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At least 523 records · Page 29Linked to original sources
PubMed1993

Calcium/calmodulin-dependent protein kinase II regulates hippocampal synaptic transmission.

Extracellular application of protein kinase inhibitors was used to examine the role of calcium/calmodulin-dependent protein kinase II (CaM-KII) in synaptic transmission in the CA1 region of rat hippocampus. Bath application of the broad spectrum, membrane permeable kinase inhibitor H7 (250 microM) decreased excitatory synaptic responses elicited in hippocampal slices. Whereas H7 inhibits several protein kinases and has non-specific effects, several synthetic peptides have been developed as specific inhibitors of CaM-KII. Using in situ phosphorylation in hippocampal slices, we demonstrate that extracellular application of synthetic peptide inhibitors of CaM-KII preferentially suppresses the phosphorylation of synapsin I at the CaM-KII specific site. This suppression was not reversed by the application of a calcium ionophore indicating the decrease in phosphorylation does not result only from blockade of presynaptic calcium influx. Thus, it appears the peptides gain access to intracellular compartments and retain their inhibitory properties. Further, we found that extracellular application of these peptide inhibitors decreased excitatory synaptic responses elicited in the CA1 region of hippocampal slices with relative potencies consistent with their ability to block CaM-KII activity in vitro. Peptide application did not alter the input resistance of postsynaptic cells nor responses elicited by glutamate iontophoresis. These results suggest that CaM-KII activity, possibly through phosphorylation of presynaptic synapsin I, is required for sustained synaptic transmission at mammalian synapses.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1994

Cytochemical polarity in lateral geniculate interneurons.

To determine the cytochemical composition of presynaptic dendrites, we have examined the distribution of synapsin 1, calcium and calmodulin-dependent protein kinase II (CaM-II), microtubule-associated protein 2 (MAP-2) and spectrin in cat lateral geniculate (LGN) class III cells by immune-EM. Special attention was paid to the dendrites of these interneurons because they are both pre- and postsynaptic. The dendritic proteins MAP-2 and RBC spectrin were not observed in interneuron dendrites but these proteins were localized in relay cell dendrites. The synaptic vesicle-associated protein synapsin 1 was present in all synaptic vesicle containing profiles, including dendritic terminals. CaM-II, the major postsynaptic density protein, was found in all dendrites. Thus, the LGN interneuron dendritic compartment displays both axonal and dendritic cytochemical properties. The results suggest the possibility of unique molecular interactions in interneuron dendritic terminals.

Animals↗
PubMed1992

The indusium griseum in Alzheimer's disease: an immunocytochemical study.

The immunocytochemical features of the indusium griseum (IG) were compared with the corresponding hippocampus in 5 patients with Alzheimer's disease (AD) and 5 age-matched nondemented individuals using antibodies against beta-amyloid, the A68 protein (Alz-50 antibody), tau, ubiquitin and synapsin I. beta-Amyloid-positive plaques were prominent in the AD hippocampus but were not present in the IG. Numerous Alz-50, tau and ubiquitin-positive neurofibrillary tangles and dystrophic neurites were observed in the AD hippocampus but were infrequent in the IG. Synapsin I immunoreactivity was significantly reduced in both the AD hippocampus and the AD IG when compared to age-matched patients. These findings suggest that the IG may be resistant to factors that trigger production of abnormal AD-associated proteins. Loss of synaptic input alone may not account for the AD-associated changes in the hippocampus since synaptic depletion was seen in both the hippocampus and the unaffected AD IG.

Aged↗
PubMed1990

DARPP-32 development in the caudate nucleus is independent of afferent input from the substantia nigra.

