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PubMed2006

Chronic vitamin D3 treatment protects against neurotoxicity by glutamate in association with upregulation of vitamin D receptor mRNA expression in cultured rat cortical neurons.

The vitamin D receptor (VDR) is believed to mediate different biologic actions of vitamin D3, an active metabolite of vitamin D, through regulation of gene expression after binding to specific DNA-response element (VDRE) on target genes. To further understand roles of both vitamin D3 and VDR in the central nervous system, we examined VDRE binding in nuclear extracts prepared from discrete rat brain regions and cultured rat cortical neurons by electrophoretic mobility shift assay. The highest activity of VDRE binding was found in the cerebellum among other brain regions examined, but sequence specific by taking into consideration the efficient competition with excess unlabeled VDRE but not with mutated VDRE. On in situ hybridization analysis, cells stained for VDR mRNA were abundant in neuron-enriched areas of cerebral cortex, hippocampus and cerebellar cortex in the mouse brain. Chronic treatment of vitamin D3 increased the expression of microtubule-associated protein-2, growth-associated protein-43 and synapsin-1 in cultured rat cortical neurons, suggesting a trophic role of vitamin D3 in differentiation and maturation of neurons. Neuronal cell death by brief glutamate exposure was significantly protected in cultured cortical neurons chronically treated with vitamin D3. Parallel studies showed that VDR mRNA was significantly upregulated 12-24 hr after brief glutamate exposure in cultured neurons chronically treated with vitamin D3, but not in those with vehicle alone. Our results suggest that vitamin D3 may play a role in mechanisms relevant to protective properties against the neurotoxicity of glutamate through upregulation of VDR expression in cultured rat cortical neurons.

Animals↗

PubMed1986

Developmental features of rat cerebellar neural cells cultured in a chemically defined medium.

We studied some aspects of the differentiation of rat cerebellar neural cells obtained from 8-day postnatal animals and cultured in a serum-free, chemically defined medium (CDM). The ability of the cells to take up radioactive transmitter amino acids was analyzed autoradiographically. The L-glutamate analogue 3H-D-aspartate was taken up by astroglial cells, but not by granule neurons, even in late cultures (20 days in vitro). This is in agreement with the lack of depolarization-induced release of 3H-D-aspartate previously observed in this type of culture. In contrast, 3H-(GABA) was scarcely accumulated by glial-fibrillary-acidic-protein (GFAP)-positive astrocytes, but taken up by glutamate-decarboxylase-positive inhibitory interneurons and was released in a Ca2+-dependent way upon depolarization: 3H-GABA evoked release progressively increased with time in culture. Interestingly, the expression of the vesicle-associated protein synapsin I was much reduced in granule cells cultured in CDM as compared to those maintained in the presence of serum. These data would indicate that in CDM the differentiation of granule neurons is not complete, while that of GABAergic neurons is not greatly affected. Whether the diminished differentiation of granule cells must be attributed only to serum deprivation or also to other differences in the composition of the culture medium remains to be established. 3H-GABA was avidly taken up also by a population of cells which were not recognized by antibodies raised against GFAP, glutamate decarboxylase, and microtubule-associated protein 2. These cells exhibited a stellate morphology, were stained by the monoclonal antibody A2B5, and have been characterized elsewhere [Levi et al, 1986] as bipotential precursors of oligodendrocytes and of a subpopulation of astrocytes bearing a stellate shape and capable of high-affinity 3H-GABA uptake.

Animals↗

PubMed1992

Development of calcitonin-gene-related peptide, chromogranin A, and synaptic vesicle markers in rat motor endplates, studied using immunofluorescence and confocal laser scanning.

