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PubMed1989

[Effect of long-term administration of haloperidol: ultrastructural changes in the prefrontal cortex].

Haloperidol, when injected regularly during 3 weeks at a dose of 0.1 mg/kg, influenced glial cells and neuropile. The conditions of the glial cells suggested their increased metabolism. Morphometry revealed increased density of axodendritic synapses and reduced density of axospinal synapses at the spinal collumin the IV layer of medial prefrontal cortex. Virtually all the parameters measured in axodendritic synapses were decreased (presynaptic terminal area, mytochondrial total area and their count in the presynaptic terminal, the length of postsynaptic dense area). The data indicate that ultrastructural changes resulted from decrease of efficiency of synaptic transmission which occurred in several synapses as a result of haloperidol induced receptor block.

Animals↗

PubMed1990

The distribution of GABA in lumbar motoneuronal cell groups. A quantitative ultrastructural study in rat.

gamma-Aminobutyric acid (GABA)-containing profiles were identified at the ultrastructural level in rat lumbar motoneuronal cell groups by means of the postembedding immunogold technique, which is assumed to give very accurate quantitative results. It was found that 84.5% of the GABA-labeled terminals were of the F-type (containing many flattened vesicles), whereas P-type terminals (presynaptic to other terminals) constituted 9.2% of the GABAergic terminal profiles. A few of the GABA-labeled terminal profiles (1.7%) were G-type (containing many granular vesicles and presumed serotonergic), possibly indicating co-existence of GABA and serotonin. It is concluded that in spinal motoneuronal cell groups the large majority of the GABAergic terminal profiles were involved in postsynaptic inhibition of motoneurons, while only a minority was engaged in presynaptic inhibition.

Animals↗

PubMed1998

A Ca2+-induced Ca2+ release mechanism involved in asynchronous exocytosis at frog motor nerve terminals.

The extent to which Ca2+-induced Ca2+ release (CICR) affects transmitter release is unknown. Continuous nerve stimulation (20-50 Hz) caused slow transient increases in miniature end-plate potential (MEPP) frequency (MEPP-hump) and intracellular free Ca2+ ([Ca2+]i) in presynaptic terminals (Ca2+-hump) in frog skeletal muscles over a period of minutes in a low Ca2+, high Mg2+ solution. Mn2+ quenched Indo-1 and Fura-2 fluorescence, thus indicating that stimulation was accompanied by opening of voltage-dependent Ca2+ channels. MEPP-hump depended on extracellular Ca2+ (0.05-0.2 mM) and stimulation frequency. Both the Ca2+- and MEPP-humps were blocked by 8-(N, N-diethylamino)octyl3,4,5-trimethoxybenzoate hydrochloride (TMB-8), ryanodine, and thapsigargin, but enhanced by CN-. Thus, Ca2+-hump is generated by the activation of CICR via ryanodine receptors by Ca2+ entry, producing MEPP-hump. A short interruption of tetanus (<1 min) during MEPP-hump quickly reduced MEPP frequency to a level attained under the effect of TMB-8 or thapsigargin, while resuming tetanus swiftly raised MEPP frequency to the previous or higher level. Thus, the steady/equilibrium condition balancing CICR and Ca2+ clearance occurs in nerve terminals with slow changes toward a greater activation of CICR (priming) during the rising phase of MEPP-hump and toward a smaller activation during the decay phase. A short pause applied after the end of MEPP- or Ca2+-hump affected little MEPP frequency or [Ca2+]i, but caused a quick increase (faster than MEPP- or Ca2+-hump) after the pause, whose magnitude increased with an increase in pause duration (<1 min), suggesting that Ca2+ entry-dependent inactivation, but not depriming process, explains the decay of the humps. The depriming process was seen by giving a much longer pause (>1 min). Thus, ryanodine receptors in frog motor nerve terminals are endowed with Ca2+ entry-dependent slow priming and fast inactivation mechanisms, as well as Ca2+ entry-dependent activation, and involved in asynchronous exocytosis. Physiological significance of CICR in presynaptic terminals was discussed.

