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PubMed2001

Neuron-specific expression of therapeutic proteins: evaluation of different cellular promoters in recombinant adenoviral vectors.

In order to achieve neuron-restricted expression of antiapoptotic proteins, cellular promoters were investigated for their expression profiles in the context of adenoviral vectors. Both the synapsin 1 gene and the tubulin alpha1 gene promoters were strictly neuron specific in cocultures of primary neurons with their essential feeder cells. The neuron-specific enolase gene promoter exhibited only weak activity in cultured hippocampal neurons and was not neuron specific in preparations of cerebellar granule cells. By attaining virtually 100% transduction efficiency we were able to generate "quasi-transgenic" primary neuron cultures using both differentiated and completely undifferentiated hippocampal neurons. In a functional assay, we used the synapsin promoter to evaluate the effect of Bcl-X(L) overexpression on potassium-withdrawal-induced apoptosis of cerebellar granule neurons. We found nearly complete inhibition of caspase-9 and -3 activation and apoptosis, indicating a major role for mitochondrial pathways in this paradigm of neuronal cell death. The excellent suitability of the synapsin promoter as a strong panneuronal promoter was further demonstrated by its restricted neuronal activity in various brain regions of adult rats in vivo.

Adenoviridae↗
PubMed1999

Altered intramuscular innervation and synapse formation in internal sphincter achalasia.

Internal anal sphincter achalasia (IASA) is a condition with a clinical presentation similar to Hirschsprung's disease, but with the presence of ganglion cells on rectal biopsy. The diagnosis of IASA is made on anorectal manometry, which demonstrates the absence of a rectosphincteric reflux on rectal balloon inflation. In order to understand the nature of neuronal abnormalities in this condition, we performed immunohistochemistry using PGP 9.5 (a general neuronal marker) and synapsin I (a presynaptic marker) in IAS specimens from 10 patients with IASA and 8 normal controls. In the IAS of normal controls, there were many PGP 9.5 and synapsin I-positive nerve fibers. In IASA PGP 9.5-immunoreactive fibers were markedly reduced and synapsin I-positive fibers were either absent or markedly reduced. Our findings demonstrate that the IAS in achalasia patients has defective intramuscular innervation as well as defective innervation of the neuromuscular junction, thereby contributing to the motility dysfunction.

Anal Canal↗
PubMed1996

Distribution of Rab3a in rat nervous system: comparison with other synaptic vesicle proteins and neuropeptides.

In the present study we have investigated the distribution of Rab3a in rat peripheral nervous system and compared it with the distribution of other synaptic vesicle proteins (synaptophysin, synapsin I), neuropeptides (CGRP, SP, NPY) and tyrosine hydroxylase (TH). Rab3a immunoreactivity (-IR) was always colocalized with synaptophysin-IR and synapsin I-IR in nerve terminals of the spinal cord and peripheral nerve endings. In many cases, Rab3a-IR was also present in the same axons and terminals as peptides. In crushed sciatic nerve axons, Rab3a was colocalized, proximal to the crush, with synaptophysin-IR, synapsin I-IR, CGRP-IR, and TH-IR, but only partially co-localized with NPY-IR and SP-IR. In the area distal to the crush, Rab3a-IR was very weakly positive in a few thin axons, while larger amount of synaptophysin, CGRP, NPY and SP immunoreactivities were detected. The subcellular distribution of peptides and Rab3a differed in that peptides were observed mainly in large granular structures, while Rab3a-IR was observed mainly as diffuse, finely granular immunoreactivity, in addition to a few exceptional large granules present in some axons. The results demonstrate that Rab3a is widely distributed in different types of neurons, i.e. motor, sensory, autonomic adrenergic and cholinergic neurons, and colocalized with other synaptic vesicle proteins, suggesting that Rab3a may play an essential role in neuronal function. Furthermore, Rab3a is present in many peptide containing axons and terminals, but with an apparently different subcellular distribution, being affiliated mostly with small synaptic vesicles and only occasionally with large vesicles, that may represent peptide contained vesicles.

Animals↗
PubMed1996

Perinatal exposure to morphine: reactive changes in the brain after 6-hydroxydopamine.

