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PubMed1998

Modulation of synapsin I gene expression in rat cortical neurons by extracellular matrix.

1. Neuronal differentiation depends on crosstalk between genetic program and environmental cues. In this study we tried to dissect this complex interplay by culturing neurons from fetal rat brain cortices in a chemically defined, neuron-specific, medium and on different substrata, either artificial (poly-D-lysine) or natural. 2. Among the extracellular matrix compounds used in this study, two (collagen I and fibronectin) allowed only a weak attachment of cortical neurons to the substratum, while the others (collagen IV, laminin, and basal lamina from Engelbreth-Holm-Swarm sarcoma) allowed both firm attachment and moderate to extensive neurite outgrowth from neuronal cell bodies. 3. By using synapsin I gene expression as a parameter of neuronal differentiation, we found that neurite outgrowth and neuronal differentiation are not linearly linked. Synapsin I gene expression, in fact, was maximal in neurons cultured on laminin, while the fastest neuritic outgrowth was recorded in cultures on poly-D-lysine. 4. The data presented in this paper are consistent with the hypothesis that the extracellular matrix plays an active role in modulating the differentiative program of neurons.

Animals↗
PubMed2002

A protein kinase A-dependent molecular switch in synapsins regulates neurite outgrowth.

Cyclic AMP (cAMP) promotes neurite outgrowth in a variety of neuronal cell lines through the activation of protein kinase A (PKA). We show here, using both Xenopus laevis embryonic neuronal culture and intact X. laevis embryos, that the nerve growth-promoting action of cAMP/PKA is mediated in part by the phosphorylation of synapsins at a single amino acid residue. Expression of a mutated form of synapsin that prevents phosphorylation at this site, or introduction of phospho-specific antibodies directed against this site, decreased basal and dibutyryl cAMP-stimulated neurite outgrowth. Expression of a mutation mimicking constitutive phosphorylation at this site increased neurite outgrowth, both under basal conditions and in the presence of a PKA inhibitor. These results provide a potential molecular approach for stimulating neuron regeneration, after injury and in neurodegenerative diseases.

Animals↗
PubMed2003

Human synapsin 1 gene promoter confers highly neuron-specific long-term transgene expression from an adenoviral vector in the adult rat brain depending on the transduced area.

Targeting therapeutic transgene expression to defined tissues is a major task in the development of safe and efficient gene therapy protocols. Recombinant adenovirus is an attractive vector because it can be prepared in huge quantity and new generation vectors possess very large cloning capacities combined with reduced immunogenicity. In the brain, adenovirus transduces mainly glial cells, making it difficult to use this vector system in applications that need expression of therapeutic proteins in neurons. Here, we show that by using a small fragment of the human synapsin 1 gene promoter, we were able to restrict transgene expression from an adenoviral vector exclusively to neurons. Furthermore, we obtained stable long-term transgene expression from this vector in striatum and thalamus at appropriate vector dose. Other promoters like the CMV and U1snRNA promoters also mediated transgene expression over several months, but mainly in glial cells. Although the NSE promoter was relatively neuron specific, it still expressed in glial cells also, and was clearly outperformed by the synapsin promoter with respect to transcriptional neuronal targeting. As an important feature of adenoviral-mediated gene transfer to the brain, we demonstrate that dopaminergic neurons of the substantia nigra do not allow for long-term expression from adenoviral vectors. Strikingly, these neurons appeared to specifically attenuate transgene expression by deleting the adenoviral genome.

Adenoviridae↗
PubMed1998

Differential increases in chromogranins, but not synapsin I, in cortical neurons following spreading depression: implications for functional roles and transmitter peptide release.

