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PubMed1987

Distribution of calcium and potassium in presynaptic nerve terminals from cerebellar cortex.

The elemental composition of the presynaptic nerve terminals in rapidly frozen synapses of the cerebellar molecular layer was determined by electron probe x-ray microanalysis and elemental imaging of characteristic x-rays. Elemental imaging of thin freeze-dried cryosections from fresh cerebellar slices frozen within 20 sec of removal from the brain showed normal concentrations of potassium (95 +/- 6 mmol/liter wet tissue +/- SEM) and calcium (0.8 +/- 0.4 mmol/liter) in whole presynaptic terminals, even though mitochondrial and nonmitochondrial sites containing up to 30 mmol of calcium per liter were present elsewhere in the neuropil. Quantitative electron probe analysis of synaptic vesicle clusters and intraterminal mitochondria indicated that their calcium concentrations were 0.4 +/- 0.1 and 1.2 +/- 0.2 mmol/liter, respectively. The low calcium content of presynaptic organelles was confirmed by the absence of detectable deposits in preparations freeze-substituted so as to stabilize calcium content. Similar experiments were carried out on cerebellar slices rapidly frozen after incubation in vitro. The distribution of potassium and calcium in presynaptic terminals of resting and depolarized (55 mM potassium) slices was qualitatively and quantitatively similar to that in freshly excised cortex, although resting slices lacked the few calcium-rich sites that appeared in other areas of the neuropil after stimulation. The calcium concentrations in whole terminals, synaptic vesicles, and mitochondria of resting slices were 1.4 +/- 0.7, 0.7 +/- 0.2, and 0.9 +/- 0.2 mmol/liter, respectively. Thus, amounts of calcium typical of storage organelles in other tissues are not present within cerebellar synaptic vesicles, suggesting that they have a limited role in calcium storage and release.

Animals↗
PubMed1987

[Vesicle population of synapses in the hippocampus of the rat following early postnatal deprivation and administration of pyridostigmine].

Newborn male Wistar rats were subjected to early postnatal social and nutritional deprivation by separation of the pups from their mother animals from Day 3 to Day 14 for 16 hours daily. One group of the deprived animals was treated by daily injections of pyridostigmine (1 microgram/0.05 ml saline from Day 1 to Day 4, 5 micrograms/0.05 ml saline from Day 5 to Day 14). At the age of 14 days or 6 months, 5 deprived, 5 deprived and pyridostigmine treated rats and 5 controls were investigated. In the stratum radiatum of the hippocampal CA 1-region the vesicle population of axospinodendritic synapses was examined for quantitative ultrastructural changes using electron microscopic and morphometric methods. The vesicle density (number of vesicles/micron 2 terminal area) was determined in the whole presynaptic terminal as well as in distinct zones in the presynaptic terminal. 14 days of deprivation did not change the vesicle density in the whole presynaptic terminal, but did change the distribution of the vesicles. In 14 days old deprived rats the vesicle density was found to be decreased by about 10% in the presynaptic area bordering the synaptic contact zone (area 1), and it was increased by about 7% in the more distant area of the presynaptic terminal (area 2). Deprivation and simultaneous pyridostigmine treatment resulted in an elevated vesicle density in the whole presynaptic terminal by about 25%, in area 1 by about 8%, and in area 2 by about 30%. At the age of 6 months, the early postnatally deprived rats showed an increase in the vesicle density by about 8% in all areas of the presynaptic terminal when compared with the controls. Simultaneous pyridostigmine treatment led to a reduced vesicle density in the whole presynaptic terminal by about 5%, in area 1 by about 9%, and in area 2 by about 4%. The findings obtained following deprivation are interpreted as being the expression of an insufficient requirement of synaptic mechanisms caused by a lack of sensoric inputs during the early postnatal period. The results obtained in the neonatally pyridostigmine treated rats suggest permanent changes in the neurotransmitter metabolism following treatment with the psychotrophic drug. This may reflect a mechanism to compensate the effect of deprivation by neonatal pyridostigmine administration.