Action Potentials↗

PubMed2003

Phorbol ester uncouples adenosine inhibition of presynaptic Ca2+ transients at hippocampal synapses.

Synaptic transmission involves Ca2+ influx at presynaptic terminals. Adenosine receptors inhibit transmission, and this effect can be abolished by activation of PKC with phorbol esters. Whether protein kinase C (PKC) acts via alterations in Ca2+ entry at the presynaptic terminal is unknown. In the present study, we recorded the presynaptic Ca2+ transients (preCa(delta)) in hippocampal stratum radiatum, using fluorescence photometry. The calcium dye Fura-2 AM was used to load the Schaffer collateral/commissural tract and its terminals. Tetrodotoxin (TTX)-sensitive Na+ channels and Cd2+-sensitive, high-voltage activated Ca2+ channels (HVACCs) were required to elicit the preCa(delta). Application of the phorbol ester phorbol-12,13-dibutyrate (PDBu) abolished the adenosine inhibition of both preCa(delta) and the field excitatory postsynaptic potentials (fEPSPs). PDBu consistently potentiated fEPSPs, and also increased preCa(delta) in a large majority of the slices examined. Regardless of whether potentiation was observed, PDBu always prevented adenosine inhibition of preCa(delta). In contrast, the inactive phorbol ester, 4alpha-phorbol, did not alter adenosine inhibition of preCa(delta), indicating that PKC activation is necessary for the occurrence of the observed effects. Our findings suggest that PKC activation abolishes adenosine's inhibitory effect on synaptic activity involving presynaptic Ca2+ entry.

Adenosine↗

PubMed1996

Spike waves and synaptic ultrastructure in human epileptic brains.

OBJECTIVE: To find morphological changes of synapses related to the spike discharge by observation on ultrastructures of the EEG spike foci of cerebral cortexes. MATERIAL AND METHODS: The cerebral cortexes were obtained surgically from the EEG spike (recorded by flaky silver electrodes on the surface of cortexes) foci and nonspike areas within the limits of the brain tissue that would be removed in 20 cases of human epilepsy, and were processed for transmission electron microscopic (TEM) observation. RESULTS: In the spike foci, presynaptic terminals of axospinal asymmetric synapses were obviously swollen but postsynaptic spines were relatively unaffected. In these synapses, the synaptic vesicles remarkably decreased in number and accumulated predominantly at the presynaptic membranes or aggregated. Similar changes were observed in the presynaptic terminals of the axospinal asymmetric synapses in the nonspike areas but were of milder degree than in the spike foci. CONCLUSION: Axospinal asymmetric synapses may release a large quantity of excitatory neurotransmitters, which may result in epileptic abnormal electric activities during seizure.

Adolescent↗

PubMed1995

Protein kinase C modulates calcium channels in isolated presynaptic nerve terminals of rat hippocampus.

Nerve terminals ("synaptosomes") isolated from rat brain hippocampus were loaded with the fluorescent Ca2+ indicator fura-2 and were subjected to depolarization with an elevated K+ concentration in a stopped-flow spectrophotometer to measure the activity of voltage-gated Ca2+ channels in the presynaptic membrane. Three components of Ca2+ influx were seen, which were tentatively identified as two classes of voltage-dependent Ca2+ channels with different inactivation kinetics (tau of approximately 60 ms and 1 s, respectively) and Na+/Ca2+ exchange working in the "reverse" mode. The activity of both classes of voltage-dependent Ca2+ channels was slightly augmented by the phorbol ester phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C (PKC), but the effect of PMA was markedly enhanced by the protein phosphatase inhibitor okadaic acid (OKA). The PKC inhibitors calphostin C and dihydrosphingosine (DHS) caused a prompt decrease in voltage-dependent Ca2+ channel activity, but the effect of DHS could be slowed by coaddition of OKA. These results suggest that the activity of presynaptic voltage-dependent Ca2+ channels in the hippocampus is under a dynamic balance between PKC phosphorylation (leading to activation) and protein phosphatase dephosphorylation (leading to inactivation) and that both of these metabolic pathways are tonically active in the nerve terminals.

