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PubMed2002

ATPases of synaptic plasma membranes from hippocampus after ischemia and recovery during ageing.

Plasticity and relationships between individual ATPases linked to energy-utilizing systems of hippocampus, a very sensitive functional area to both age and ischemia, were studied during ageing on synaptic plasma membranes of 1-year-old "adult" and 2-year-old "aged" rats after 15 min of complete cerebral ischemia and different reperfusion times (01, 24, 48, 72, and 96 h). Activities of Na+, K+, Mg(2+)-ATPase, Mg(2+)-ATPase ouabain insensitive, Na+, K(+)-ATPase, "direct" or "basal" Mg(2+)-ATPase, and acetylcholinesterase (AChE) were evaluated in synaptic plasma membranes, where they play the major role in the regulation of presynaptic nerve ending homeostasis. This in vivo study of recovery time-course from 15 mins of cerebral ischemia indicated specific biochemical assessments of functional meaning: (a) Na+K(+)-ATPase of synaptic plasma membranes in adult and aged animals is stimulated by ischemia; (b) this "hyperactivity" is more markedly related to adult than to aged animals; (c) these abnormalities still persist after 72 and 96 h during the recirculation times, indicating the delayed postischemic suffering of the brain; (d) specific Mg(2+)-ATPase enzyme system possess a lower catalytic power in aged animals than in adult ones, but remained unaltered in adult animals by ischemia and reperfusion; (e) Mg(2+)-ATPase is stimulated in aged animals by ischemia, further increasing during reperfusion up to 72-96 h, indicating the delayed hyperactivity of hippocampus; (f) the increased metabolic activity of hippocampus is indicated by the increased activity of cholinergic system; (g) integrity of synaptic plasma membranes seems not to be altered by 15 min ischemia to a critical extent to compromise their catalytic functionality during reperfusion; (h) AChE activity increases in both adult and aged at some survival times. There are logical reasons for the hypothesis that the modifications in ATPase's catalytic activities in synaptic plasma membranes, which have been modified by ischemia in presynaptic terminals, may play important functional role during recovery time in cerebral tissue in vivo, especially as regards its responsiveness to noxious stimuli, particularly during the recirculation period from acute (or chronic) brain injury.

Aging↗
PubMed1997

Glyceraldehyde-3-phosphate dehydrogenase activity and F-actin associations in synaptosomes and postsynaptic densities of porcine cerebral cortex.

1. Glyceraldehyde-3-phosphate dehydrogenase (G3PD) is a glycolytic enzyme that has also been implicated in a wide variety of functions within neurons. Because of the well-documented role of G3PD as an actin-binding protein, we sought evidence for a G3PD-actin complex in synaptosomes and postsynaptic densities (PSDs). 2. We have shown G3PD association with 0.5-microgram synaptosomal particles by immunofluorescence as similarly demonstrated for actin (Toh et al., Nature 264:648-650, 1976). An immunoblot analysis also showed G3PD and actin to be enriched in synaptosomes. Further analysis of subcellular fractions from synaptosomes showed the PSD but not the synaptosomal plasma membranes to be enriched in G3PD and actin. 3. Highest levels of G3PD catalytic activity were found in synaptosomes and PSDs. Although synaptosomes showed significant activity for phosphoglycerate kinase (PGK), an enzyme in sequence with G3PD for ATP production in the glycolytic pathway, no such activity was detected in the PSD fraction. 4. Our studies indicate that a G3PD-actin complex may exist at the synapse. A physical association of G3PD with endogenous F-actin in synaptosomes and PSDs was demonstrated by combined phalloidin shift velocity sedimentation/immunoblot studies. By this approach, synaptosomal G3PD-actin complexes were also found to be significantly less dense than the PSD G3PD-actin complexes. 5. G3PD and PGK catalytic activity in synaptosomes suggests a role in glycolysis, as well as actin binding, in the presynaptic terminals. On the other hand, the high levels of G3PD activity in PSDs but lack of PGK activity suggests that G3PD is involved in nonglycolytic functions, such as actin binding and actin filament network organization.

Actins↗
PubMed2000

Detection and micro-scale isolation of a low molecular mass paralysis toxin from the tick, Argas (Persicargas) walkerae.

