopy showed that short strands cross-linked microvesicles to each other, which highly resemble the structures observed in our studies of the presynaptic nerve terminals of central and peripheral nervous system and in vitro reconstitution of synapsin I and synaptic vesicles. Immunocytochemistry showed that synapsin I was localized to the region of cluster of microvesicles. Second, using this system, we examined localization of synapsin I and synaptophysin in nerve endings after electrical stimulation. Besides release of neurosecretory granules, clusters of microvesicles dissappeared and both microvesicles and synaptophysin were scattered over nerve endings. These changes were also confirmed by quick-freeze, freeze-substitution. Immunocytochemistry of the stimulated sample revealed that synapsin I was also scattered. The results show that microvesicles in neurohypophysis have similar characteristics of typical synaptic vesicles and synapsin I has a role as a scaffold to cross-link microvesicles to be clustered in resting nerve endings. This scaffold of synapsin I was disengaged after stimulation to redistribute microvesicles and synapsin I itself, which may be the mechanism of synapsin I to regulate the availability of synaptic vesicles for release.

Animals↗

PubMed1999

The significance of immunocytochemical markers, synaptophysin and neurofilaments in diagnosis of ganglioglioma.

Ganglioglioma is a tumor composed of neoplastic neurons and neoplastic glial cells mixed in different proportions. Astrocytes are the essential glial component. The tumor proliferates mostly in the temporal lobe cortex, scarcely in other areas of the brain. In ganglioglioma the population of ganglionic neurons is very difficult to diagnose. In the last ten years, immunocytochemical reaction with synaptophysin and neurofilament protein (NFP) triad considered as neoplastic neuron markers seemed to differentiate neoplastic nerve cells from normal neurons occurring incidentally within neoplastic proliferation area. In our study, the reaction with synaptophysin and NFP was performed on fragments of normal frontal lobe, pons and cerebellum as well as on fragments of post-operation tumor diagnosed as ganglioglioma. A positive synaptophysin reaction was obtained on the surface of neoplastic neurons in gangliogliomas, as well as on the surface of normal neurons in the encephalon, cerebellum and pons. Both neoplastic and normal neurons and their processes showed the expression of neurofilaments protein triad. Thus, a positive reaction of neurons with synaptophysin and NFP seems to be nonpathognomic in the diagnosis of the neoplastic neuron population in gangliogliomas.

Adult↗