Experimental damage of cerebral cortex induces a slow-moving depolarization and subsequent depression of activity called cortical spreading depression (CSD) which is associated with various ionic, metabolic and genomic changes. Chromogranins are a family of water-soluble acidic proteins with a widespread distribution in secretory, large dense-core vesicles of neurons. We have earlier reported that secretogranin II (SgII) mRNA is increased in cerebral cortex hours after a unilateral craniotomy which would have induced CSD. To investigate further the regulation of chromogranin systems and the nature of genomic and biochemical changes produced by CSD, this study examined the temporal changes in chromogranin A (CgA), chromogranin B (CgB) and SgII mRNAs and CgB and SgII immunoreactivity (IR) in cerebral cortex and hippocampus following unilateral KCl-induced CSD. For comparison, the levels of mRNA for synapsin I, a protein present in small synaptic vesicles was also examined. Rats were killed at various times after 10 min or 2 h of CSD and levels of chromogranins mRNAs were determined by semiquantitative in situ hybridization histochemistry, while changes in corresponding peptide products were detected by immunohistochemistry. CSD increased both SgII and CgB mRNA levels in ipsilateral cortex--levels of SgII mRNA were significantly (P < 0.01) increased at 1-6 h after CSD (165-225% of levels in contralateral cortex), but were not significantly above control values at later time points. Increased expression of CgB mRNA was delayed and prolonged compared with SgII and was significantly (P < 0.05) increased between 3 and 24 h (120-145%) after CSD, peaked at 2 days (180%), and was still elevated at 1 week (130%) compared with contralateral cortex. No alteration in CgA mRNA was observed in the ipsilateral cortex of the same animals across the entire time-course except for an increase in piriform cortex at 1-2 days. In contrast, levels of synapsin I mRNA in affected cortex were identical to those in contralateral cortex and cortex in sham-operated rats, at all times after CSD. Levels of chromogranin (SN-IR and PE-11-IR) were also increased in ipsilateral cortex following CSD. A strong increase in SN-IR in neuronal cell bodies and fibres was observed at 12 h and a moderate increase in PE-11-IR was observed 24-72 h after CSD. These results demonstrate that chromogranin transcripts and gene products are differentially regulated by neuronal depolarization/depression occurring during CSD and suggest that these chromogranin proteins may have differing functional roles in peptide transmitter release and distinct effects on neuronal function in rat brain.

Animals↗
PubMed1995

Laminin and neuropeptide Y are increased by synapsin transfection in cultured NG108-15 neuroblastoma/glioma hybrid cells.

We have investigated the presence and expression of laminin and neuropeptide Y (NPY) in several NG108-15 cell lines transfected with synapsin Ib, IIa, or IIb. The content of laminin, a basal membrane glycoprotein that promotes adhesion and induces neurite out-growth and neuronal differentiation, was increased in all transfected cell lines examined. In cells that were chemically differentiated with prostaglandin E1 plus 3-isobutyl-1-methylxanthine, laminin levels were increased even further. The content of NPY, suggested to be a neurotransmitter/neuromodulator in peripheral sympathetic neurons as well as in central neurons, was also increased in all transfected cell lines examined. Immunohistochemical analysis combined with confocal laser microscopy showed that NPY staining was granular and very often enriched in neuritic varicosities. The distribution and the staining pattern of NPY were consistent with storage of NPY in large dense-cored vesicles. The results indicate that, in differentiated neurons, the synapsins increase the levels of a neuropeptide transmitter stored in large dense-cored vesicles and of an extracellular matrix protein associated with neuronal maturation.

Glioma↗
PubMed1994

Interaction of Grb2 via its Src homology 3 domains with synaptic proteins including synapsin I.

Grb2 is a 25-kDa adaptor protein composed of a Src homology 2 (SH2) domain and two flanking Src homology 3 (SH3) domains. One function of Grb2 is to couple tyrosine-phosphorylated proteins (through its SH2 domain) to downstream effectors (through its SH3 domains). Using an overlay assay, we have identified four major Grb2-binding proteins in synaptic fractions. These proteins interact with wild-type Grb2 but not with Grb2 containing point mutations in each of its two SH3 domains corresponding to the loss of function mutants in the Caenorhabditis elegans Grb2 homologue sem-5. Two of the proteins, mSos and dynamin, were previously shown to bind Grb2. The third protein of 145 kDa is brain specific and to our knowledge has not been previously described. The fourth protein is synapsin I. Dynamin is required for synaptic vesicle endocytosis and synapsin I is thought to mediate the interaction of synaptic vesicles with the presynaptic cytomatrix. These data suggest that Grb2, or other proteins containing SH3 domains, may play a role in the regulation of the exo/endocytotic cycle of synaptic vesicles and therefore of neurotransmitter release.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Association of schizophrenia in African Americans to polymorphism in synapsin III gene.