The presence of calcitonin-gene-related peptide (CGRP) and chromogranin A was investigated in the developing rat (E18-adult) motor system, using immunofluorescence and confocal laser scanning, and compared with synaptic vesicle markers, synaptophysin and synapsin I. In lumbar motor perikarya CGRP-LI and Chr A-LI were present in high intensities in E18 and P1 perikarya in the anterior horn. With increasing age immunoreactivity decreased. Chr A-LI was sparse in the adult. In peroneal endplates, p38-LI and SYN I-LI were present in all stages, including E18. Peptide-LI was very weak or absent in early stages (E18 and P1), but abundant in P8 and P18, especially CGRP-LI, and decreased again in P32 and adult animals. These observations indicate that the peptides have precise functions during certain developmental stages, possibly related to synapse maturation, receptor concentration, and reduction of supernumerary endplates. Both peptides are rapidly transported anterogradely in adult motor axons, and may serve physiological functions also in the adult.

Animals↗

PubMed1988

Neonatal deafferentation prevents normal expression of synaptic vesicle antigens in the developing rat superior cervical ganglion.

The effect of neonatal deafferentation of the rat superior cervical ganglion (SCG) on the expression of two synaptic vesicle proteins was studied to assess the role of transsynaptic influences in the regulation of these neural antigens in the SCG. The two proteins studied were a 65 kilodalton integral membrane protein of synaptic vesicles (SV), and synapsin-1 (S-1), a synaptic vesicle phosphoprotein. Antigen levels were quantified by radioimmunoassay using antibodies directed against the proteins. Distribution of SV in control, deafferented and reinnervated ganglia from 30-day-old rats was visualized by immunohistochemical labeling. Levels of both antigens were reduced following deafferentation of the SCG on postnatal days 1-3. The reduction in S-1 levels at 30 days was less than that observed for SV. The amount of S-1 remaining in deafferented ganglia was consistent with estimates of the postsynaptic pool in the SCG reported previously. SV levels, in contrast, were reduced to 24% of control levels, suggesting that SV synthesis in principal ganglionic neurons might be affected. The time course of postnatal development of S-1 in the SCG differed from previous studies of SV expression, with significant increases occurring after the second week after birth. The differences in response to deafferentation may reflect functional differences of the two vesicle-associated proteins. These studies demonstrate that transsynaptic regulation of antigens other than those directly associated with neurotransmitters occurs in the SCG.

Animals↗

PubMed1988

Quantitation of nerve terminal populations: synaptic vesicle-associated proteins as markers for synaptic density in the rat neostriatum.

This study has assessed the contributions of the corticostriatal fibers, the ascending striatopetal fibers, and the intrinsic neostriatal neurons to the nerve terminal population found in the rat neostriatum (caudatoputamen). For this purpose, we have analysed the levels of two different synaptic vesicle-associated proteins, synapsin I and protein p38 (also called synaptophysin), in the neostriatum after specific lesions. Our results indicate that 45-50% of the synaptic vesicle proteins in the rat neostriatum derive from the corticostriatal fibers, that approximately 25-30% of the synaptic vesicle proteins are present in kainic acid-sensitive structures, presumably intrinsic terminals and local collaterals, and that ascending fibers contain 20-25% of the vesicle-associated proteins in the neostriatum. These three neuronal populations therefore comprise 95-100% of the synaptic vesicle-associated proteins in the rat neostriatum, and thus make up most of the nerve terminals in this brain region. The results, which are in general agreement with previous morphometric studies on the rat basal ganglia, therefore indicate that nerve terminals in the central nervous system can be quantitated by use of these biochemical nerve terminal markers. The results also indicate that a somewhat higher percentage of neostriatal nerve terminals belongs to the corticostriatal fibers that previously believed.

Animals↗

PubMed2000

Effect of 17-beta-estradiol and progesterone on angiotensin II-induced changes in inositol-1,4,5-trisphosphate content and protein kinase C activity in anterior pituitary.

