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PubMed1996

Neuron-specific gene expression of synapsin I. Major role of a negative regulatory mechanism.

The synapsins are a family of neuron-specific phosphoproteins that selectively bind to small synaptic vesicles in the presynaptic nerve terminal. The human synapsin I gene was functionally analyzed to identify control elements directing the neuron-specific expression of synapsin I. By directly measuring the mRNA transcripts of a reporter gene, we demonstrate that the proximal region of the synapsin I promoter is sufficient for directing neuron-specific gene expression. This proximal region is highly conserved between mouse and human. Deletion of a putative binding site for the zinc finger protein, neuron-restrictive silencer factor/RE-1 silencing transcription factor (NRSF/REST), abolished neuron-specific expression of the reporter gene almost entirely, allowing constitutively acting elements of the promoter to direct expression in a non-tissue-specific manner. These constitutive transcriptional elements are present as a bipartite enhancer, consisting of the region upstream (nucleotides -422 to -235) and downstream (nucleotides -199 to -143) of the putative NRSF/REST-binding site. The latter contains a motif identical to the cAMP response element. Both regions are not active or are only weakly active in promoting transcription on their own and show no tissue-specific preference. From these data we conclude that neuron-specific expression of synapsin I is accomplished by a negative regulatory mechanism via the NRSF/REST binding motif.

Animals↗

PubMed2003

Synapsin I-associated phosphatidylinositol 3-kinase mediates synaptic vesicle delivery to the readily releasable pool.

Maintaining synaptic transmission requires replenishment of docked synaptic vesicles within the readily releasable pool (RRP) from synaptic vesicle clusters in the synapsin-bound reserve pool. We show that synapsin forms a complex with phosphatidylinositol 3-kinase (PI 3-kinase) in intact nerve terminals and that synapsin-associated kinase activity increases on depolarization. Disruption of either PI 3-kinase activity or its interaction with synapsin inhibited replenishment of the RRP, but did not affect exocytosis from the RRP. Thus we conclude that a synapsin-associated PI 3-kinase activity plays a role in synaptic vesicle delivery to the RRP. This also suggests that PI 3-kinase contributes to the maintenance of synaptic transmission during periods of high activity, indicating a possible role in synaptic plasticity.

Androstadienes↗

PubMed1995

Synapsin I deficiency results in the structural change in the presynaptic terminals in the murine nervous system.

Synapsin I is one of the major synaptic vesicle-associated proteins. Previous experiments implicated its crucial role in synaptogenesis and transmitter release. To better define the role of synapsin I in vivo, we used gene targeting to disrupt the murine synapsin I gene. Mutant mice lacking synapsin I appeared to develop normally and did not have gross anatomical abnormalities. However, when we examined the presynaptic structure of the hippocampal CA3 field in detail, we found that the sizes of mossy fiber giant terminals were significantly smaller, the number of synaptic vesicles became reduced, and the presynaptic structures altered, although the mossy fiber long-term potentiation remained intact. These results suggest significant contribution of synapsin I to the formation and maintenance of the presynaptic structure.

Animals↗

PubMed2000

Increment of synapsin I immunoreactivity in the hippocampus of the rat kindling model of epilepsy.

Synapsin is a vesicle-associated protein that is thought to be involved in synaptogenesis and neurotransmitter release. In this study, we investigated the repeated amygdala kindling-induced changes in levels of synapsin I, a marker of enhanced synaptic activity, using immunohistochemistry. Eight hours after the last seizure, synapsin I immunoreactivity (IR) was increased bilaterally in the polymorphic zone of the dentate gyrus, the hilus and the stratum lucidum in area CA3 of the hippocampus. However, 4 weeks after the last kindled seizures, synapsin I IR was not significantly changed in any of the brain regions studied. Therefore, the increased levels of synapsin I protein observed in these brain regions early after the last seizure may reflect the plastic changes that occur in the specific neural networks of the hippocampus directly after kindling-induced seizure activity.

Amygdala↗

PubMed1992

Synapsin I regulates glutamate release from rat brain synaptosomes.