Animals↗
PubMed1991

Characterization of a calcium current in a vertebrate cholinergic presynaptic nerve terminal.

Calcium currents were recorded from a cholinergic presynaptic nerve terminal in the chick ciliary ganglion using the whole-cell voltage-clamp technique. The presynaptic element of this synapse is in the form of a calyx that envelops the postsynaptic ciliary neuron. A method was developed to isolate the ciliary neuron, expose the calyx, and apply patch-clamp electrodes under visual control. The presynaptic Ca current activated at +30 mV with a fast time constant of about 1.5 msec and deactivated at -80 mV with a time constant of about 0.5 msec, values that are consistent with a role in action-potential-dependent transmitter release. The calyx Ca current was blocked by 0.1 mM Cd or 2 microM omega-conotoxin and was resistant to voltage-dependent inactivation. The presynaptic Ca channel exhibits similarities to the N-type group but differs from these by the minimal voltage-dependent inactivation. This type of channel, designated CaN-PT (N-like, presynaptic terminal), may play a key role in transmitter release at many vertebrate fast-transmitting synapses.

Animals↗
PubMed1999

Ion channels in presynaptic nerve terminals and control of transmitter release.

The primary function of the presynaptic nerve terminal is to release transmitter quanta and thus activate the postsynaptic target cell. In almost every step leading to the release of transmitter quanta, there is a substantial involvement of ion channels. In this review, the multitude of ion channels in the presynaptic terminal are surveyed. There are at least 12 different major categories of ion channels representing several tens of different ion channel types; the number of different ion channel molecules at presynaptic nerve terminals is many hundreds. We describe the different ion channel molecules at the surface membrane and inside the nerve terminal in the context of their possible role in the process of transmitter release. Frequently, a number of different ion channel molecules, with the same basic function, are present at the same nerve terminal. This is especially evident in the cases of calcium channels and potassium channels. This abundance of ion channels allows for a physiological and pharmacological fine tuning of the process of transmitter release and thus of synaptic transmission.

Animals↗
PubMed1985

Interactions among presynaptic fiber terminations in the CA1 region of the rat hippocampus.

The excitability of Schaffer collateral terminal regions in the CA1 area of rat hippocampal slices is usually increased and occasionally decreased for about 300 ms following the activation of the same or other nearby fibers. The increased excitability appears to be at least partly Ca2+ dependent. Exposure of the slices to slightly elevated extracellular K+ levels (4.5 mM) increased while exposure to 12 mM K+ decreased the excitability of Schaffer collateral terminal regions. These results indicate that presynaptic terminals in hippocampus interact with each other possibly through a build-up in extracellular K+ or secondary to the release of transmitters.

Action Potentials↗
PubMed2000

G-Protein types involved in calcium channel inhibition at a presynaptic nerve terminal.

The inhibition of presynaptic calcium channels via G-protein-dependent second messenger pathways is a key mechanism of transmitter release modulation. We used the calyx-type nerve terminal of the chick ciliary ganglion to examine which G-proteins are involved in the voltage-sensitive inhibition of presynaptic N-type calcium channels. Adenosine caused a prominent inhibition of the calcium current that was totally blocked by pretreatment with pertussis toxin (PTX), consistent with an exclusive involvement of G(o)/G(i) in the G-protein pathway. Immunocytochemistry was used to localize these G-protein types to the nerve terminal and its transmitter release face. We used two approaches to test for modulation by other G-protein types. First, we treated the terminals with ligands for a variety of G-protein-linked neurotransmitter receptor types that have been associated with different G-protein families. Although small inhibitory effects were observed, these could all be eliminated by PTX, indicating that in this terminal the G(i) family is the sole transmitter-induced G-protein inhibitory pathway. Second, we examined the kinetics of calcium channel inhibition by uncaging the nonselective and irreversible G-protein activator GTPgammaS, bypassing the receptors. A large fraction of the rapid GTPgammaS-induced inhibition persisted, consistent with a G(o)/G(i)-independent pathway. Immunocytochemistry identified G(q), G(11), G(12), and G(13) as potential PTX-insensitive second messengers at this terminal. Thus, our results suggest that whereas neurotransmitter-mediated calcium channel inhibition is mainly, and possibly exclusively, via G(o)/G(i), other rapid PTX-insensitive G-protein pathways exist that may involve novel, and perhaps transmitter-independent, activating mechanisms.