Animals↗

PubMed1994

The formation of glutamatergic synapses in cultured central neurons: selective increase in miniature synaptic currents.

The formation of synapses between cultured rat thalamic neurons was studied with electrophysiological and immunocytochemical methods. Thalamic neurons in culture form predominantly glutamatergic synapses. Already after 3 days in vitro glutamatergic miniature EPSCs occurred spontaneously and their frequency was strongly increased after K+ depolarization, while GABAergic mIPSCs were found after K+ depolarization at lower frequency. This demonstrates that both, excitatory glutamatergic and inhibitory GABAergic synapses were functional in close succession to initial neurite outgrowth. Synapses formed independent of spontaneous electrical activity, which was absent during the first week in culture. Spontaneous action potentials appeared during the second week and chronic action potential blockade by addition of tetrodotoxin reduced neuronal survival and the number of glutamatergic synapses per neuron. During in vitro differentiation the number of synapsin I immunoreactive presynaptic terminals and the frequency of spontaneous glutamatergic miniature EPSCs increased closely correlated, while the frequency of GABAergic mIPSCs after K+ depolarization did not increase. Thus, the continous formation of presynaptic terminals, including possible maturation of transmitter release, appeared to underlie the increase in mEPSC frequency. Analysis of miniature EPSC amplitudes at different stages in vitro revealed an increase in amplitudes, suggesting synaptic differentiation after initial establishment of functional transmission in glutamatergic synapses. This process was synapse specific as amplitudes of GABAergic mIPSCs were invariant.

Action Potentials↗

PubMed2005

Distinct kinetic changes in neurotransmitter release after SNARE protein cleavage.

Neurotransmitter release is triggered by calcium ions and depends critically on the correct function of three types of SNARE [soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptor] proteins. With use of the large calyx of Held presynaptic terminal from rats, we found that cleavage of different SNARE proteins by clostridial neurotoxins caused distinct kinetic changes in neurotransmitter release. When elevating calcium ion concentration directly at the presynaptic terminal with the use of caged calcium, cleavage of SNAP-25 by botulinum toxin A (BoNT/A) produced a strong reduction in the calcium sensitivity for release, whereas cleavage of syntaxin using BoNT/C1 and synaptobrevin using tetanus toxin (TeNT) produced an all-or-nothing block without changing the kinetics of remaining vesicles. When stimulating release by calcium influx through channels, a difference between BoNT/C1 and TeNT emerged, which suggests that cleavage of synaptobrevin modifies the coupling between channels and release-competent vesicles.

Action Potentials↗

PubMed1977

The synaptic spinule in the dendritic spine: electron microscopic study of the hippocampal dentate gyrus.

The present report calls attention to a component of certain synaptic junctions which has received little attention since its description in 1962 by Westrum and Blackstad. This component, which we term the synaptic spinule, is found in dendritic spine synapses in rat telencephalon (e.g., hippocampus, caudate nucleus, temporal and frontal cortex). Its major feature is an invagination of the presynaptic terminal by the presynaptic membrane, with the postsynaptic membrane protruding into this invagination. The synaptic spinule occurs in close association with the post-synaptic density, often occurring between breaks in this specialization. Serial sections reveal that when a synaptic spinule is present, a spine apparatus is observed near the dendritic protrusion. Coated vesicles are sometimes observed associated with the synaptic spinule; in all such instances they are associated with the presynaptic membrane. We studied the distribution of synaptic spinules in the dentate gyrus of the hippocampus. In contrast to its presence in the molecular layer, the synaptic spinule has not been observed in terminals of the subgranular layer of the dentate hilus. It is speculated that the synaptic spinule may play a role in exchange of material at dendritic spine synaptic junctions.