DARPP-32, a dopamine- and adenosine 3':5'-monophosphate regulated neuronal phosphoprotein, Mr 32 kDa, is a phenotypic marker of the medium-size spiny neurons of the mammalian caudate-putamen. In the present study, we examined the ontogeny of DARPP-32 protein and mRNA, and compared it to the ontogeny of tyrosine hydroxylase and synapsin I, a synaptic-vesicle phosphoprotein. In vivo, the amount of DARPP-32 protein per mg total protein increased throughout the first three postnatal weeks, and then declined to plateau at adult levels. The mRNA level closely paralleled the protein, except that its rise preceded that of the protein. Tyrosine hydroxylase levels rose throughout the first 4 postnatal weeks, and synapsin I levels rose steadily during the same period. Primary reaggregate cultures containing cells from the caudate-putamen expressed DARPP-32 with a time course similar to that seen in vivo. The level of expression was not altered by coculturing with dopaminergic neurons from the rostral mesencephalic tegmentum. Thus, the postnatal increase in DARPP-32 levels in the caudate-putamen appears to be independent of transsynaptic or end-organ influences from the substantia nigra.

Animals↗
PubMed1987

Immunohistochemical studies on synapse formation by embryonic cerebellar tissue transplanted into the cerebellum of the weaver mutant mouse.

Normal cerebellar tissue, obtained from 15-day-old CBA/JNCij mouse embryos, was transplanted into the cerebellum of 4-week-old weaver mice. At the 6th week after the transplantation, the grafted tissue was distinguishable from the host cerebellum, developing a trilaminar organization. The formation of synapses by the implanted granule cells was analyzed immunohistochemically with antiserum against synaptic vesicle protein, Synapsin I. Some areas in the host cerebellum as well as in the grafted tissue were intensely stained by anti-Synapsin I serum, suggesting that the implanted granule cells make synaptic contacts with the neuronal cells.

Animals↗
PubMed1995

Ageing affects cytosolic Ca2+ binding proteins and synaptic markers in the retina but not in cerebral cortex neurons of the rat.

Two cerebral cortex areas (frontal and occipital) and the retina of rats varying in age from 0.4 to 30 months were investigated for the expression levels and distribution of two cytosolic high affinity Ca2+ binding proteins, calbindin-28 and calretinin, and of two presynaptic protein markers. Of these latter proteins, one is integral (synaptophysin) the other peripheral (synapsin I) to the synaptic vesicle membranes. In the cortex areas, no significant changes of the markers were observed, except for a drop of calretinin from 0.4 to 2 months, probably related to a stage of neuronal development. In the retina, calbindin-28 decreased progressively during ageing (-40% at 30 months) while calretinin remained unchanged. Concomitantly, the two synaptic vesicle proteins dropped, synaptophysin > 50% and synapsin I > 85%. The role of these changes in sustaining the functional alterations previously described in the retina of aged animals remains to be investigated.

Aging↗
PubMed1989

Dopamine-regulated phosphorylation of synaptic vesicle-associated proteins in rat neostriatum and substantia nigra.

Dopamine, acting through dopamine D1 receptors and cyclic AMP-dependent protein kinase, has been found to increase the state of phosphorylation of the synaptic vesicle-associated phosphoproteins synapsin I and protein III in slices of rat neostriatum and substantia nigra. In the neostriatum, the effect of dopamine was mimicked by SKF 38393, a D2 receptor agonist, and was abolished by preincubation of the slices with fluphenazine or SCH 23390, antipsychotic drugs which are potent D1 receptor antagonists, but not by the D2 receptor antagonists l-sulpiride or spiroperidol. The maximal effect of dopamine in the neostriatum represented approximately 30-35% of the maximal effect induced by 8-bromo cyclic AMP, suggesting that a similar fraction of nerve terminals in the neostriatum may express the dopamine D1 receptor. Evidence for a small population of beta-adrenergic receptors regulating nerve terminal protein phosphorylation in the neostriatum, distinct from the D1 dopamine receptors, was also obtained. In the substantia nigra, the effect of dopamine also appeared to be mediated through a D1 dopamine receptor, since it was abolished by fluphenazine and SCH 23390. The maximal effect of dopamine in the substantia nigra represented approximately two-thirds of the effect induced by 8-bromo cyclic AMP, suggesting that a similar fraction of nerve terminals in the substantia nigra may express the dopamine D1 receptor. The ability of dopamine D1 receptor activation to stimulate both synapsin I and protein III phosphorylation and GABA release in both the neostriatum and substantia nigra may be causally linked.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1988

The organization of cytoplasm at the presynaptic active zone of a central nervous system synapse.