This study describes the isolation of a 11 kDa paralysis toxin from crude larval extracts of Argas (Persicargas) walkerae by exploiting the cross-reactivity of a monoclonal antibody (4B12), directed against the paralysis toxin of Rhipicephalus evertsi evertsi. This low molecular mass is in contrast to previous findings of a 60-70 kDa toxin for A. (P.) walkerae, but is similar to neurotoxins isolated from venomous forms of the class Arachnida, which comprise the orders Araneae (spiders). Scorpionida (Scorpions) and Acari (ticks and mites). Since numerous antigenic bands, ranging between 11 and 115 kDa, were detected by the monoclonal antibody 4B12, the possibility of toxin-complex formation and the effect of pH on the latter were investigated by means of HPLC and ammonium sulphate precipitation. The results suggest that physiological conditions, with respect to pH and ionic strength, promote the formation of heterogeneous toxin-complexes while an acidic pH favours the formation of a more homogeneous toxin-containing complex. Furthermore, the effect of partially purified toxin on neurotransmitter release from crude rat brain synaptosomes was investigated, since tick paralysis toxins are hypothesised to inhibit neurotransmitter release from the presynaptic terminal. Both calcium-dependent, as well as calcium-independent release was inhibited by the toxin-containing sample.

Animals↗
PubMed2003

Localization of microtubule-associated protein (MAP) 1B in the postsynaptic densities of the rat cerebral cortex.

1. Although microtubule-associated protein (MAP) 1B and its phosphorylation have been suggested to be important for synapse formation among cortical neurons, the localization of MAP1B in synapses has not yet been confirmed. In this report, we examine the localization of MAP1B in synaptic regions. 2. The localization of MAP1B was observed by immunohistochemical and electron microscopic techniques using specific antibodies against MAP1B. 3. MAP1B immunoreactivities were widely distributed in the cerebral cortex and were observed in the postsynaptic area but not in presynaptic terminals. 4. These synapses were classified as the asymmetrical type. 5. Only some synapses exhibited MAP1B immunoreactivities. MAP1B-immunopositive synapses accounted for about half of the total synapses. 6. Such a localization suggests MAP1B's important roles in synaptic functions.

Animals↗
PubMed2003

Neurotransmitter modulation of neuronal calcium channels.

There are many different calcium channels expressed in the mammalian nervous system, but N-type and P/Q-type calcium channels appear to dominate the presynaptic terminals of central and peripheral neurons. The neurotransmitter-induced modulation of these channels can result in alteration of synaptic transmission. This review highlights the mechanisms by which neurotransmitters affect the activity of N-type and P/Q-type calcium channels. The inhibition of these channels by voltage-dependent and voltage-independent mechanisms is emphasized because of the wealth of information available on the intracellular mediators and on the effect of these pathways on the single-channel gating.

Action Potentials↗
PubMed2002

Long-term potentiation and spatial learning are associated with increased phosphorylation of TrkB and extracellular signal-regulated kinase (ERK) in the dentate gyrus: evidence for a role for brain-derived neurotrophic factor.

In this study, the authors investigate changes in the presynaptic terminal of the dentate gyrus that accompany 2 types of hippocampal-dependent plasticity: spatial learning and long-term potentiation (LTP). Parallel changes occurred in the dentate gyrus of rats that had undergone training in the Morris water maze and had sustained LTP. In both cases, KCl-induced brain-derived neurotrophic factor release was increased, and this was accompanied by increased phosphorylation of TrkB and the mitogen-activated protein kinase, ERK. Glutamate release was also enhanced, and the data suggest that this may be a consequence of increased activation of TrkB and ERK. Because the data indicate that similar cellular modifications are shared by these 2 forms of plasticity, they provide circumstantial evidence that LTP satisfies some of the requirements of a memory-inducing cellular substrate.

Animals↗
PubMed1983

Enkephalin reduces quantal content at the frog neuromuscular junction.

Opiate peptides, particularly Met-enkephalin, have been shown to block or reduce Ca2+-dependent events in a variety of neurones. Our own observations on the effect of enkephalin on developing Rohon-Beard neurones in Xenopus spinal cord suggested that enkephalin might interact directly with Ca2+ channels in vertebrate neurones. This possibility prompted us to look for an effect of enkephalin on another population of neuronal Ca2+ channels--those in the presynaptic terminals at the frog neuromuscular junction. We were encouraged to try this preparation by an early report that morphine, in rather high concentrations, reduced the amount of acetylcholine (ACh) released from frog muscle by nerve stimulation. Our present results indicate that Met-enkephalin reversibly and specifically reduces the quantal content of transmitter release from nerve terminals in the frog cutaneous pectoris muscle, probably by means of an effect on inward Ca2+ current.