Linkage studies in families with schizophrenia have pointed to chromosome 22q12-q13 as one of several regions of the genome that may contain a susceptibility gene. The gene coding for synapsin III, an intrinsic synaptic vesicle membrane protein, maps to this target region. Two tightly linked single-nucleotide polymorphisms were recently found in a small subset of patients with SZ - a synonymous variant, L469L (469G>A), and a non-synonymous variant, S470N (470G>A) - which results in the loss of a mitogen-activated protein kinase serine phosphorylation site. We also found a slight increase in 470A in Caucasian patients from the US with schizophrenia. But, the sample size and allele frequency were too small to draw definitive conclusions. However, both single-nucleotide polymorphisms were much more polymorphic in African American controls than in Caucasian controls, thereby providing a better sample cohort to analyze for schizophrenia involvement. For the codon 469 single-nucleotide polymorphisms, a 50-fold increase was observed in the frequency of 469A in African Americans compared with Caucasians. Furthermore, there was an increase in the percentage of African American patients with schizophrenia who were homozygous for the 469A allele compared with controls who were homozygous (11 versus 5%; AA vs. all other genotypes - Fisher statistic=3.08, P=0.04, one-tailed). An increase in 470A heterozygotes was also found, but the results fell short of being statistically significant. The findings support a role for synapsin III in a subset of African American patients with schizophrenia and raises questions about selective pressure in Africa to account for the extraordinary disparity of the 469 and 470 single-nucleotide polymorphisms in different ethnic populations.

Black or African American↗
PubMed1986

Axonal transport of synapsin I- and cholinergic synaptic vesicle-like material; further immunohistochemical evidence for transport of axonal cholinergic transmitter vesicles in motor neurons.

The axonal transport of organelles in motor axons in the sympathectomized rat sciatic has been studied using two antisera which recognize specific components of synaptic vesicles. Anti-synapsin I recognizes synapsin I (SYN I) which is affiliated with the external membrane of synaptic vesicles, while rabbit-anti-synaptic vesicle antiserum (RASVA) recognizes integral membrane glycoproteins in cholinergic synaptic vesicles. Immunofluorescence studies, including cytofluorimetric scanning, show that immunoreactive (IR) material recognized by both antisera: rapidly accumulate proximal to a crush; the material has a granular appearance in the microscope; is redistributed in an isolated segment, and that the transport of the material is sensitive to vinblastine. Thus the proximodistal transport has the characteristics of fast axonal transport. Furthermore, recycling organelles, accumulating on the distal side of a crush are recognized by RASVA, but carry only very little SYN I-IR. The results give further support to the hypothesis that motor cholinergic axons transport axonal cholinergic vesicles towards the motor endplates.

Animals↗
PubMed1984

Synapsin I in nerve terminals: selective association with small synaptic vesicles.

Immunocytochemistry revealed that synapsin I is preferentially (and possibly exclusively) associated with small (40- to 60-nanometer) synaptic vesicles and not with large (greater than 60-nanometer) dense-core vesicles in bovine hypothalamus. These observations may explain why synapsin I is found exclusively in neurons, since small synaptic vesicles are specific to neurons whereas large dense-core vesicles in neurons may be considered the equivalent of secretory organelles in endocrine cells.

Animals↗
PubMed2004

Identification of a mutation in synapsin I, a synaptic vesicle protein, in a family with epilepsy.

A four generation family is described in which some men of normal intelligence have epilepsy and others have various combinations of epilepsy, learning difficulties, macrocephaly, and aggressive behaviour. As the phenotype in this family is distinct from other X linked recessive disorders linkage studies were carried out. Linkage analysis was done using X chromosome microsatellite polymorphisms to define the interval containing the causative gene. Genes from within the region were considered possible candidates and one of these, SYN1, was screened for mutations by direct DNA sequencing of amplified products. Microsatellite analysis showed that the region between MAOB (Xp11.3) and DXS1275 (Xq12) segregated with the disease. Two point linkage analysis demonstrated linkage with DXS1039, lod score 4.06 at theta = 0, and DXS991, 3.63 at theta = 0. Candidate gene analysis led to identification of a nonsense mutation in the gene encoding synapsin I that was present in all affected family members and female carriers and was not present in 287 control chromosomes. Synapsin I is a synaptic vesicle associated protein involved in the regulation of synaptogenesis and neurotransmitter release. The SYN1 nonsense mutation that was identified is the likely cause of the phenotype in this family.