Introduction of the dephosphorylated from of synapsin I into rat brain synaptosomes using freeze-thaw (transient) permeabilization significantly decreased the K(+)-induced release of glutamate. In contrast, introduction of synapsin I that had been phosphorylated by Ca2+/calmodulin-dependent protein kinase II was without effect on glutamate release. Addition of dephosphosynapsin I after freeze-thaw treatment also had no effect. Thus, the action of synapsin I was dependent on the phosphorylation state of synapsin I and on its entry into the synaptosomes. Our results implicate synapsin I as an important component in the regulation of neurotransmitter release in the mammalian nervous system.

Animals↗

PubMed1994

Aberrant neurites and synaptic vesicle protein deficiency in synapsin II-depleted neurons.

Synapsin I and synapsin II are neuron-specific phosphoproteins that have a role in the regulation of neurotransmitter release and in the formation of nerve terminals. After depletion of synapsin II by antisense oligonucleotides, rat hippocampal neurons in culture were unable to consolidate their minor processes and did not elongate axons. These aberrant morphological changes were accompanied by an abnormal distribution of intracellular filamentous actin (F-actin). In addition, synapsin II suppression resulted in a selective decrease in the amounts of several synaptic vesicle-associated proteins. These data suggest that synapsin II participates in cytoskeletal organization during the early stages of nerve cell development.

Actins↗

PubMed2002

Transforming growth factor beta1 alters synapsin distribution and modulates synaptic depression in Aplysia.

Transforming growth factor beta1 (TGF-beta1) induces long-term synaptic facilitation and long-term increases in excitability in Aplysia. Here we report that this growth factor has acute effects as well. Treatment of pleural-pedal ganglia with TGF-beta1 for 5 min activated mitogen-activated protein kinase (MAPK) and stimulated the phosphorylation of synapsin in a MAPK-dependent manner. This phosphorylation appeared to modulate synapsin distribution in cultured sensory neurons. Control neurons exhibited a punctate distribution of synapsin along neurites, which appeared to represent high concentration aggregates of synapsin. TGF-beta1-treated sensory neurons showed a significant reduction in the number of these puncta, an effect that was blocked by the MAP/ERK kinase inhibitor U0126. The functional consequence of TGF-beta1 was tested by examining its effects on synaptic transmission at the sensorimotor synapse. Application of TGF-beta1 reduced the magnitude of synaptic depression. This effect was dependent on MAPK, consistent with the hypothesis that TGF-1 mobilizes synaptic vesicles through the phosphorylation of synapsin.

Animals↗

PubMed1999

Synapsins as major neuronal Ca2+/S100A1-interacting proteins.

The mammalian S100A1 protein can activate the invertebrate myosin-associated giant protein kinase twitchin in a Ca(2+)-dependent manner by more than 1000-fold in vitro; however, no mammalian S100-dependent protein kinases are known. In an attempt to identify novel mammalian Ca(2+)/S100A1-regulated protein kinases, brain extracts were subjected to combined Ca(2+)-dependent affinity chromatography with S100A1 and an ATP analogue. This resulted in the purification to near-homogeneity of the four major synapsin isoforms Ia, Ib, IIa and IIb. All four synapsins were specifically affinity-labelled with the ATP analogue 5'-p-fluorosulphonylbenzoyladenosine. S100A1 bound to immobilized synapsin IIa in BIAcore experiments in a Ca(2+)-dependent and Zn(2+)-enhanced manner with submicromolar affinity; this interaction could be competed for with synthetic peptides of the proposed S100A1-binding sites of synapsin. Double-labelling confocal immunofluorescence microscopy demonstrated that synapsins and S100A1 are both present in the soma and neurites of PC12 cells, indicating their potential to interact in neurons in vivo.

Adenosine Triphosphate↗

PubMed2005

Estradiol modulates the synapsins phosphorylation by various protein kinases in the rat brain under in vitro and in vivo conditions.