Acetylcholine↗
PubMedDate not supplied

Possible association of alcohol tolerance with increased synaptic Ca2+ sensitivity.

The inhibitory effect of ethanol on neurotransmitter release has been suggested to be due to either reduced Ca2+ entry or increased removal of free intracellular Ca2+ from the synapse. The use of the Ca2+ ionophore, A23187, to allow direct access of external Ca2+ to the presynaptic interior should help to determine which of these two factors is the more important, as ethanol should inhibit A23187-induced release of transmitter only if increased Ca2+ removal from the synapse is important. Here we show in rat striatal slices that, although 3H-dopamine release evoked by depolarization with 40 mM K+ is inhibited by 50 mM ethanol, the release evoked by A23187 is enhanced by the presence of ethanol in vitro. The results suggest that ethanol reduces depolarization-induced transmitter release by reducing Ca2+ entry to the presynaptic terminal. However, for brain slices taken from rats made tolerant to ethanol, 3H-dopamine release in the absence of ethanol showed altered characteristics; both K+ depolarization and A23187 released a significantly greater fraction of 3H-dopamine from these slices than from controls. Thus tolerance to the inhibitory effect of ethanol on release may develop by a mechanism involving increased sensitivity of the terminal to Ca2+ entry.

Alcoholism↗
PubMedDate not supplied

A venom peptide with a novel presynaptic blocking action.

The venom of the fish-eating marine mollusc, Conus geographus, contains several neurotoxic peptides having different targets. A novel peptide has recently been isolated from the venom of C. geographus by Drs B. M. Olivera and W. R. Gray and colleagues in our department (in preparation). We report here that this peptide, designated omega CgTX (omega C. geographus toxin), irreversibly blocks nerve stimulus-evoked release of transmitter at the frog skeletal neuromuscular junction. Experiments indicate that the toxin acts by preventing action potential. Consistent with this is the demonstration that omega CgTX also irreversibly attenuates the Ca2+ component of the action potential in dorsal root ganglion (DRG) neurones from embryonic chick. omega CgTX thus provides a unique and potentially powerful probe for exploring the presynaptic terminal.

Action Potentials↗
PubMedDate not supplied

Synaptic connectivity of a local circuit neurone in lateral geniculate nucleus of the cat.

Although receptive fields of relay cells in the lateral geniculate nucleus of the cat nearly match those of their retinal afferents, only 10-20% of the synapses on these cells derive from the retina and are excitatory. Many more (30-40%) are inhibitory and largely control the gating of retinogeniculate transmission. These inhibitory synapses derive chiefly from two cell types: intrinsic local circuit neurones and cells in the adjacent perigeniculate nucleus. It has been difficult to study the functional organization of these inhibitory pathways; most efforts have relied on indirect approaches. Here we describe the use of direct techniques to study a local circuit neurone by iontophoresing horseradish peroxidase (HRP) into it, which completely labels the soma and processes of cells for subsequent light- and electron microscopic analysis. Although the response properties of the labelled cell are virtually indistinguishable from those of many relay cells, its morphology is typical of 'class 3' neurones (see Fig. 1 legend), which are widely believed to be interneurones (but see ref. 12). Here, we refer to the cell as a 'local circuit neurone', which allows for the possibility of a projection axon, rather than as an 'interneurone', a term that commonly excludes a projection axon. We find that the labelled cell has a myelinated axon, but that the axon loses its myelin within 50 microns of the soma and has not yet been traced further. The dendrites of the labelled cell possess presynaptic terminals that act as intrinsic sources of inhibition on geniculate relay cells. We also characterize other morphological aspects of this inhibitory circuitry.

Animals↗
PubMedDate not supplied

Oxytocin induces morphological plasticity in the adult hypothalamo-neurohypophysial system.