Adenosine↗
PubMed1998

Temperature-sensitive neuromuscular transmission in Kv1.1 null mice: role of potassium channels under the myelin sheath in young nerves.

In mammalian myelinated nerves, the internodal axon that is normally concealed by the myelin sheath expresses a rich repertoire of K channel subtypes thought to be important in modulating action potential propagation. The function of myelin-covered K channels at transition zones, however, has remained unexplored. Here we show that deleting the voltage-sensitive potassium channel Kv1.1 from mice confers a marked temperature-sensitivity to neuromuscular transmission in postnatal day 14 (P14)-P21 mice. Using immunofluorescence and electrophysiology, we examined contributions of four regions of the peripheral nervous system to the mutant phenotype: the nerve trunk, the myelinated segment preceding the terminal, the presynaptic terminal membrane itself, and the muscle. We conclude that the temperature-sensitive neuromuscular transmission is accounted for solely by a deficiency in Kv1.1 normally concealed in the myelinated segments just preceding the terminal. This paper demonstrates that under certain situations of physiological stress, the functional role of myelin-covered K channels is dramatically enhanced as the transition zone at the neuromuscular junction is approached.

Age Factors↗
PubMed2000

Two peptidergic drugs increase the synaptophysin immunoreactivity in brains of 6-week-old rats.

An increase of synaptic density has been found in the hippocampus, the dendate gyrus and in the entorhinal cortex of 6-week-old rats after 7 days of treatment with the peptidergic drug Cerebrolysin, its peptide preparation E021 and the diluted peptide preparation E021dil. Rats received drugs on postnatal days 1-7 (2.5 ml/kg, each day). Controls received saline. The animals were sacrificed on days 42-48 of their life, after they had undergone behavioural testing in a Morris water maze. Slices of brain were stained immunohistochemically with anti-synaptophysin, a specific marker of presynaptic terminals. The synaptophysin-immunoreactivity of presynaptic terminals was quantified using light microscopy and a computerised image analysis system. Our results showed that rats benefit from the treatment with both drugs. A significant increase in the number of synaptophysin-immunoreactive presynaptic terminals was found in the entorhinal cortex and the hippocampal subfields CA1, CA2, CA3 stratum radiatum and CA3 stratum lucidum. The increased immunoreactive presynaptic terminals found in the present study are in accordance with the positive effects of the drugs on spatial learning and memory in young rats (Gschanes & Windisch 1999).

Amino Acids↗
PubMed1990

Calcium currents recorded from a vertebrate presynaptic nerve terminal are resistant to the dihydropyridine nifedipine.

The influx of Ca ions into the presynaptic nerve terminal through ion channels is a key link between the action potential and the release of chemical transmitters. It is not clear, however, which types of Ca channel are involved in neurosecretion at vertebrate synapses. In particular, there is disagreement as to whether these channels are sensitive to dihydropyridine blockers, characteristic of L-type Ca channels. We have used the chicken ciliary ganglion calyx synapse to test the effect of the dihydropyridine nifedipine on Ca current recorded directly from a cholinergic presynaptic nerve terminal. We used a control neuron to define the experimental conditions under which L-type Ca channels are blocked by 10 microM nifedipine. We then tested the effect of the dihydropyridine on Ca currents recorded from the presynaptic terminal using the same conditions. Nifedipine did not reduce the calyx Ca current nor did it block chemical transmission through the ganglion. The lack of effect of the dihydropyridine was not due to restricted access since omega-conotoxin GVIA, a peptide toxin that blocks transmission at this synapse, rapidly blocked the calyx Ca current. Thus, the predominant Ca channel in this presynaptic nerve terminal is not dihydropyridine sensitive and, hence, cannot be characterized as L-type.