Adolescent↗
PubMed1990

Synapsin-1 is found in a microtubule-associated complex of proteins isolated from bovine brain.

We have prepared microtubules from brain tissue by stabilizing the cellular microtubules in 6.7 M glycerol buffer, instead of the usual procedure which extracts the solubilized protein and then reassembles microtubules in vitro at some later time. There are substantial differences in the microtubule associated proteins obtained by the two methods, and brain spectrin is a major component of the stabilized microtubules. We have now modified the buffer used for the isolation of stabilized microtubules to minimize their tendency to aggregate. When the stabilized microtubules were further purified by sucrose density gradient centrifugation, we were able to distinguish previously unidentified polypeptides at 49, 74 (doublet), and 100 kilodaltons (doublet). These bands maintained staining intensity in the same proportion to tubulin as in the original homogenate, whereas background proteins were diminished in staining intensity. We now report the identification of the 74-kilodalton doublet polypeptides as synapsin-1 by peptide mapping. Synapsin-1 is a protein known to bind to brain spectrin and also to microtubules, and may thus serve as a linker between these cytoskeletal components.

Amino Acid Sequence↗
PubMed2001

Polymorphisms in the promoter and coding regions of the synapsin III gene. A lack of association with schizophrenia.

The human synapsin III gene, located on chromosome 22q12-13, has previously been reported to indicate a susceptibility for schizophrenia. Noval rare variants (Thr136Thr in exon 3, Pro468Ser, Glu525Gln and Pro534Leu in exon 12, and 1769 G/C in the untranslated region of exon 13) were found in addition to the polymorphic variant (-196 G/A in the promoter region). No significant differences in genotypic or allelic frequencies of the -196 G/A polymorphism were found between 87 unrelated schizophrenic patients and 100 healthy controls, even when the patients were diagnostically subdivided into subtypes and course specifiers. Furthermore, allelic frequencies of the GATG repeat in intron 1 were not significantly different between the patients and the controls. These results suggest that synapsin III gene polymorphisms are not associated with schizophrenia.

Adult↗
PubMed2006

Analysis of synapsin III-196 promoter mutation in schizophrenia and bipolar disorder.

BACKGROUND: The 22q13-linked gene synapsin III is a positional candidate gene for schizophrenia (SZ). One interesting synapsin III single nucleotide polymorphism (SNP), -196G/A, has been identified in the promoter region. The -196A allele results in a 6/8 base match to the core recognition octamer sequence for Oct-1, a member of the POU family of transcription factors. OBJECTIVE: To determine whether or not the -196 SNP is associated with either SZ or bipolar disorder (BD). METHODS: A case control comparison was used to determine whether or not differences in allele or genotype distribution occurred in patients with SZ and BD. Electromobility gel shift assay (EMSA) was used to determine whether the -196 SNP affected protein binding. RESULTS: A trend towards significance was detected when the allele distribution was analyzed in Caucasian patients with SZ (n = 145; 191 controls) and a cohort of subjects from the Czech Republic with BD (n = 82; 94 controls). No association was found in bipolar patients from the United States (n = 127) or in African-American patients with SZ (n = 124; 133 controls). EMSA showed that the region encompassing the -196 SNP binds to a brain protein in an allele-specific manner. CONCLUSIONS: These data, while inconclusive, suggest that -196 SNP should be further investigated as a candidate for 22q13-linked SZ.

Black or African American↗
PubMed2004

Using the atomic force microscope to study the interaction between two solid supported lipid bilayers and the influence of synapsin I.

To measure the interaction between two lipid bilayers with an atomic force microscope one solid supported bilayer was formed on a planar surface by spontaneous vesicle fusion. To spontaneously adsorb lipid bilayers also on the atomic force microscope tip, the tips were first coated with gold and a monolayer of mercapto undecanol. Calculations indicate that long-chain hydroxyl terminated alkyl thiols tend to enhance spontaneous vesicle fusion because of an increased van der Waals attraction as compared to short-chain thiols. Interactions measured between dioleoylphosphatidylcholine, dioleoylphosphatidylserine, and dioleoyloxypropyl trimethylammonium chloride showed the electrostatic double-layer force plus a shorter-range repulsion which decayed exponentially with a decay length of 0.7 nm for dioleoylphosphatidylcholine, 1.2 nm for dioleoylphosphatidylserine, and 0.8 nm for dioleoyloxypropyl trimethylammonium chloride. The salt concentration drastically changed the interaction between dioleoyloxypropyl trimethylammonium chloride bilayers. As an example for the influence of proteins on bilayer-bilayer interaction, the influence of the synaptic vesicle-associated, phospholipid binding protein synapsin I was studied. Synapsin I increased membrane stability so that the bilayers could not be penetrated with the tip.