The axoplasm at the presynaptic active zone of excitatory synapses between parallel fibers and Purkinje cell spines contains a meshwork of distinct filaments intermingled with synaptic vesicles, seen most clearly after the rapid freezing, freeze-etch technique of tissue preparation. One set of filaments extends radially from synaptic vesicles and intersects similar filaments associated with vesicles as well as larger filaments arising from the presynaptic membrane. The small, vesicle-associated filaments appear to link synaptic vesicles to one another and to enmesh them in the vicinity of the synaptic junction. The vesicle-associated filaments could be synapsin I because they have the same molecular dimensions and are distributed in the same pattern as synapsin I immunoreactivity.

Animals↗
PubMed1993

The transglutaminase hypothesis for the action of tetanus toxin.

Tetanus toxin potently and almost irreversibly inhibits the release of neurotransmitters from nerve terminals. The toxin binds to and activates transglutaminase, a Ca(2+)-dependent enzyme that can form stable crosslinks between substrate proteins. Transglutaminase is present in nerve terminals and recognizes synapsin I, an abundant synaptic vesicle phosphoprotein involved in neurotransmission, as an excellent substrate. The neuroparalytic action of tetanus toxin might be due, at least in part, to the stimulation of synaptic transglutaminase and the consequent crosslinking of synapsin I.

Animals↗
PubMed2005

Exercise restores levels of neurotrophins and synaptic plasticity following spinal cord injury.

We have conducted studies to determine the potential of exercise to benefit the injured spinal cord using neurotrophins. Adult rats were randomly assigned to one of three groups: (1) intact control (Con); (2) sedentary, hemisected at a mid-thoracic level (Sed-Hx), or (3) exercised, hemisected (Ex-Hx). One week after surgery, the Ex-Hx rats were exposed to voluntary running wheels for 3, 7, or 28 days. BDNF mRNA levels on the lesioned side of the spinal cord lumbar region of Sed-Hx rats were approximately 80% of Con values at all time points and BDNF protein levels were approximately 40% of Con at 28 days. Exercise compensated for the reductions in BDNF after hemisection, such that BDNF mRNA levels in the Ex-Hx rats were similar to Con after 3 days and higher than Con after 7 (17%) and 28 (27%) days of exercise. After 28 days of exercise, BDNF protein levels were 33% higher in Ex-Hx than Con rats and were highly correlated (r=0.86) to running distance. The levels of the downstream effectors for the action of BDNF on synaptic plasticity synapsin I and CREB were lower in Sed-Hx than Con rats at all time points. Synapsin I mRNA and protein levels were higher in Ex-Hx rats than Sed-Hx rats and similar to Con rats at 28 days. CREB mRNA values were higher in Ex-Hx than Sed-Hx rats at all time points. Hemisection had no significant effects on the levels of NT-3 mRNA or protein; however, voluntary exercise resulted in an increase in NT-3 mRNA levels after 28 days (145%). These results are consistent with the concept that synaptic pathways under the regulatory role of BDNF induced by exercise can play a role in facilitating recovery of locomotion following spinal cord injury.

Animals↗
PubMed2005

Dietary curcumin counteracts the outcome of traumatic brain injury on oxidative stress, synaptic plasticity, and cognition.