Animals↗
PubMed1996

Ryanodine-sensitive component of calcium transients evoked by nerve firing at presynaptic nerve terminals.

Whether Ca2+ released from stores within the presynaptic nerve terminals also contributes to the Ca2+ elevation evoked by action potentials was tested in intact bullfrog sympathetic ganglia. Intraterminal Ca2+ transients (Delta[Ca2+]i) were evoked by electrical shocks to the presynaptic nerves at 20 Hz and were monitored by fura-2 fluorimetry. Ca2+ released through intraterminal ryanodine-sensitive channels accounted for 46% of the peak Ca2+ elevation. Moreover, in half of the terminals when intraterminal release was blocked by ryanodine, Delta[Ca2+]i reached a plateau at 200 +/- 24 nM. Because 20 Hz is a frequency favorable for the release of a neuropeptide, luteinizing hormone releasing hormone (LHRH) from these presynaptic nerve terminals, and because the threshold level for LHRH release is 186 nM, intraterminal Ca2+ release during nerve firing is likely to play a major role in regulating LHRH release. The intraterminal ryanodine channels were facilitated by caffeine as in other tissue. The releasable ryanodine-sensitive store could elevate the intraterminal [Ca2+] by an amount as high as 1.6 microM at a rate as fast as 250 nM/sec. The store could be refilled within 100 sec after a maximal discharge of its content by 20 Hz firing. Oscillation of [Ca2+]i evoked by 20 Hz nerve firing occurred in normal Ringer solution, in ryanodine, and in caffeine with a periodicity of approximately 10 sec. Besides the facilitatory effects on the ryanodine-sensitive channels, caffeine also had inhibitory effects on Delta[Ca2+]i via its action on a different process.

Animals↗
PubMed1995

Measurements of exocytosis from single presynaptic nerve terminals reveal heterogeneous inhibition by Ca(2+)-channel blockers.

The effect of various Ca(2+)-channel blockers on exocytosis has been studied at the level of single presynaptic terminals in rat hippocampal cell cultures. The fluorescence change of the styryl dye FM 1-43 has been used as a measure of exocytosis during electrical stimulation. omega-Conotoxin GVIA (2-10 microM) completely inhibited exocytosis in approximately 45% of the boutons in the field of view, while in approximately 55% exocytosis was inhibited incompletely (by 38%). This heterogeneity in response of presynaptic boutons was not seen with isradipine (5 microM) or omega-agatoxin IVA (80 nM), which inhibited exocytosis by 23% and 17%, respectively. However, it was observed with a combination of all three blockers. Pre- and postsynaptic events could be separated in single synapses by measuring FM1-43 release and NMDA-induced changes in the intracellular Ca2+ concentration independently.

Action Potentials↗
PubMed1985

Suppression by phenytoin of convulsant-induced afterdischarges at presynaptic nerve terminals.

The mechanisms underlying the induction of afterdischarges at presynaptic nerve terminals by convulsant aminopyridines and their suppression by the anticonvulsant drug phenytoin were studied at the frog neuromuscular preparation. Addition of aminopyridine to the perfusing solution induced the appearance of afterdischarges in motor nerve fibres following their primary response to a single nerve stimulus. The afterdischarges seemed to originate at or near the nerve terminals and to propagate both antidromically and orthodromically. The latter resulted in repetitive activation of the neuromuscular synapse. Focal recordings of nerve terminal potentials suggested that aminopyridines may induce afterdischarges by slowing spike repolarization and thereby producing a prolonged depolarization of nerve terminals. Phenytoin suppressed the aminopyridine-induced afterdischarges and the resultant repetitive excitation of the postsynaptic muscle fibres. This effect of phenytoin was associated with a depression of the action potential at the motor nerve terminals but not at their parent axons. These results single the presynaptic nerve terminals as preferential sites for convulsant and anticonvulsant actions.