Adsorption↗
PubMed1991

Immunocytochemical localization of synaptophysin (protein p38) and synapsin I in nerve terminals of rat neurohypophysis.

Synaptophysin and synapsin I, the synaptic vesicle-associated proteins, were demonstrated immunocytochemically in nerve terminals of the neurohypophysis of rats. Although both are associated with microvesicles 50-60 nm in diameter, they are not localized on or around the large neurosecretory granules nor the clear vacuoles, 100-200 nm in diameter. These findings strongly suggest that the microvesicles in the nerve terminal of the neurohypophysis are, for the most part, not the structures involved in the retrieval of the limiting membranes of the released neurosecretory granules, but rather typical synaptic vesicles. The clear vacuoles, which are negative for synaptophysin and synapsin I, are considered to be related to the retrieval of the limiting membranes of the released neurosecretory granules.

Animals↗
PubMed1991

Synapsin I and Synaptophysin expression during ontogenesis of the mouse peripheral vestibular system.

Synapsin I and Synaptophysin are selectively localized in axonal endings of CNS neurons where they are associated with small synaptic vesicle membranes. The development of expression of these 2 proteins was studied by immunocytochemistry during ontogenesis of the peripheral vestibular system in the mouse. Both proteins are localized in vestibular ganglion neurons and in their peripheral sensory extensions as early as gestational day 14. While the entire periphery of these fibers is labeled during embryogenesis, both proteins are subject to relocation during the postnatal maturation of these fibers. In the mature vestibular receptors they disappear from the fibers themselves but are found concentrated in their intraepithelial endings and in the neuronal cell body. These observations show that the distribution pattern of Synapsin I and Synaptophysin in peripheral extensions of vestibular afferent neurons during development is identical to that described in axonal processes of CNS neurons. This suggests that the peripheral processes of the vestibular afferent neurons present structural and biochemical characteristics of axons. These characteristics are consistent with a bimodal sensory and secretory function of mature endings.

Aging↗
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↗
PubMed1994

Antibodies to an epitope on synapsin I detect a protein associated with the endocytic compartment in non-neuronal cells.

To detect potential substrate proteins for Ca2+/calmodulin-dependent protein kinase II outside the central nervous system, antibodies were made to a synthetic peptide corresponding to a sequence within synapsin I which is phosphorylated by this enzyme. In neural tissues, this antibody (212) identified an 86/80 kDa doublet corresponding to synapsin I. In rat liver, intestinal enterocytes and the clone 9 cell line this antibody identified two proteins of 170 and 85 kDa. These proteins were present in the particulate fraction of liver postnuclear supernatant, and were released into the soluble fraction when extracted with 100 mM NaCl. In liver, enterocytes, and clone 9 cells, these antigens were localized by immunocytochemical techniques to small intracellular vesicles. The endocytic compartment of clone 9 cells was labeled by continuous uptake of horseradish peroxidase; antibody 212-labeled vesicles exhibited overlap with the compartment. To confirm the identity of this compartment as endosomal, rat liver endosomes were labeled in vivo by intravenous injection of horseradish peroxidase. Horseradish peroxidase-containing endosomes of approximately 80 nm were recognized by antibody 212. Occasionally, larger endosomes (approximately 300-500 nm) were also labeled. In clone 9 cells, partial overlap was observed between the 212 antigen and a transferrin receptor-positive, brefeldin A-sensitive compartment. In clone 9 cells double-labeled with anti-tubulin and antibody 212, then imaged using confocal microscopy, these vesicles appeared to be associated with microtubules. This antigen has properties similar to that of CLIP-170, a membrane-associated endosomal phosphoprotein. These findings demonstrate that a 170/85 kDa antigen containing an epitope for the Ca2+/calmodulin-dependent protein kinase II phosphorylation sequence is associated with an endocytic compartment.

Animals↗