The pervasive action of oxidative stress on neuronal function and plasticity after traumatic brain injury (TBI) is becoming increasingly recognized. Here, we evaluated the capacity of the powerful antioxidant curry spice curcumin ingested in the diet to counteract the oxidative damage encountered in the injured brain. In addition, we have examined the possibility that dietary curcumin may favor the injured brain by interacting with molecular mechanisms that maintain synaptic plasticity and cognition. The analysis was focused on the BDNF system based on its action on synaptic plasticity and cognition by modulating synapsin I and CREB. Rats were exposed to a regular diet or a diet high in saturated fat, with or without 500 ppm curcumin for 4 weeks (n = 8/group), before a mild fluid percussion injury (FPI) was performed. The high-fat diet has been shown to exacerbate the effects of TBI on synaptic plasticity and cognitive function. Supplementation of curcumin in the diet dramatically reduced oxidative damage and normalized levels of BDNF, synapsin I, and CREB that had been altered after TBI. Furthermore, curcumin supplementation counteracted the cognitive impairment caused by TBI. These results are in agreement with previous evidence, showing that oxidative stress can affect the injured brain by acting through the BDNF system to affect synaptic plasticity and cognition. The fact that oxidative stress is an intrinsic component of the neurological sequel of TBI and other insults indicates that dietary antioxidant therapy is a realistic approach to promote protective mechanisms in the injured brain.

Analysis of Variance↗
PubMed2005

Generation of lentiviral transgenic rats expressing glutamate receptor interacting protein 1 (GRIP1) in brain, spinal cord and testis.

In neuroscience, rats have several advantages over mice as a model organism. For instance, behavioral experiments are more advanced and the larger size of the brain is better suited for surgical manipulation and biochemistry. Furthermore, the vascular physiology of rats is considered closer to human, providing clinical relevance. Because transgenesis rates achieved by conventional pronuclear injection are extremely low (0.2-3.5%), the availability of transgenic rats in neuroscience is limited. Lentivirus infection is an efficient way to integrate exogenous genes into the genome of a one-cell embryo to generate transgenic animals. We report here the generation of synapsin I promoter driven GRIP1-transgenic rats using lentiviral transgenesis. GRIP1 was chosen as a transgene because it interacts with AMPA receptors and is involved in glutamate receptor signaling. From a single infection experiment, 45% of the offspring carried the transgene and 40% achieved germ-line transmission. The expression of GRIP1 was observed at low levels in brain, spinal cord and testis. Interestingly, one transgenic copy lacked a 147 bp fragment in the GRIP1 coding region most likely caused by alternative splicing of genomic lentiviral RNA. Co-immunoprecipitation from rat brains showed that transgenic GRIP1 is in complex with the endogenous GluR2 subunit of AMPA receptors. These results indicate that functional transgenic GRIP1 protein is expressed in rat brain using lentiviral vectors containing a human synapsin I promoter. Tissue specific lentiviral transgenic rats will be a powerful tool for various applications in modern neuroscience.

Amino Acid Sequence↗
PubMed2004

Exercise reverses the harmful effects of consumption of a high-fat diet on synaptic and behavioral plasticity associated to the action of brain-derived neurotrophic factor.

A diet high in total fat (HF) reduces hippocampal levels of brain-derived neurotrophic factor (BDNF), a crucial modulator of synaptic plasticity, and a predictor of learning efficacy. We have evaluated the capacity of voluntary exercise to interact with the effects of diet at the molecular level. Animal groups were exposed to the HF diet for 2 months with and without access to voluntary wheel running. Exercise reversed the decrease in BDNF and its downstream effectors on plasticity such as synapsin I, a molecule with a key role in the modulation of neurotransmitter release by BDNF, and the transcription factor cyclic AMP response element binding protein (CREB), important for learning and memory. Furthermore, we found that exercise influenced the activational state of synapsin as well as of CREB, by increasing the phosphorylation of these molecules. In addition, exercise prevented the deficit in spatial learning induced by the diet, tested in the Morris water maze. Furthermore, levels of reactive oxygen species increased by the effects of the diet were decreased by exercise. Results indicate that exercise interacts with the same molecular systems disrupted by the HF diet, reversing their effects on neural function. Reactive oxygen species, and BDNF in conjunction with its downstream effectors on synaptic and neuronal plasticity, are common molecular targets for the action of the diet and exercise. Results unveil a possible molecular mechanism by which lifestyle factors can interact at a molecular level, and provide information for potential therapeutic applications to decrease the risk imposed by certain lifestyles.