Synapsins are the neuronal phosphoproteins which play very important role in processes of synaptic neurotransmission. They are physiological substrates for Ser/Thr protein kinases. The reversible phosphorylation of synapsins may be modified by several compounds including steroid hormones. The aim of our study was to investigate, if the one of neuroactive steroid--17beta-estradiol--could modulate the phosphorylation of synapsins by PKA, CaM-PK and PKC in rat brain and what type of mechanism of their action is possible. The activity of kinases was evaluated as phosphorylation of synapsin in cerebral cortex and hippocampus in vivo and in vitro conditions. We conclude that 17E2 has inhibitory effect on synapsins phosphorylation by all tested kinases in vitro and in vivo conditions. The lack of nuclei in synaptosomal membrane fraction and short time of hormone exposure can be evidence of direct, non-genomic mechanism of estradiol action.

Animals↗

PubMed1986

[Demonstration and localization of synapsin I in vestibular receptors in the cat: immunocytochemical study].

The presence and localization of synapsin I, a neuron-specific phosphoprotein, was investigated in the cat vestibular epithelium, using a rabbit antisynapsin I anti-serum. The staining was performed by immunofluorescence or by a peroxidase-antiperoxidase (PAP) technique. A strong immunoreactivity was observed with both methods. This immunoreactivity appeared as spherical patches distributed in the lower part of the epithelium. This distribution pattern is very similar to that of the efferent synaptic endings which form axodendritic synapses with the afferent nerve chalice of type I hair cells, or axosomatic synapses with type II hair cells. Some of the nerve chalices were also labelled; in this case, the immunoreactivity was more evident with PAP staining. These results thus suggest the presence of large amounts of synapsin I in the vestibular efferent nerve endings. These endings are known to be filled with numerous synaptic vesicles. This localization of synapsin I is well correlated with previous work that report a close association between synapsin I and small synaptic vesicles. The presence of synapsin I in sensory endings such as the afferent nerve chalices was unexpected and is under investigation.

Animals↗

PubMed1997

Enhanced dopamine release and phosphorylation of synapsin I and neuromodulin in striatal synaptosomes after repeated amphetamine.

Repeated, intermittent treatment of rats with amphetamine followed by a withdrawal period leads to an enhancement in amphetamine-induced dopamine release. We previously reported an increased stoichiometry of site 3-phospho-synapsin I and increased levels of phospho-Ser41-neuromodulin in striatum after repeated amphetamine. In this study, we examined whether the enhanced amphetamine-induced dopamine release and increased levels of these phosphoproteins would be detected in synaptosomes from rats pretreated and withdrawn from repeated amphetamine. Enhanced amphetamine-induced dopamine release was detected in striatal synaptosomes from rats treated with repeated amphetamine compared with controls. The enhanced dopamine release was Ca++ dependent. State-specific antibodies were used to measure the levels of site 3-phospho-synapsin I, phosphorylated by CaM kinase II, and phospho-Ser41-neuromodulin, phosphorylated by protein kinase C, in incubated striatal S1 fractions and synaptosomes. The levels of site 3-phospho-synapsin I and phospho-Ser41-neuromodulin were increased by 40% and 30%, respectively, in amphetamine-pretreated rats compared with controls. Total neuromodulin and synapsin I was not altered. There was a significant 26% increase in CaM kinase II activity in the synaptosomes from amphetamine-pretreated rats but no change in content. No change in protein kinase C activity or content of the alpha-isozyme was detected after repeated amphetamine. Our results demonstrate that the enhanced amphetamine-induced dopamine release and occurring after repeated amphetamine can be detected in synaptosome preparations. Repeated amphetamine leads to alterations in phosphorylation/dephosphorylation activities that can be detected in the incubated synaptosomes. Because the enhanced amphetamine-induced dopamine release after repeated amphetamine appears to be Ca++ sensitive, it is possible that the altered phosphorylation systems, and perhaps site 3-phospho-synapsin I and phospho-Ser41-neuromodulin, play a role in the enhanced dopamine release.

Amphetamine↗

PubMedDate not supplied

Immunohistochemistry of synapsin I and synaptophysin in human nervous system and neuroendocrine tumors. Applications in diagnostic neuro-oncology.