Angiotensin II (AngII) is known to act in the anteriorpituitary through phosphatidiloinositol breakdown, increasing the level of inositol-1,4,5-trisphosphate (IP(3)) and diacyloglycerol (DAG), a potential activator of protein kinase C (PKC). We examined the effect of estradiol and progesterone treatment in vivo on IP(3) levels and activity of PKC under the influence of AngII. Three groups of intact female rats received in vivo injections of 17-beta-estradiol, progesterone, and oil (control) for five days, and then the in vitro effect of AngII was examined using homogenate of the anterior pituitary. AngII increased either the IP(3) concentration or the synapsin I phosphorylation catalyzed by PKC. Estradiol enhanced the basal (without AngII) IP(3) level and PKC activity induced by AngII. Progesterone did not change the basal and AngII-induced IP(3) concentrations. On the other hand, it decreased the basal PKC activity and blocked the effect of AngII. Our data suggest that ovarian steroids can modulate the effect of AngII on the anterior pituitary gland.

Angiotensin II↗

PubMed1998

Rabies virus entry into endosomes in IMR-32 human neuroblastoma cells.

Early events in rabies virus entry into cultured IMR-32 human neuroblastoma cells were investigated. After adsorption of rabies virus to the cell surface in the cold and warming to 37 degrees C in the presence of tracers for early endosomes, rabies virus and tracers were localized by immunofluorescence microscopy. After 5 min, rabies virus colocalized with Lucifer Yellow, Texas Red-dextran, rhodamine-wheat germ agglutinin, and transferrin receptor in puncta in the cell body, neurites, and nerve terminals. Rabies virus did not colocalize with lysosomal glycoprotein. An acidotropic probe revealed that some of the virus-containing puncta were acidified. Rabies virus also colocalized with synapsin I, a synaptic vesicle marker, in swellings along processes, indicating some virus enters nerve terminals. Electron microscopy revealed the presence of rabies virus within irregular membrane compartments located near the cell surface in the cell body and neurites. The membrane of the virus particle was often continuous with that of the vacuole. It is concluded that rabies virus enters IMR-32 neuroblastoma cells by adsorptive endocytosis and that, shortly after entry, rabies virus is located within and fuses with acidic endosomes.

Adsorption↗

PubMed2002

Reduced cortical synaptic plasticity and GluR1 expression associated with fragile X mental retardation protein deficiency.

Lack of expression of the fragile X mental retardation protein (FMRP), due to silencing of the FMR1 gene, causes the Fragile X syndrome. Although FMRP was characterized previously to be an RNA binding protein, little is known about its function or the mechanisms underlying the Fragile X syndrome. Here we report that the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor subunit, GluR1, was decreased in the cortical synapses, but not in the hippocampus or cerebellum, of FMR1 gene knockout mice. Reduced long-term potentiation (LTP) was also found in the cortex but not in the hippocampus. Another RNA binding protein, FXR; the N-methyl-D-aspartate receptor subunit, NR2; and other learning-related proteins including c-fos, synapsin, myelin proteolipid protein, and cAMP response element binding protein were not different between FMR1 gene knockout and wild-type mice. These findings suggest that the depressed cortical GluR1 expression and LTP associated with FMRP deficiency could contribute to the Fragile X phenotype.

Animals↗

PubMed2002

Adenoviral-mediated, high-level, cell-specific transgene expression: a SYN1-WPRE cassette mediates increased transgene expression with no loss of neuron specificity.

Viral vectors are excellent tools for studying gene function in the brain, although a limitation has been the ability to effectively target transgene expression to specific neuronal populations. This generally cannot be overcome by the use of neuron-specific promoters, as most are too large to be used with current viral vectors and expression from these promoters is often relatively weak. We therefore developed a composite expression cassette, comprising 495 bp of the weak human SYN1 (synapsin-1) promoter and 800 bp of the woodchuck hepatitis virus posttranscriptional regulatory element (WPRE). Studies in hippocampal cultures, organotypic cultures, and in vivo showed that the 3' addition of the WPRE to the SYN1 element greatly increased enhanced green fluorescent protein expression levels with no loss of neuronal specificity. In vivo studies also showed that transgene expression was enhanced with no loss of neuronal specificity in dentate-gyrus neurons for at least 6 weeks following transfection. Therefore, unlike most powerful promoter systems, which mediate expression in neurons and glia, this SYN1-WPRE cassette can target powerful long-term transgene expression to central nervous system neurons when delivered at relatively low titers of adenovirus. Its use should therefore facilitate both gene therapy studies and investigations of neuronal gene function.