Animals↗

PubMed1996

Low-calcium-induced enhancement of chemical synaptic transmission from photoreceptors to horizontal cells in the vertebrate retina.

According to the classical calcium hypothesis of synaptic transmission, the release of neurotransmitter from presynaptic terminals occurs through an exocytotic process triggered by depolarization-induced presynaptic calcium influx. However, evidence has been accumulating in the last two decades indicating that, in many preparations, synaptic transmitter release can persist or even increase when calcium is omitted from the perfusing saline, leading to the notion of a "calcium-independent release" mechanism. Our study shows that the enhancement of synaptic transmission between photoreceptors and horizontal cells of the vertebrate retina induced by low-calcium media is caused by an increase of calcium influx into presynaptic terminals. This paradoxical effect is accounted for by modifications of surface potential on the photoreceptor membrane. Since lowering extracellular calcium concentration may likewise enhance calcium influx into other nerve cells, other experimental observations of "calcium-independent" release may be reaccommodated within the framework of the classical calcium hypothesis without invoking unconventional processes.

Ambystoma↗

PubMed2006

Ethanol potentiates GABAergic synaptic transmission in a postsynaptic neuron/synaptic bouton preparation from basolateral amygdala.

Interactions between ethanol and synaptic transmission mediated by gamma -amino-N-butyric acid (GABA) have been suggested to contribute to alcohol intoxication. Ethanol effects on postsynaptic GABAA receptors have been the major focus of this line of research. There is increasing evidence that ethanol potentiation of GABAergic transmission involves increased GABA release from presynaptic terminals. In the present study, a mechanically isolated neuron/bouton preparation from the basolateral amygdala was used to examine the effects of ethanol on spontaneous GABAergic synaptic currents elicited by GABA release from the presynaptic terminals. We found that ethanol application produced a rapid increase in the frequency of spontaneous GABAergic synaptic currents. An acute tolerance to ethanol was also observed, and this tolerance involved GABAB receptor activation. The ethanol-induced potentiation did not involve alterations in the function of postsynaptic GABAA receptors and was independent of presynaptic action potential firing. These findings indicate that ethanol potentiates GABA release, most likely via a direct action on presynaptic boutons.

Action Potentials↗

PubMed2002

Depression of fast excitatory synaptic transmission in large aspiny neurons of the neostriatum after transient forebrain ischemia.

Spiny neurons in the neostriatum die within 24 hr after transient global ischemia, whereas large aspiny (LA) neurons remain intact. To reveal the mechanisms of such selective cell death after ischemia, excitatory neurotransmission was studied in LA neurons before and after ischemia. The intrastriatally evoked fast EPSCs in LA neurons were depressed < or =24 hr after ischemia. The concentration-response curves generated by application of exogenous glutamate in these neurons were approximately the same before and after ischemia. A train of five stimuli (100 Hz) induced progressively smaller EPSCs, but the proportion of decrease in EPSC amplitude at 4 hr after ischemia was significantly smaller compared with control and at 24 hr after ischemia. Parallel depression of NMDA receptor and AMPA receptor-mediated EPSCs was also observed after ischemia, supporting the involvement of presynaptic mechanisms. The adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine blocked the inhibition of evoked EPSCs at 4 hr after ischemia but not at 24 hr after ischemia. Electron microscopic studies demonstrated that the most presynaptic terminals in the striatum had a normal appearance at 4 hr after ischemia but showed degenerating signs at 24 hr after ischemia. These results indicated that the excitatory neurotransmission in LA neurons was depressed after ischemia via presynaptic mechanisms. The depression of EPSCs shortly after ischemia might be attributable to the enhanced adenosine A1 receptor function on synaptic transmission, and the depression at late time points might result from the degeneration of presynaptic terminals.

Animals↗

PubMed2001

Changes in presynaptic proteins, SNAP-25 and synaptophysin, in the hippocampal CA1 area in ischemic gerbils.