The effects of neonatal 6-hydroxydopamine treatment on the brain of control rats and of rats perinatally exposed to morphine were examined. Noradrenaline levels were increased in the pons-medulla, mesencephalon and caudate of 8-week-old control rats lesioned with neonatal 6-hydroxydopamine; perinatal morphine treatment prevented such an increase. In the caudate, there was a loss of dopamine and an increase of serotonin following the neurotoxic lesion; exposure to perinatal morphine prevented the serotonin increase. Brain expression of synapsin I mRNA was particularly abundant in cerebral cortex, hippocampus, dentate gyrus and olfactory bulb. In perinatal morphine-treated rats, the expression of synapsin I mRNA was significantly reduced; interestingly, the neonatal treatment with 6-hydroxydopamine normalized its expression. Therefore, brain-reactive neurochemical changes triggered by 6-hydroxydopamine were suppressed by perinatal morphine exposure whereas the association of morphine exposure and 6-hydroxydopamine lesion promoted the normal mRNA expression of the synaptic marker synapsin I.

Adrenergic Agents↗
PubMed1991

Substance P and its fragments affect Ca2+/calmodulin-dependent synaptosomal membrane protein phosphorylation from rat cerebral cortex.

1. We have used synaptosomal membranes to study the influence of substance P and its fragments and analogues of its C-terminal fragment on Ca2+/calmodulin-dependent synapsin I endogenous phosphorylation. 2. SP1-11, SP1-4, [Tyr8]SP6-11 and [pGlu6, Tyr8]SP6-11 at 10(-3) M greatly inhibited synapsin I phosphorylation. 3. SP6-11 at all investigated concentrations and SP1-11, SP1-4, [Tyr8]SP6-11, [pGlu6, Tyr8]SP6-11 at 10(-4) and 10(-5) M were ineffective. 4. The results indicate that SP1-11 and its N-terminal fragment and analogues of its C-terminal fragment act on the phosphorylation of specific synaptic protein (synapsin I) and therefore may influence the release of neurotransmitters, membrane conductance and potentiation or inhibition of other signalling systems.

Animals↗
PubMed1994

Synaptotagmin I is present mainly in autonomic and sensory neurons of the rat peripheral nervous system.

The distribution of synaptotagmin I in the peripheral nervous system of the rat was investigated by immunofluorescence and confocal laser scanning microscopy. After crushing of the sciatic nerve, synaptotagmin I-like immunoreactivity accumulated proximally as well as distally to the crushes in thin and medium-sized axons. Double labelling studies revealed that synaptotagmin I co-localized with tyrosine hydroxylase, a marker of sympathetic adrenergic neurons, and with substance P, a marker for sensory neurons. No synaptotagmin I-like immunoreactivity was found in large axons, while accumulations of the synaptic vesicle proteins synaptophysin and synapsin I were found in all types of axons. Furthermore, no synaptotagmin I-like immunoreactivity was detected in motor endplates. In contrast, the protein was found in muscle spindles of young rats and in perivascular terminals, where it co-localized with synaptophysin and synapsin I. Lumbar sympathectomy resulted in a marked reduction of the amount and intensity of synaptotagmin I-like immunoreactivity in sciatic nerve. High magnification revealed that synaptotagmin I-like immunoreactivity was mainly distributed in a fine granular pattern, but large, brightly fluorescent granules which were not labelled by anti-synaptophysin or anti-synapsin I were occasionally observed. We conclude that synaptotagmin I is mainly expressed in adrenergic and sensory neurons and is absent from, or below detection levels, in motoneurons.

Animals↗
PubMed2005

Dissociation of synaptic zinc level and zinc transporter 3 expression during postnatal development and after sensory deprivation in the barrel cortex of mice.

In the neocortex, synaptic zinc level is regulated by sensory experience. Previously, we found that trimming of mystacial vibrissae resulted in an increase of synaptic zinc level in corresponding deprived barrels in the cortex of mice. The present study focused on the relationship between synaptic zinc and zinc transporter 3 (ZnT3) protein expression in the barrel cortex of mice during postnatal development and after sensory deprivation of selected vibrissae. Using immunocytochemistry and western blot analysis, we found that ZnT3 expression is delayed as compared with the onset of synaptic zinc and presynaptic markers, such as synapsin I and synaptophysin. Further, neither long-term deprivation in young mice nor short deprivation in adult mice, that resulted in an increase of synaptic zinc level, produced alterations in ZnT3, synapsin I or synaptophysin expression in deprived barrels. These results suggest that in the barrel cortex ZnT3, synapsin I or synaptophysin are not determinant for the activity-dependent regulation of the synaptic zinc level.