Adenoviridae↗

PubMed1992

The characteristics of blood-brain barrier in three different conditions--infarction, selective neuronal death and selective loss of presynaptic terminals--following cerebral ischemia.

We investigated the extravasation of serum albumin using immunohistochemistry in three different conditions, i.e., infarction, selective neuronal death and selective loss of presynaptic terminals following cerebral ischemia in gerbils. In selective neuronal death, which is typically found in the CA1 neurons of the hippocampus after 5-min bilateral cerebral ischemia, selective damage of postsynaptic components with intact presynaptic sites was demonstrated by immunohistochemical examination for microtubule-associated protein 2 and synapsin I, and albumin extravasation did not become apparent before postsynaptic structures were destroyed. In cerebral infarction, which was consistently observed in the thalamus after 15-min forebrain ischemia, massive albumin extravasation was visible early after ischemia due probably to the ischemic endothelial necrosis. In selective loss of presynaptic terminals, which was detected at the molecular layer of the dentate gyrus in the contralateral, nonischemic hippocampus after unilateral cerebral ischemia, immunoreaction for albumin was not visualized. Since endothelium and glial cells were intact in morphological aspects in selective damage of both pre- and postsynaptic sites, it was thought that extravasation was facilitated by the stimulation of endothelial cells and glial cells with unknown factors that were induced by the destruction of post- but not presynaptic elements.

Albumins↗

PubMed1994

Characterization of GABAergic neurons in hippocampal cell cultures.

The morphological characteristics of GABAergic neurons and the distribution of GABAergic synaptic terminals were examined in cultures of hippocampal neurons from 4-35 days in vitro. Neurons expressing GABA immunoreactivity represented about 6% of the total number of cultured neurons at all time points. Although the morphological characteristics of GABAergic cells suggested a heterogeneous population, GABAergic cells as a class were notably different from the non-GABAergic, presumably pyramidal cells. Most GABAergic cells had more fusiform or polygonal shaped somata, non-spiny and less tapering dendrites and appeared more phase-dense than nonGABAergic cells. Quantitative analysis revealed that GABAergic cells had fewer primary dendrites, more elongated dendritic arbors, and longer dendritic segments than non-GABAergic neurons-characteristics that are similar to GABAergic cells in situ. Double immunostaining revealed that GAD65-positive varicosities were also immunopositive for synapsin I, suggesting that GAD65-positive varicosities that contacted somata and dendrites represented presynaptic specializations. Confocal microscopy revealed the proportion of the synaptic specializations on the cell soma that were GAD65-positive was greater than on the dendrites, suggesting that somata and dendrites differ in their ability to induce the formation of presynaptic specializations by GABAergic axons. These data indicate that the GABAergic cells that develop in culture exhibit distinctive morphological characteristics and participate in different synaptic interactions that nonGABA cells. Thus many of the features that distinguish GABAergic neurons in culture are reminiscent of the characteristics that distinguish GABAergic neurons in situ.

Animals↗

PubMed1994

Concomitant protein phosphorylation and endogenous acetylcholine release induced by nicotine: dependency on neuronal nicotinic receptors and desensitization.