The hypothalamo-neurohypophysial system offers a unique example in the adult mammalian central nervous system (CNS) of a functional and structural plasticity related to a physiological state. During lactation, oxytocin neurones evolve a synchronized electrical activation which permits pulsatile hormone release at milk ejection. At the same time, in the supraoptic (SON) and paraventricular nuclei, glial coverage of neurones diminishes, so that large portions of their surface membrane become directly juxtaposed; synaptic remodelling also associates pairs of neurones through the formation of common presynaptic terminals. These structural changes, reversible after weaning, affect exclusively oxytocinergic neurones and could facilitate their synchronized electrical activity. As several observations suggest that oxytocin itself is released centrally, we have examined the effect of prolonged intracerebroventricular infusions of oxytocin on the structure of the SON of non-lactating animals. We report here that the peptide indeed engenders the structural reorganization characteristic of the oxytocin system when it is physiologically activated. Similar infusion of vasopressin has no effect. Our observations thus demonstrate that a central neuropeptide can induce anatomical changes in the adult CNS, and suggest that oxytocin can regulate its own release by contributing to the dramatic restructuring of the nuclei containing the neurones responsible for its secretion.

Animals↗
PubMed1988

Ankyrin and spectrin associate with voltage-dependent sodium channels in brain.

The segregation of voltage-dependent sodium channels to specialized regions of the neuron is crucial for propagation of an action potential. Studies of their lateral mobility indicate that sodium channels are freely mobile on the neuronal cell body but are immobile at the axon hillock, presynaptic terminal and at focal points along the axon. To elucidate the mechanisms that regulate sodium channel topography and mobility, we searched for specific proteins from the brain that associate with sodium channels. Here we show that sodium channels labelled with 3H-saxitoxin (STX) are precipitated in the presence of exogenous brain ankyrin by anti-ankyrin antibodies and that 125I-labelled ankyrin binds with high affinity to sodium channels reconstituted into lipid vesicles. The cytoplasmic domain of the erythrocyte anion transporter competes for the latter interaction. Neither the neuronal GABA (gamma-aminobutyric acid) receptor channel complex nor the dihydropyridine (DHP) receptor bind brain ankyrin. The results indicate that brain ankyrin links the voltage-dependent sodium channel to the underlying cytoskeleton and may help to maintain axolemmal membrane heterogeneity and control sodium channel mobility.

Animals↗
PubMed1988

Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain.

In the vascular system, endothelium-derived relaxing factor (EDRF) is the name of the local hormone released from endothelial cells in response to vasodilators such as acetylcholine, bradykinin and histamine. It diffuses into underlying smooth muscle where it causes relaxation by activating guanylate cyclase, so producing a rise in cyclic GMP levels. It has been known for many years that in the central nervous system (CNS) the excitatory neurotransmitter glutamate can elicit large increases in cGMP levels, particularly in the cerebellum where the turnover rate of cGMP is low. Recent evidence indicates that cell-cell interactions are involved in this response. We report here that by acting on NMDA (N-methyl-D-aspartate) receptors on cerebellar cells, glutamate induces the release of a diffusible messenger with strikingly similar properties to EDRF. This messenger is released in a Ca2+-dependent manner and its activity accounts for the cGMP responses that take place following NMDA receptor activation. In the CNS, EDRF may link activation of postsynaptic NMDA receptors to functional modifications in neighbouring presynaptic terminals and glial cells.

Animals↗
PubMed1989

Associative long-term depression in the hippocampus induced by hebbian covariance.

A brief, high-frequency activation of excitatory synapses in the hippocampus produces a long-lasting increase in synaptic strengths called long-term potentiation (LTP). A test input, which by itself does not have a long-lasting effect on synaptic strengths, can be potentiated through association when it is activated at the same time as a separate conditioning input. Neural network modelling studies have also predicted that synaptic strengths should be weakened when test and conditioning inputs are anti-correlated. Evidence for such heterosynaptic depression in the hippocampus has been found for inputs that are inactive or weakly active during the stimulation of a conditioning input, but this depression does not depend on any pattern of test input activity and does not seem to last as long as LTP. We report here an associative long-term depression (LTD) in field CA1 that is produced when a low-frequency test input is negatively correlated in time with a high-frequency conditioning input. LTD of synaptic strength is also produced by activating presynaptic terminals while a postsynaptic neuron is hyperpolarized. This confirms theoretical predictions that the mechanism for associative LTD is homosynaptic and follows a hebbian covariance rule.

Action Potentials↗
PubMed1989

Arachidonic acid induces a long-term activity-dependent enhancement of synaptic transmission in the hippocampus.