Age Factors↗
PubMed2006

Synaptic plasticity modulates the spontaneous recovery of locomotion after spinal cord hemisection.

Several evidences have demonstrated that adult mammals could achieve a wide range of spontaneous sensory-motor recovery after spinal cord injury by means of various forms of neuroplasticity. In this study we evaluated the possibility that after low-thoracic spinal cord hemisection in the adult rat, significant hindlimb locomotor recovery could occur, and that this recovery may be driven, at least in part, by mechanisms of synaptic plasticity. In order to address these issues, we measured the expression levels of synapsin-I and brain-derived neurotrophic factor by Western blotting, at various time points after hemisection and correlated them with the motor performance on a grid walk test. Regression analysis showed that the expression of synapsin-I was strongly correlated with the spontaneous recovery of hindlimb locomotion (R=0.78). Conversely, neither the expression levels of synapsin-I nor the locomotor recovery were associated with the expression of brain-derived neurotrophic factor. Overall results indicate that after spinal cord hemisection, substantial recovery of hindlimb locomotion could occur spontaneously, and that synaptic plasticity within spinal circuitries below the level of the lesion, could be an important mechanism involved in these processes.

Analysis of Variance↗
PubMed2003

Interplay between brain-derived neurotrophic factor and signal transduction modulators in the regulation of the effects of exercise on synaptic-plasticity.

This study was designed to identify molecular mechanisms by which exercise affects synaptic-plasticity in the hippocampus, a brain area whose function, learning and memory, depends on this capability. We have focused on the central role that brain-derived neurotrophic factor (BDNF) may play in mediating the effects of exercise on synaptic-plasticity. In fact, this impact of exercise is exemplified by our finding that BDNF regulates the mRNA levels of two end products important for neural function, i.e. cAMP-response-element binding (CREB) protein and synapsin I. CREB and synapsin I have the ability to modify neuronal function by regulating gene-transcription and affecting synaptic transmission, respectively. Furthermore, we show that BDNF is capable of concurrently increasing the mRNA levels of both itself and its tyrosine kinaseB (TrkB) receptor, suggesting that exercise may employ a feedback loop to augment the effects of BDNF on synaptic-plasticity. The use of a novel microbead injection method in our blocking experiments and Taqman reverse transcription polymerase reaction (RT-PCR) for RNA quantification, have enabled us to evaluate the contribution of different pathways to the exercise-induced increases in the mRNA levels of BDNF, TrkB, CREB, and synapsin I. We found that although BDNF mediates exercise-induced hippocampal plasticity, additional molecules, i.e. the N-methyl-D-aspartate receptor, calcium/calmodulin protein kinase II and the mitogen-activated protein kinase cascade, modulate its effects. Since these molecules have a well-described association to BDNF action, our results illustrate a basic mechanism through which exercise may promote synaptic-plasticity in the adult brain.

Analysis of Variance↗
PubMed2004

Voluntary exercise following traumatic brain injury: brain-derived neurotrophic factor upregulation and recovery of function.