A general consensus exists that the presynaptic terminals in the hippocampal CA1 area are resistant to ischemic stress in spite of the loss of their target cells (CA1 pyramidal neurons). We have verified this by immunostaining and Western immunoblotting using the antibodies for presynaptic proteins, synaptosomal-associated protein of 25 kDa (SNAP-25) and synaptophysin in gerbils after bilateral carotid artery ligature. In the immunohistochemical analysis, decreases in SNAP-25 and synaptophysin immunoreactivities in the strata radiatum and oriens, especially around the apical dendrite of CA1 neurons, and disappearance of SNAP-25 immunoreactivity in the alveus were observed on day 2 after ischemia. On days 7 and 14, SNAP-25-positive granular materials were expressed in the CA1 area, and intense synaptophysin immunoreactivity around surviving CA1 neurons was observed. Western immunoblot analysis revealed significant decreases of SNAP-25 and synaptophysin (about 60% of control levels) on day 2, and then increase of their proteins (130--140% of control levels) on day 14. These results indicate that presynaptic degeneration occurs in the hippocampal CA1 area after ischemia, and it precedes the delayed neuronal death of CA1 neurons. The presynaptic terminal damage may be responsible for some pathological changes in ischemic brains.

Animals↗

PubMed2004

Presynaptic mechanism underlying cAMP-dependent synaptic potentiation.

The adenylyl cyclase activator forskolin presynaptically facilitates synaptic transmission at many synapses, but the exact intracellular mechanism underlying this effect is not known. We studied this issue at the calyx of Held, where it is possible to make simultaneous presynaptic and postsynaptic whole-cell recordings. Bath application of forskolin or intracellular application of cAMP into presynaptic terminals strongly potentiated EPSCs. The forskolin-induced synaptic potentiation was associated with increases in release probability (P) and number of releasable synaptic vesicles (N). Forskolin had no effect on the peak amplitudes of presynaptic Ca2+ currents or K+ currents, suggesting that the main target of cAMP resides in downstream of Ca2+ influx. Intracellular application of the selective Epac agonist 8-(4-chlorophenylthio)-2'-O-methyl-cAMP into presynaptic terminals potentiated EPSCs, suggesting that Epac is the main target of cAMP-induced synaptic potentiation. We conclude that an increase in cAMP concentration in the nerve terminal facilitates transmitter release by increasing both release probability and number of releasable vesicles via activating the Epac pathway at the calyx of Held.

Animals↗

PubMed1996

The structure of the neurofilament cytoskeleton in the squid giant axon and synapse.

Stereo views of thick sections (< 0.5 micron), or freeze etch replicas taken from selected regions of the squid giant axon and giant synapse, using an electron energy loss spectroscopic ultrastructural method, revealed a meshwork of anastomosing neurofilaments intersecting at a wide range of angles. This type of architectural organisation differs significantly from the ladder-like construction of the mammalian neurofilament cytoskeleton, in which longitudinally oriented core filaments are interconnected by lateral crossbridges. The deviant organization of squid neurofilaments is consistent with recent evidence that squid neurofilament proteins more closely resemble nuclear lamin rather than mammalian neurofilament proteins. A proximo-distal gradient of increasing width of the neurofilament meshes along the giant axon correlated well with the previously described gradient of increasing neurofilament phosphorylation. In these thick sections the presynaptic terminal of the giant synapse exhibited a mature neurofilament cytoskeleton that extended to the active zones without detectable signs of degradation. The observations are discussed in the context of current hypotheses concerned with the function of phosphorylation of neurofilaments, and with the steady state maintenance of the cytoskeleton in the squid axon and presynaptic terminal.

Animals↗

PubMed1998

Postnatal development of phase-locked high-fidelity synaptic transmission in the medial nucleus of the trapezoid body of the rat.