4-Aminopyridine↗
PubMed1993

Currents and channels in the presynaptic nerve terminal.

Synaptic transmission is a key element in neuronal communication in the nervous system. It is determined by two basic sets of processes: release of transmitter from the presynaptic nerve ending and the detection and response by the postsynaptic cell. The release of transmitter is crucially dependent on the interplay among the ion channels in the surface membrane of the presynaptic terminal. In this article we describe the methods used in the study of the ion channels in secretory nerve endings and present the 16 calcium, sodium, chloride, cationic and potassium ion channels discovered in various preparations. We speculate about the physiological and pathophysiological roles of some of these ion channels.

Animals↗
PubMed1982

Quantitative ultrastructural changes in rat cortical synapses during early-, mid- and late-adulthood.

Quantitative ultrastructural analysis of rat parietal cortex was undertaken to determine the nature of the synaptic changes occurring in the molecular layer over a series of ages in early- (3 months), mid- (6 and 10 months) and late- (17 months) adulthood. The total number of synapses remained constant until 10 months of age, but decreased significantly by 17 months. Asymmetrical synapses on dendritic shafts were lost earlier (by 6 months) than asymmetrical synapses on dendritic spines (by 17 months). Symmetrical axodendritic synapses remained constant throughout adulthood. Analysis of synaptic terminal parameters revealed the following. Both individual and total presynaptic terminal areas decreased over the age range studied. Individual and total postsynaptic terminal areas, however, remained constant over the 3--17-month period. Positive correlations were obtained for the relationships between presynaptic terminal area and both age and synaptic vesicle number. The presynaptic terminal area was largest and contained the greatest number of vesicles at 3 months of age. This age was, in addition, characterized by the least numbers of mitochondria in the presynaptic terminal and spine apparatus in the postsynaptic terminal. The vacuolar and tubular cisternae of the presynaptic terminal were considerably reduced at 17 months. These data suggest that in the molecular layer of the cerebral cortex the period of adulthood is characterized by a diversity of synaptic changes. The 3-month age may reflect the end of the developmental phase and may be marked by changes in synaptic functional activity. The asymmetrical axodendritic synapses may constitute an intermediate form of synapse, capable of being transformed into axospinous synapses as dendritic spines continue to be formed in the adult.

Aging↗
PubMed1998

Bassoon, a novel zinc-finger CAG/glutamine-repeat protein selectively localized at the active zone of presynaptic nerve terminals.

The molecular architecture of the cytomatrix of presynaptic nerve terminals is poorly understood. Here we show that Bassoon, a novel protein of >400,000 Mr, is a new component of the presynaptic cytoskeleton. The murine bassoon gene maps to chromosome 9F. A comparison with the corresponding rat cDNA identified 10 exons within its protein-coding region. The Bassoon protein is predicted to contain two double-zinc fingers, several coiled-coil domains, and a stretch of polyglutamines (24 and 11 residues in rat and mouse, respectively). In some human proteins, e.g., Huntingtin, abnormal amplification of such poly-glutamine regions causes late-onset neurodegeneration. Bassoon is highly enriched in synaptic protein preparations. In cultured hippocampal neurons, Bassoon colocalizes with the synaptic vesicle protein synaptophysin and Piccolo, a presynaptic cytomatrix component. At the ultrastructural level, Bassoon is detected in axon terminals of hippocampal neurons where it is highly concentrated in the vicinity of the active zone. Immunogold labeling of synaptosomes revealed that Bassoon is associated with material interspersed between clear synaptic vesicles, and biochemical studies suggest a tight association with cytoskeletal structures. These data indicate that Bassoon is a strong candidate to be involved in cytomatrix organization at the site of neurotransmitter release.