Voluntary exercise leads to an upregulation of brain-derived neurotrophic factor (BDNF) and associated proteins involved in synaptic function. Activity-induced enhancement of neuroplasticity may be considered for the treatment of traumatic brain injury (TBI). Given that during the first postinjury week the brain is undergoing dynamic restorative processes and energetic changes that may influence the outcome of exercise, we evaluated the effects of acute and delayed exercise following experimental TBI. Male Sprague-Dawley rats underwent either sham or lateral fluid-percussion injury (FPI) and were housed with or without access to a running wheel (RW) from postinjury days 0-6 (acute) or 14-20 (delayed). FPI alone resulted in significantly elevated levels of hippocampal phosphorylated synapsin I and phosphorylated cyclic AMP response element-binding-protein (CREB) at postinjury day 7, of which phosphorylated CREB remained elevated at postinjury day 21. Sham and delayed FPI-RW rats showed increased levels of BDNF, following exercise. Exercise also increased phosphorylated synapsin I and CREB in sham rats. In contrast to shams, the acutely exercised FPI rats failed to show activity-dependent BDNF upregulation and had significant decreases of phosphorylated synapsin I and total CREB. Additional rats were cognitively assessed (learning acquisition and memory) by utilizing the Morris water maze after acute or delayed RW exposure. Shams and delayed FPI-RW animals benefited from exercise, as indicated by a significant decrease in the number of trials to criterion (ability to locate the platform in 7 s or less for four consecutive trials), compared with the delayed FPI-sedentary rats. In contrast, cognitive performance in the acute FPI-RW rats was significantly impaired compared with all the other groups. These results suggest that voluntary exercise can endogenously upregulate BDNF and enhance recovery when it is delayed after TBI. However, when exercise is administered to soon after TBI, the molecular response to exercise is disrupted and recovery may be delayed.

Animals↗
PubMed2002

RE-1 silencing transcription factor-4 (REST4) is neither a transcriptional repressor nor a de-repressor.

The zinc finger protein RE-1 silencing transcription factor (REST) is a transcriptional repressor that represses neuronal genes in non-neuronal tissues. A neuronal splice form of REST, termed REST4, has been described in the rat. It encompasses the N-terminus of REST, including the N-terminal repressor domain and five of the eight zinc fingers of the DNA-binding domain. The biological function of REST4 is controversial. Transcriptional repression as well as transcriptional de-repression activity has been attributed to the REST4 protein of rat. Here, we have expressed a 'humanized' version of REST4 (hREST4) to facilitate a comparison of the biological functions of hREST4 and REST. The biological activity the human REST protein has been extensively studied in the past. Additionally, hREST4 has a high degree of homology with the REST4 protein of rat. An immunofluorescence analysis showed that hREST4 is expressed in the nucleus, indicating that the protein may have a potential impact on gene regulation. We analyzed the biological function of hREST4 in NS20Y neuroblastoma cells using human synapsin I promoter/reporter gene constructs. The human synapsin I gene is negatively regulated by REST. The results show that hREST4, in contrast to the full-length human REST protein, does not impair human synapsin I promoter activity. Moreover, co-transfection experiments with expression vectors encoding REST and hREST4 did not reveal any evidence that REST4 blocks the transcriptional repression activity of REST.

Amino Acid Sequence↗
PubMed2003

RE-1 silencing transcription factor (REST) regulates human synaptophysin gene transcription through an intronic sequence-specific DNA-binding site.

Synaptophysin, one of the major proteins on synaptic vesicles, is ubiquitously expressed throughout the brain. Synaptophysin and synapsin I, another synaptic vesicle protein, are also expressed by retinoic acid-induced neuronally differentiated P19 teratocarcinoma cells. Here, we show that inhibition of histone deacetylase activity in P19 cells is sufficient to activate transcription of the synaptophysin and synapsin I genes, indicating that neuronal differentiation and impairment of histone deacetylases results in a similar gene expression pattern. The transcription factor REST, a repressor of neuronal genes in non-neuronal tissues, has been shown to function via recruitment of histone deacetylases to the transcription unit, indicating that modulation of the chromatin structure via histone deacetylation is of major importance for REST function and neuron-specific gene transcription. Furthermore, REST has been shown to be the major regulator of neuronal expression of synapsin I. Here, we have identified a functional binding site for REST in the first intron of the human synaptophysin gene indicating that REST blocks human synaptophysin gene transcription through an intronic neuron-specific silencer element. The synaptophysin promoter is, however, devoid of neuron-specific genetic elements and directs transcription in both neuronal and non-neuronal cells. Using a dominant-negative approach we have identified the transcription factor Sp1 as one of the regulators responsible for constitutive transcription of the human synaptophysin gene.

Amino Acid Sequence↗
PubMed1995

Production of monoclonal antibodies against neurofilament-associated proteins: demonstration of association with neurofilaments by a coimmunoprecipitation method.