Synaptic transmission in the medial nucleus of the trapezoid body of rats was analyzed in postnatal days 4-13 (P4-P13) by applying the whole-cell patch-recording technique to brain slices. In P4-P6 animals, evoked EPSCs fluctuated extensively in amplitude and occurred in marked asynchrony, followed by spontaneous EPSCs. With development of animals, the evoked EPSCs increased in amplitude, and the rise time became faster. In addition, the synaptic transmission became phase-locked. The coefficient of variation (CV) of EPSC amplitude decreased with development (0.32 +/- 0.03 for P4-P5 and 0. 05 +/- 0.01 for P9-P11). The amplitude of miniature EPSCs did not change throughout the postnatal days investigated (-30.2 +/- 0.3 pA at -70 mV). The CV was dependent on extracellular Ca2+ concentration ([Ca2+]o) and was reduced with the increase of [Ca2+]o, and this [Ca2+]o dependence was shifted toward lower [Ca2+]o with development. Direct patch recording of the presynaptic terminals demonstrated an increase in Ca2+ currents during these postnatal days. The phase-locked high-fidelity transmission in this synapse is achieved with development likely through the increase of Ca2+ currents and Ca2+ sensitivity of transmitter release mechanisms in the presynaptic terminal.

Action Potentials↗

PubMed1995

Detecting changes in calcium influx which contribute to synaptic modulation in mammalian brain slice.

The control of neurotransmitter release by modulation of presynaptic calcium influx was investigated at the granule cell to Purkinje cell synapse in rat cerebellar slices. Excitatory post-synaptic currents were measured using whole cell voltage clamp, and changes in presynaptic Ca influx were determined with the Ca-sensitive dye mag-fura-5. Single stimuli of the parallel fibers evoked rapid changes in mag-fura-5 fluorescence which increased from 10 to 90% in 1.4 msec, and then decayed within hundreds of milliseconds to prestimulus levels. These fluorescence changes were unaffected by disruption of internal stores with ryanodine or thapsigargin, and were reduced by 79% by the calcium channel toxin omega-conotoxin-MVIIC. We conclude that these signals result from calcium entry into presynaptic terminals through voltage gated calcium channels opened by action potentials. These fluorescence signals allow us to quantitate changes in calcium influx. We used this approach to study the enhancement of stimulus-evoked synaptic currents by 3-isobutyl-1-methylxanthine (IBMX), a phosphodiesterase inhibitor and antagonist of adenosine receptors. Both enhancement of calcium influx into presynaptic terminals, and reduction in the firing threshold of the parallel fibers, were found to contribute to IBMX-mediated synaptic enhancement. Changes in presynaptic calcium influx were also quantified with a novel method, which is unaffected by changes in fiber threshold. These studies illustrate some of the difficulties encountered when determining the factors responsible for synaptic enhancement and demonstrate how measurements of presynaptic calcium influx can contribute to our understanding of synaptic modulation. The approach described here promises to be widely useful in elucidating the role of calcium influx in the modulation of synapses in brain slice.

1-Methyl-3-isobutylxanthine↗

PubMed1988

Ultrastructural evidence that horizontal cell axon terminals are presynaptic in the human retina.

The organization of the rod spherule and of the horizontal cell axon terminals within the invagination of the rod spherule in the human retina was examined in serial sections by electron microscopy. Twenty-one rod spherules were reconstructed in this study. Axon terminal processes of type I horizontal cells consistently make one or two small punctate synapses onto each rod spherule within the invagination. In addition, these axon terminal processes make distinct synapses upon rod bipolar dendrites outside the spherule before both processes enter the invagination. This is the first positive description of a synapse from a horizontal cell axon terminal process onto a photoreceptor terminal and the first identification of a synapse from a horizontal cell to a rod bipolar cell in the mammalian outer plexiform layer. We speculate that the axon terminal-to-rod synapse is responsible for feedback while the synapse upon the rod bipolar cell is feed-forward and serves to expand the receptive field of the rod bipolar cell beyond its dendritic field. Alternatively, the latter may contribute to a center-surround organization of the rod bipolar's receptive field.

Axons↗