Synapsin I is a phosphoprotein localized to the cytoplasmic surface of synaptic vesicles and is one of the best characterized neuron-specific proteins. Synaptophysin is an integral membrane glycoprotein, also located on presynaptic vesicles, which has been shown to be a useful immunohistochemical marker for neuroendocrine/neuronal differentiation in tumor diagnosis. The sensitivity and specificity of immunohistochemical staining for these two proteins in formalin-fixed, paraffin-embedded tissues was studied in a series of 67 neuroectodermal, neuroendocrine, and non-neural tumors. Intense immunoreactivity for both synapsin I and synaptophysin was observed in tumors containing well-differentiated neurons (gangliocytoma, ganglioglioma, neurocytoma). In these tumors, immunostaining was primarily concentrated along the outer surface of the cell membrane of the neuronal cells. Primitive neuroectodermal tumors (PNETs) (cerebral PNET, medulloblastoma, neuroblastoma) and most neuroendocrine tumors generally showed less intense and more variable immunoreactivity for these proteins. In most cases, immunostaining for synapsin I was sharper and often more intense than for synaptophysin. Some PNETs and neuroendocrine tumors that were immunoreactive for synapsin I did not stain for synaptophysin. We conclude that synapsin I is a reliable, sensitive immunohistochemical marker for neuronal/neuroendocrine differentiation in human neoplasms and may offer some advantages over synaptophysin when applied to formalin-fixed, paraffin-embedded tissues, particularly in the evaluation of primitive neuroectodermal tumors and neuroendocrine tumors.

Brain Neoplasms↗

PubMed1990

Synapsin I-like immunoreactivity in nerve fibers associated with lingual taste buds of the rat.

Immunoreactivity to synapsin I, a neuronal phosphoprotein, was localized in free-floating tissue sections prepared from lingual tissue of rats. Many nerve fibers within the tissue exhibited clear immunoreactivity including motor endplates on striated muscle, autonomic fibers innervating blood vessels or glands, and sensory fibers innervating muscles or the lingual epithelium including taste buds. Numerous immunoreactive fibers occurred within each taste bud, with fewer, fine fibers being dispersed in the epithelium between taste buds. The majority of the intragemmal immunoreactive fibers extended throughout the taste buds most of the distance outward from the basal lamina toward the surface of the epithelium. Fine, perigemmal fibers reached nearly to the epithelial surface. Ultrastructural analysis of the immunoreactive sensory fibers revealed that synapsin I-immunoreactivity occurred diffusely throughout the cytoplasm, and heavily in association with microvesicles. The synaptic vesicles at the taste receptor cell-to-afferent fiber synapse were, however, not immunoreactive for synapsin I, although these vesicles fall into the size class shown to be immunoreactive in other systems. This absence of synapsin I may be a common property of vesicles in axonless short receptor cells.

Animals↗

PubMed1988

A domain of synapsin I involved with actin bundling shares immunologic cross-reactivity with villin.

Synapsin I is a neuronal phosphoprotein that can bundle actin filaments in vitro. This activity is under phosphorylation control, and may be related to its putative in vivo role of regulating the clustering and release of small synaptic vesicles. We have compared human and bovine synapsin I by peptide mapping, and have used NTCB (2-nitro-5-thiocyano benzoic acid) cleavage to generate a series of peptide fragments from bovine synapsin I. After chymotryptic digestion, 88% of the tyrosine-containing fragments appear to be structurally identical in human and bovine synapsin I, as judged by their positions on high-resolution two-dimensional peptide maps. The alignment of the NTCB peptides within the parent protein have been determined by peptide mapping, and the ability of these fragments to precipitate with actin bundles has been measured. Only peptides that are derived from regions near the ends of the protein are active. One such 25-kDa peptide which sediments with actin also cross-reacts with antibodies to chicken villin, an actin binding and bundling protein derived from the intestinal microvillus. Since in other respects villin appears to be an unrelated protein, these results suggest the possibility that certain actin binding proteins may show immunologic cross-reactivity due to convergent evolution within the acting binding domain.

Actins↗

PubMed1997

Identification, expression, and crystallization of the protease-resistant conserved domain of synapsin I.