A panel of monoclonal antibodies (MAbs) was produced against mouse brain proteins that bind to the tail domain of the neurofilament (NF) heavy (200-kDa) subunit (NF-H) in vitro. An in vivo association of the MAb ligands with NFs was confirmed by examining reactivity of the MAbs with immunoprecipitated NF-H complexes. Using this method we demonstrated association of the ligands of three of the MAbs with NFs. In contrast, glial fibrillary acidic protein and an unknown 97-kDa brain protein were not associated with NFs by this criterion. An 80-kDa doublet that coimmunoprecipitated with NF-H complexes, recognized by MAb 223, was shown by immunocytochemistry and immunoblotting to be synapsin Ia and Ib. Using a complementary approach, we confirmed an association of synapsin with NFs by demonstrating that immunoprecipitated synapsin I complexes contained NF-H and NF medium (160-kDa) subunits. MAbs 63 and 105 recognized a more complex set of proteins that had predominantly synaptic localizations. These data suggest that NFs may provide important support for attachment and/or transport of synaptic proteins in brain.

Animals↗
PubMed1990

Rabbit ileal villus cell brush border Na+/H+ exchange is regulated by Ca2+/calmodulin-dependent protein kinase II, a brush border membrane protein.

Ileal brush border membranes contain an endogenous Ca2+/calmodulin (CaM)-dependent protein kinase activity that modulates the activity of the apical membrane Na+/H+ exchanger. To further characterize this kinase, synapsin I, a substrate for Ca2+/CaM-dependent protein kinases, was added to preparations of ileal brush border membranes. In the presence of Ca2+/CaM, synapsin I was phosphorylated. Phosphopeptide mapping demonstrated that the addition of Ca2+/CaM to brush border membranes stimulated the phosphorylation of sites in synapsin I specific for Ca2+/CaM-dependent protein kinase II. Immunoblots containing brush border and microvillus membrane proteins were probed with an antibody that recognizes the 50-kDa subunit of rat brain Ca2+/CaM-dependent protein kinase II. This antibody labeled major and minor species of 50 and 53 kDa, respectively, with more labeling of the brush border than the microvillus membranes. Right-side-out ileal villus cell brush border vesicles were prepared containing CaM, ATP, and 350 nM free Ca2+. Na+/H+ exchange was inhibited by the presence of Ca2+/CaM/ATP within the vesicles. A 21-amino acid peptide inhibitor of CaM kinase II was enclosed within some vesicle preparations by freeze-thaw. The effect on Na+/H+ exchange of Ca2+/CaM/ATP was partially reversed by the inhibitor peptide. These studies demonstrate the presence of Ca2+/CaM-dependent protein kinase II in rabbit ileal villus cell brush border membranes. Based on the effect of a specific inhibitor peptide of Ca2+/CaM kinase II, it is concluded that this kinase inhibits brush border Na+/H+ exchange, which participates in the regulation of ileal Na+ absorption.

Animals↗
PubMed1986

Protein p38: an integral membrane protein specific for small vesicles of neurons and neuroendocrine cells.

An intrinsic membrane protein of brain synaptic vesicles with Mr 38,000 (p38, synaptophysin) has recently been partially characterized (Jahn, R., W. Schiebler, C. Ouimet, and P. Greengard, 1985, Proc. Natl. Acad. Sci. USA, 83:4137-4141; Wiedenmann, B., and W. W. Franke, 1985, Cell, 41:1017-1028). We have now studied the presence of p38 in a variety of tissues by light and electron microscopy immunocytochemistry and by immunochemistry. Our results indicate that, within the nervous system, p38, like the neuron-specific phosphoprotein synapsin I, is present in virtually all nerve terminals and is selectively associated with small synaptic vesicles (SSVs). No p38 was detectable on large dense-core vesicles (LDCVs). p38 and synapsin I were found to be present in similar concentrations throughout the brain. Outside the nervous system, p38 was found in a variety of neuroendocrine cells, but not in any other cell type. In neuroendocrine cells p38 was localized on a pleiomorphic population of small, smooth-surfaced vesicles, which were interspersed among secretory granules and concentrated in the Golgi area, but not on the secretory granules themselves. Immunoblot analysis of endocrine tissues and cell lines revealed a band with a mobility slightly different from that of neuronal p38. This difference was attributable to a difference in glycosylation. The finding that p38, like synapsin I, is a component of SSVs of virtually all neurons, but not of LDCVs, supports the idea that SSVs and LDCVs are organelles of two distinct pathways for regulated neuronal secretion. In addition, our results indicate the presence in a variety of neuroendocrine cells of an endomembrane system, which is related to SSVs of neurons but is distinct from secretory granules.