Animals↗
PubMed2001

Differential changes in synaptic terminal protein expression between nucleus accumbens core and shell in the amphetamine-sensitized rat.

Repeated, intermittent administration of psychostimulant drugs such as D-amphetamine (AMPH) produces a state of behavioral sensitization to the drug that can last up to weeks to months. The molecular basis of this enhanced sensitivity to AMPH is poorly understood; however, adaptive changes in the mesocorticolimbic dopamine system has been postulated to be of primary importance. In the present investigation we used Western blotting to examine the expression of candidate presynaptic proteins involved in regulating neurotransmitter release and synaptic plasticity. Specifically, syntaxin 1, synaptophysin and synapsin I protein levels were examined in the nucleus accumbens (Nacc) and ventral tegmental area (VTA) of Sprague-Dawley rats following AMPH-sensitization. Animals received five repeated administrations of AMPH (1.5 mg/kg, i.p. on alternate days) followed by 14 days of withdrawal. Levels of syntaxin 1 and synaptophysin were found to be significantly reduced in the Nacc core of sensitized animals compared to saline-treated and untreated controls. However, syntaxin 1 expression was significantly increased in the Nacc shell subregion of sensitized animals. No significant difference in the level of synapsin I was noted in any of the brain regions. Further, expression of none of the synaptic proteins was significantly altered in the VTA of sensitized animals. Given the importance of syntaxin and synaptophysin in learning and memory processes and in the regulation of neurotransmitter release, changes in these proteins suggest their involvement in the associative learning aspects of sensitization and differential neurotransmitter release in the Nacc subregions.

Amphetamine-Related Disorders↗
PubMed2003

Polarized targeting of IgLON cell adhesion molecule OBCAM to dendrites in cultured neurons.

Opioid-binding cell adhesion molecule (OBCAM) belongs to the immunoglobulin superfamily CAMs and shows a dendritically polarized distribution in hypothalamic magnocellular neurons. In the present study, the cellular localization of OBCAM was monitored in cultured cortical and hippocampal neurons to examine its polarized distribution. Double labeling immunofluorescence microscopy after fixation showed only faint OBCAM immunoreactivity in the neuronal somata during the early stages of culture, whereas the immunoreactivity was strong in MAP2-positive somata and dendrites of fully polarized neurons after longer culture. Moreover, the immunoreactivity for OBCAM showed a punctate pattern in the dendrites similar to the immunostaining pattern of synapsin I. High resolution revealed close apposition with only a partial overlap of synapsin I and OBCAM immunoreactivities, suggesting the synaptic localization of OBCAM to the dendrites. When the fully polarized neurons were reacted with anti-OBCAM antibody before fixation, OBCAM immunoreactivity became stronger on the dendritic surface than the somatic surface. Extracellular immunoreactivity was eliminated with phosphatidylinositol-specific phospholipase C and this immunoreactivity resisted extraction with the nonionic detergent Triton X-100 at 4 degrees C, indicating that OBCAM is attached to the rafts via a glycosylphosphatidyl inositol anchor. These results indicate that OBCAM is efficiently targeted to the dendritic surface of fully polarized cortical and hippocampal neurons. OBCAM is, hence, concluded to be a dendrite-associated CAM in cortical and hippocampal neurons as in hypothalamic magnocellular neurons.

Animals↗
PubMed1999

Immunohistochemical demonstration of a neuronal calmodulin-binding protein, NAP-22, in the rat spinal cord.