1. Nicotine stimulated two Ca(2+)-dependent processes in rat frontal cortex synaptosomes: the phosphorylation of an 80-kDa protein band and the release of endogenous ACh.3 Both effects were mediated by neuronal nAChRs and coincided with depolarization of the synaptosomal plasma membrane induced by the drug. Changes in the state of phosphorylation of the 80-kDa band (presumed to contain synapsin I) were correlated with changes in the release of ACh as follows, from 2 to 4. 2. Blockade of predominant, nerve terminal P-type Ca2+ channels with omega-agatoxin-IVA, did not prevent nicotine from stimulating ACh release. In contrast, exposure to the toxin partially inhibited the release promoted by the depolarizing agent veratridine and attenuated protein phosphorylation induced by either nicotine or veratridine. Taken together, these data suggest that, upon nicotine stimulation. Ca2+ enters nerve terminals through two distinct pathways. The first, via Ca2+ channels, is necessary (but not sufficient) for both nicotine-induced phosphorylation and ACh release. The second, both necessary and sufficient for nicotine-induced phosphorylation and release, is the neuronal nAChR itself. 3. Preincubation of the synaptosomes with a subeffective concentration of nicotine inactivated both nicotine-induced ACh liberation and phosphorylation. This shows that diminished release is associated to decreased phosphorylation of the 80-kDa protein band, most likely as a consequence of nicotine-promoted nAChR desensitization. 4. Augmented ACh release and phosphorylation of the 80-kDa protein band were achieved by using the protein phosphatase inhibitor okadaic acid. However, okadaic acid did not summate with either nicotine or veratridine to increase ACh release further. This is probably because okadaic acid, as in other neurons, increases intracellular Ca2+ (Cholewinski et al., 1993), thus promoting desensitization of ACh release.

Acetylcholine↗

PubMedDate not supplied

A subtractive cDNA library from an identified regenerating neuron is enriched in sequences up-regulated during nerve regeneration.

We have constructed a subtractive cDNA library from regenerating Retzius cells of the leech, Hirudo medicinalis. It is highly enriched in sequences up-regulated during nerve regeneration. Sequence analysis of selected recombinants has identified both novel sequences and sequences homologous to molecules characterised in other species. Homologies include alpha-tubulin, a calmodulin-like protein, CAAT/enhancer-binding protein (C/EBP), protein 4.1 and synapsin. These types of proteins are exactly those predicted to be associated with axonal growth and their identification confirms the quality of the library. Most interesting, however, is the isolation of 5 previously uncharacterised cDNAs which appear to be up-regulated during regeneration. Their analysis is likely to provide new information on the molecular mechanisms of neuronal regeneration.

Amino Acid Sequence↗

PubMed1998

Expression of Rab3A GTPase and other synaptic proteins is induced in differentiated NT2N neurons.

Postmitotic NT2N cells, which are derived from human NT2 teratocarcinoma cells by treatment with retinoic acid (RA) and mitotic inhibitors, are viewed as a good in vitro model for mature neurons of the human central nervous system. Although NT2N cells exhibit many morphological and biochemical characteristics of neurons, the expression of key protein components involved in regulated exocytosis have not been firmly established. Here we show by immunoblot analysis that mature morphologically differentiated NT2N cells contain readily detectable quantities of the synaptic vesicle-associated proteins, synaptobrevin, synapsin, and synaptophysin. They also express the presynaptic plasma membrane protein, SNAP-25, and a Rab GTPase implicated in the control of Ca(2+)-dependent exocytosis, Rab3A. These proteins were not detected in untreated NT2 cells or cells exposed to RA for only 6 d. The induction of an array of proteins known to be involved in the docking and fusion of synaptic vesicles with the plasma membrane provides further support for the validity of NT2N cells as a model for human cortical neurons and suggests that these cells may be useful for in vitro molecular studies of the Ca(2+)-regulated exocytic pathway in nerve terminals.

Biomarkers, Tumor↗

PubMedDate not supplied

Neuronal phosphoproteins. Mediators of signal transduction.