Animals↗
PubMed2004

Dietary omega-3 fatty acids normalize BDNF levels, reduce oxidative damage, and counteract learning disability after traumatic brain injury in rats.

Omega-3 fatty acids (i.e., docosahexaenoic acid; DHA) regulate signal transduction and gene expression, and protect neurons from death. In this study we examined the capacity of dietary omega3 fatty acids supplementation to help the brain to cope with the effects of traumatic injury. Rats were fed a regular diet or an experimental diet supplemented with omega-3 fatty acids, for 4 weeks before a mild fluid percussion injury (FPI) was performed. FPI increased oxidative stress, and impaired learning ability in the Morris water maze. This type of lesion also reduced levels of brain-derived neurotrophic factor (BDNF), synapsin I, and cAMP responsive element-binding protein (CREB). It is known that BDNF facilitates synaptic transmission and learning ability by modulating synapsin I and CREB. Supplementation of omega-3 fatty acids in the diet counteracted all of the studied effects of FPI, that is, normalized levels of BDNF and associated synapsin I and CREB, reduced oxidative damage, and counteracted learning disability. The reduction of oxidative stress indicates a benevolent effect of this diet on mechanisms that maintain neuronal function and plasticity. These results imply that omega-3 enriched dietary supplements can provide protection against reduced plasticity and impaired learning ability after traumatic brain injury.

Animals↗
PubMed2004

The interplay between oxidative stress and brain-derived neurotrophic factor modulates the outcome of a saturated fat diet on synaptic plasticity and cognition.

A diet high in saturated fat (HF) decreases levels of brain-derived neurotrophic factor (BDNF), to the extent that compromises neuroplasticity and cognitive function, and aggravates the outcome of brain insult. By using the antioxidant power of vitamin E, we performed studies to determine the role of oxidative stress as a mediator for the effects of BDNF on synaptic plasticity and cognition caused by consumption of the HF diet. Male adult rats were maintained on a HF diet for 2 months with or without 500 IU/kg of vitamin E. Supplementation of the HF diet with vitamin E dramatically reduced oxidative damage, normalized levels of BDNF, synapsin I and cyclic AMP-response element-binding protein (CREB), caused by the consumption of the HF diet. In addition, vitamin E supplementation preserved the process of activation of synapsin I and CREB, and reversed the HF-impaired cognitive function. It is known that BDNF facilitates the synapse by modulating synapsin I and CREB, which have been implicated in synaptic plasticity associated to learning and memory. These results show that oxidative stress can interact with the BDNF system to modulate synaptic plasticity and cognitive function. Therefore, studies appear to reveal a mechanism by which events classically related to the maintenance of energy balance of the cell, such as oxidative stress, can interact with molecular events that modulate neuronal and behavioural plasticity.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1985

Protein phosphorylation and neuronal function.

Studies in the past several years have provided direct evidence that protein phosphorylation is involved in the regulation of neuronal function. Electrophysiological experiments have demonstrated that three distinct classes of protein kinases, i.e., cyclic AMP-dependent protein kinase, protein kinase C, and CaM kinase II, modulate physiological processes in neurons. Cyclic AMP-dependent protein kinase and kinase C have been shown to modify potassium and calcium channels, and CaM kinase II has been shown to enhance neurotransmitter release. A large number of substrates for these protein kinases have been found in neurons. In some cases (e.g., tyrosine hydroxylase, acetylcholine receptor, sodium channel) these proteins have a known function, whereas most of these proteins (e.g., synapsin I) had no known function when they were first identified as phosphoproteins. In the case of synapsin I, evidence now suggests that it regulates neurotransmitter release. These studies of synapsin I suggest that the characterization of previously unknown neuronal phosphoproteins will lead to the elucidation of previously unknown regulatory processes in neurons.

Animals↗