Neuron-enriched acidic protein having a molecular mass of 22 kDa, NAP-22, is a newly isolated calmodulin-binding protein and is phosphorylated with protein kinase C (PKC). This protein is localized to biological membrane via myristoylation and found in the membrane fraction of the brain and in the synaptic vesicle fraction. To reveal the NAP-22 distribution in vivo, we investigated the spinal cord of the 4-5-week old rats using light and electron microscopy. NAP-22 immunoreactivity was observed in the gray matter with dorsoventral gradient of reactivity. Distinct reactivity was demonstrated in the nerve terminals and dendritic spines. Some reactions were also observed in the thin nerve fibers. NAP-22 immunoreactivity was associated mainly with pre- and postsynaptic membranes, synaptic vesicles and outer mitochondrial membranes. In the nerve terminals, NAP-22 was colocalized with synaptic vesicle proteins such as synapsin I or synaptobrevin 2. About 80% of the nerve terminals having immunoreactivity for synapsin I or synaptobrevin 2 showed NAP-22 immunoreactivity. From these results, NAP-22 is confirmed to be distributed in the synaptic region of the spinal cord and is involved in the synaptic function relating to PKC.

Animals↗
PubMed2000

Selective regional loss of exocytotic presynaptic vesicle proteins in Alzheimer's disease brains.

We tested whether regional or selective alterations in presynaptic proteins occur in Alzheimer's disease (AD) and correlate with tests of cognitive function. We measured the levels of seven presynaptic proteins (synaptobrevin, synaptotagmin, SNAP-25, syntaxin, SV2, Rab3a, and synapsin I) by immunoblotting in postmortem tissue from four brain regions (hippocampus, entorhinal cortex, caudate nucleus, and occipital cortex). Three subject groups were studied: AD, possible/early AD (p-AD), and age-matched controls. Synaptobrevin and synaptotagmin were significantly reduced (29%, P<0.08; 38%, P<0. 07) in hippocampus in p-AD compared to controls. In definite AD compared to controls, selective regional reductions in vesicle proteins were found: synaptobrevin (46%, P<0.05), synaptotagmin (52%, P<0.01), and Rab3a (30%, P<0.05) in hippocampus; synaptobrevin (31%, P<0.01), synaptotagmin (15%, P<0.05), and Rab3a (44%, P<0.05) in entorhinal cortex. In contrast, the levels of two vesicle proteins (synapsin I and SV2) and two presynaptic membrane proteins (syntaxin and SNAP-25) were similar to controls. Synaptobrevin was the only vesicle protein reduced in AD in all four brain regions (occipital cortex 37%, P<0.05; caudate nucleus 31%, P<0.05). By univariate analysis of all cases, Mini-Mental State Examination, Blessed (BIMC) and Free Recall scores were strongly correlated with reduced levels of synaptic vesicle proteins synaptobrevin, synaptotagmin, and Rab3a in hippocampus and entorhinal cortex. These results suggest that there are selective and early defects in presynaptic vesicle proteins, but not synaptic plasma membrane proteins in AD and that defects correlate with cognitive dysfunction in this disease.

Aged↗
PubMed1997

Time-dependent effects of in vivo pertussis toxin on morphine analgesia and G-proteins in mice.

Previous studies have indicated a long-duration of effect of in vivo pertussis toxin (PTX) on morphine analgesia in the mouse. However, the time-course of potency changes in morphine analgesia as determined in dose-response studies and biochemical correlates of PTX treatment have not been reported to date. Therefore, in the present studies the effects of in vivo PTX on morphine analgesia ED50 and PTX-catalyzed incorporation of [32P]-ADP-ribose and synapsin content in mouse spinal cord were examined. Mice were injected IT & ICV with saline or PTX (total dose = 0.2 microg) and tested for systemic morphine analgesia (tail-flick) 1, 10, 16 & 40 days later. There was no significant decrease in morphine potency 1 day following PTX treatment, whereas PTX produced a significant decrease in morphine potency at 10, 16 & 40 days. Concurrent decreases in the incorporation of [32P]-ADP-ribose in spinal cord by PTX were observed on days 10, 16 & 40. No changes were observed in synapsin content which suggests that the effect was not nonspecific. This study indicates that in vivo PTX produces co-ordinate long-lasting effects in both functional (analgesia) and biochemical (Gi/o-proteins) assays.

Adenosine Diphosphate Ribose↗