This article summarizes some of our knowledge concerning intracellular protein phosphorylation pathways in nerve cells. It also summarizes, very briefly, recent direct experimental evidence involving intracellular injection of protein kinases, protein kinase inhibitors, and substrates, indicating that protein phosphorylation mediates the actions of a variety of neurotransmitters on their target cells. Finally, it summarizes in somewhat greater detail the results of studies of three different types of substrate proteins that appear to regulate different types of biological responses in nerve cells: synapsin I, a substrate protein present in virtually all nerve terminals, which appears to regulate neurotransmitter release from those nerve terminals; the acetylcholine receptor, the phosphorylation of which regulates its rate of desensitization in the presence of acetylcholine; and DARPP-32, the phosphorylation of which converts it into a very potent phosphoprotein phosphatase inhibitor that may be involved in the regulation by the neuromodulator dopamine of the effects of the neurotransmitter glutamate. The identification and characterization of additional neuronal phosphoproteins can be expected to lead to the clarification of numerous additional molecular mechanisms by which signal transduction is carried out in nerve cells.

Animals↗

PubMed2002

Abnormal synaptic protein expression and cell death in murine scrapie.

Reduced expression of synaptophysin p38, synaptic-associated protein of molecular weight 25,000 (SNAP-25), syntaxin-1, synapsin-1, and alpha- and beta-synuclein, matching the distribution of spongiform degeneration, was found in the neurological phase of scrapie-infected mice. In addition, synaptophysin and SNAP-25 were accumulated in isolated neurons, mainly in the thalamus, midbrain and pons, and granular deposits of alpha- and beta-synuclein were present in the neuropil of the same areas. No modifications in the steady state levels of Bcl-2, Bax, Fas and Fas ligand were observed following infection. Yet antibodies against the c-Jun N-terminal peptide, which cross-react with products emerging after caspase-mediate proteolysis, recognize coarse granular deposits in the cytoplasm of reactive microglia. In situ end-labeling of nuclear DNA fragmentation showed positive nuclei with extreme chromatin condensation in the thalamus, pons, hippocampus and, in particular, the granular layer of the cerebellum. More importantly, expression of cleaved caspase-3, a major executioner of apoptosis, was seen in a few cells in the same regions, thus indicating that cell death by apoptosis in scrapie-infected mice is associated with caspase-3 activation. The present findings support the concept that synaptic pathology is a major substrate of neurological impairment and that caspase-3 activation may play a pivotal role in apoptosis in experimental scrapie. However, there is no correlation between decreased synaptic protein expression and caspase-3-associated apoptosis, which suggests that in addition to abnormal prion protein deposition, there may be other factors that distinctively influence synaptic vulnerability and cell death in murine scrapie.

Animals↗

PubMed2001

Juvenile neuroaxonal dystrophy in a Rottweiler: accumulation of synaptic proteins in dystrophic axons.

Dystrophic axons in a 2-year-old male Rottweiler with neuroaxonal dystrophy have shown synaptophysin, synapsin-I, synaptosomal-associated protein of 25 kDa (SNAP-25), Rab 3a, and alpha-synuclein immunoreactivity. Similar findings have been observed in isolated dystrophic axons in the nuclei gracillis and cunneatus in five dogs aged between 14 and 18 years. Abnormal expression of integral synaptic vesicle, synaptic vesicle-associated presynaptic plasma membrane and cytosolic proteins, which participate in the trafficking, docking and fusion of the synaptic vesicle to the plasma membrane, suggest severe disruption of axonal transport in dystrophic axons in canine neuroaxonal dystrophy.

Animals↗

PubMed1983

Substrate specificity of liver calmodulin-dependent glycogen synthase kinase.

A number of proteins were tested as potential substrates for purified rabbit liver calmodulin-dependent glycogen synthase kinase. It was found that liver phenylalanine hydroxylase and several brain proteins including tyrosine hydroxylase, microtubule-associated protein 2, and synapsin I were readily phosphorylated. Brain tubulin was very poorly phosphorylated. These results suggest that calmodulin-dependent glycogen synthase kinase may be a more general protein kinase involved in the regulation of several cellular Ca2+-dependent functions.

Animals↗