A 35-37-kDa protease-resistant domain of synapsin Ia/ Ib, apparently produced by low levels of endogenous proteases in vapor diffusion droplets, slowly formed crystals diffracting X-rays to approximately 10 A resolution. The fragment mainly consisted of the highly conserved C domain common to the synapsin I/II family plus short N- and C-terminal flanking segments. Two constructs (SynA and SynB) of synthetic gene fragments coding for the C domain of synapsin with or without C-terminal flanking sequence were expressed in Escherichia coli as fusion proteins attached to the soluble protein glutathione-S-transferase. The fusion proteins were purified by affinity chromatography. Subsequent in situ cleavage with TEV protease resulted in the release of highly pure synapsin fragments, which were further purified by ion exchange chromatography. SynA and SynB formed crystals within three days, which diffracted to better than 3 A using a conventional X-ray source and to about 2 A using a synchrotron X-ray source. SynA crystals have the symmetry of the trigonal space groups P3(1)21 or P3(2)21 and the unit cell dimensions a = b = 77.4 A, c = 188.5 A, alpha = beta = 90 degrees, gamma = 120 degrees. SynB crystals have the symmetry of the orthorhombic space group C222(1) with the unit cell dimension a = 104.6 A, b = 113.3 A, and c = 273.8 A.

Crystallography, X-Ray↗

PubMed1996

Postsynaptic element contributes to the delay in synaptogenesis in synapsin I-deficient neurons.

In a previous study, we reported a retardation in process outgrowth and synapse formation in cultured hippocampal neurons from synapsin I-deficient mice. Here we investigated whether this delay in synaptogenesis was attributable to pre- or postsynaptic elements. The experimental paradigm used in this study involved the establishment of heterochronic cocultures of neurons from wild-type and synapsin I-deficient neurons established synapses with mature wild-type postsynaptic elements after 24 and 72 h, respectively. In contrast, synapsin I-deficient postsynaptic elements were able to receive synapses only after 9 days in culture, representing a 5-day delay compared to controls. The results suggest a broad role of synapsin I in the structural development of the synapse, participating directly or indirectly in the maturation of both presynaptic and postsynaptic sites.

Animals↗

PubMed1993

Rapid binding of synapsin I to F- and G-actin. A study using fluorescence resonance energy transfer.

Synapsin I is a nerve terminal phosphoprotein which interacts with synaptic vesicles and actin in a phosphorylation-dependent manner. By using fluorescence resonance energy transfer between purified components labeled with fluorescent probes, we now show that the binding of synapsin I to actin is a rapid phenomenon. Binding of synapsin I to actin can also be demonstrated when synaptic vesicles are present in the medium and appears to be modulated by ionic strength and synapsin I phosphorylation.

Actins↗

PubMed1991

Reduced in vitro phosphorylation of synapsin I (site 1) in Alzheimer's disease postmortem tissues.

Homogenates prepared from the temporal cortex and hippocampus of individuals who had histopathologically confirmed Alzheimer's disease exhibited reduced in vitro cyclic AMP-dependent phosphorylation of synapsin I, neuronal phosphoprotein. One specific phosphorylation site (site 1) was affected while two other sites, which are phosphorylated by calcium/calmodulin kinase II, exhibited no such differences. Other phosphoproteins such as pyruvate dehydrogenase, did not show these differences. The reductions were not observed in either cerebellum or thalamus of Alzheimer's disease brain. Analysis by immunoblots indicated that the reductions were not caused by a decrease in absolute amounts of the protein. The reduced AD synapsin I phosphorylation was not overcome by the addition of purified cyclic AMP-dependent protein kinase. No differences were detected in total cyclic AMP-dependent protein kinase activity between the control and Alzheimer samples. However, dephosphorylation of the synapsin I prior to the in vitro phosphorylation reversed the differences observed between the control and AD homogenates. Thus, the reduced in vitro phosphorylation of the synapsin I in the Alzheimer homogenate reflects a reduced phosphorylatability of the protein due to either an increased phosphate content or some other alteration of the phosphorylation site.

Alzheimer Disease↗