Amino Acid Sequence↗
PubMed1981

Development of alpha-noradrenergic and Dopaminergic receptor systems depends on maturation of their presynaptic nerve terminals in the rat brain.

To study the relationship between ontogeny of rat brain catecholamine nerve terminals and the receptor systems for the catecholamine transmitters, the developmental patterns of synaptosomal uptake mechanisms were compared with those of alpha-noradrenergic and dopaminergic receptor-mediated effects. Uptakes of [(3)H]dopamine or [(3)H]norepinephrine into dopaminergic and noradrenergic nerve terminals were low during the 1st week postpartum and increased rapidly during the 2nd week. A similar pattern was obtained for ontogeny of dopaminergic receptor binding sites, as evaluated by [(3)H]domperidone binding. Stimulation of incorporation of (33)P(i) into brain phospholipids (elicited by intracisternal injection of dopamine), which is mediated by dopaminergic receptors, was shown to be highly correlated with the maturation of both receptor binding sites and presynaptic nerve terminal uptake. A similar result was seen with norepinephrine, in that the synaptosomal uptake mechanism and norepinephrine-induced stimulation (33)P(i) incorporation into phospholipids, an alpha-noradrenergic effect, developed in a parallel fashion. To test the hypothesis that development of the receptor systems is linked to nerve terminal ontogeny, presynaptic nerve terminals were destroyed in neonates by intracisternal administration of 6-hydroxydopamine. The lesions prevented the maturational increase in the number of dopamine receptor binding sites and produced a defect in development of the dopamine- and norepinephrine-induced stimulation of (33)P(i) incorporation. The results suggest that ontogeny of both dopaminergic and alpha-noradrenergic receptor systems depend upon development of the presynaptic nerve terminals containing the transmitters.

Animals↗
PubMed1987

A phosphatase activity and a synaptic vesicle antigen in multivesicular bodies of frog retinal photoreceptor terminals.

Previous work has suggested that multivesicular bodies participate in endocytosis and membrane cycling at nerve terminals, including the presynaptic terminals of retinal photoreceptors. We now have found that multivesicular bodies located in the presynaptic terminals of photoreceptors in retinae of Rana pipiens show reaction product in preparations incubated to demonstrate phosphatase activity at pH 5, using cytidine monophosphate as the substrate. Evidently, multivesicular bodies in photoreceptors can possess at least some hydrolytic enzymes during their sojourn in the terminals. We have also found that the multivesicular bodies in frog retinal photoreceptor terminal stain, immunocytochemically, for the presence of SV2, an antigen of synaptic vesicles. This observation supports the suggestion that, along with the extensive, repeated reuse of membrane components for synaptic vesicle recycling, there is some incorporation of the components into structures that are potentially degradative.

Animals↗
PubMed1997

Block of transmitter release by botulinum C1 action on syntaxin at the squid giant synapse.

Electrophysiological, morphological, and biochemical approaches were combined to study the effect of the presynaptic injection of the light chain of botulinum toxin C1 into the squid giant synapse. Presynaptic injection was accompanied by synaptic block that occurred progressively as the toxin filled the presynaptic terminal. Neither the presynaptic action potential nor the Ca2+ currents in the presynaptic terminal were affected by the toxin. Biochemical analysis of syntaxin moiety in squid indicates that the light chain of botulinum toxin C1 lyses syntaxin in vitro, suggesting that this was the mechanism responsible for synaptic block. Ultrastructure of the injected synapses demonstrates an enormous increase in the number of presynaptic vesicles, suggesting that the release rather than the docking of vesicles is affected by biochemical lysing of the syntaxin molecule.

Animals↗