Long-term potentiation (LTP) is a widely studied model of the synaptic basis of information storage in the mammalian brain. The induction of LTP is triggered by the postsynaptic entry of calcium through the channel associated with the N-methyl-D-aspartate (NMDA) receptor, whereas its maintenance is mediated, at least in part, by presynaptic mechanisms. To explain how postsynaptic events can lead to an increase in transmitter release, we have postulated the existence of a retrograde messenger to carry information from the postsynaptic side of the synapse to recently active presynaptic terminals. Candidates for a retrograde messenger include arachidonic acid or one of its lipoxygenase metabolites. Here we report that weak activation of the perforant path, when given in the presence of arachidonic acid, leads to a slow-onset persistent increase in synaptic efficacy both in vivo and in vitro. The activity-dependent potentiation thus produced is accompanied by an increase in the release of glutamate, and is non-additive with tetanus-induced LTP. These observations indicate a role for arachidonic acid as a retrograde messenger in the later, but not the initial, stages of LTP.

2-Amino-5-phosphonovalerate↗
PubMed1992

Glutamate-induced long-term potentiation of the frequency of miniature synaptic currents in cultured hippocampal neurons.

Glutamate application at synapses between hippocampal neurons in culture produces long-term potentiation of the frequency of spontaneous miniature synaptic currents, together with long-term potentiation of evoked synaptic currents. The mini frequency potentiation is initiated postsynaptically and requires activity of NMDA receptors. Although the frequency of unitary quantal responses increases strongly, their amplitude remains little changed with potentiation. Tests of postsynaptic responsiveness rule out recruitment of latent glutamate receptor clusters. Thus, postsynaptic induction can lead to enhancement of presynaptic transmitter release. The sustained potentiation of mini frequency is expressed even in the absence of Ca2+ entry into presynaptic terminals.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1993

Assembly of GABAA receptor subunits determines sorting and localization in polarized cells.

The GABAA receptor, the principal inhibitory receptor in the CNS, is distributed on cell bodies, dendrites, and in some cells at axon hillocks and presynaptic terminals. The dendritic distribution is crucial for shunting of excitatory synaptic inputs. Molecular cloning has revealed that the GABAA receptor can be formed by a diverse set of subunits and by separately encoded subunit isoforms, the expression of each of which differs in distinct areas of the central nervous system and during development. Why different genes exist to encode these isoforms is not clear, but may be linked to functional differences. Here we show that assembly of specific isoforms also codes for sorting and localization of the receptor complex. Confocal microscopy and immunoblot analysis of epithelial cells transfected with the complementary DNAs encoding the alpha 1 and beta 1 GABAA receptor subunits and probed with subunit isoform-specific antibodies show that the alpha 1 subunit is targeted to the basolateral surface, and that the beta 1 subunit is sorted to the apical membrane. In cells where alpha 1 and beta 1 isoforms are co-expressed, assembly of the beta 1 with the alpha 1 subunit isoform re-routes the alpha 1 subunit to the apical surface. The ability to assemble complexes of different isoform composition and to target these to specific regions of the cell surface would enable neurons to modulate GABAA receptor distribution and possibly alter the composition of its synapses in response to transcriptional levels of specific subunit isoforms.

Animals↗
PubMed1995

Nitric oxide mediates activity-dependent synaptic suppression at developing neuromuscular synapses.

Temporal correlation between pre- and postsynaptic activities is an important mechanism that regulates synaptic connectivity during development and synaptic plasticity in the adult. In developing neuromuscular junctions, postsynaptic activity is critical in functional suppression and, ultimately, elimination of the synapses. Although repetitive postsynaptic firing asynchronous to the presynaptic activity results in a persistent synaptic suppression, the underlying molecular mechanism remains unknown. Here we provide evidence that nitric oxide (NO), a free radical implicated in several forms of synaptic plasticity, may serve as a retrograde signal for activity-dependent suppression in the neuromuscular synapse. NO donors and activators of the cyclic GMP pathway suppressed spontaneous and evoked synaptic currents. Moreover, the synaptic suppression induced by repetitive postsynaptic depolarization was prevented by the NO-binding protein haemoglobin and by inhibitors of NO synthase. Thus, synaptic suppression may be triggered by NO released from a postsynaptic myocyte that fires asynchronously to the presynaptic terminal.

Action Potentials↗