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PubMed1996

Remodeling of the peripheral processes and presynaptic terminals of leg motoneurons during metamorphosis of the hawkmoth, Manduca sexta.

During metamorphosis of the hawkmoth, Manduca sexta, the muscles, cuticular structures, and most sensory neurons of the larval thoracic legs are replaced by new elements in the adult legs. The thoracic leg motoneurons, however, survive the loss of the larval muscles and persist to innervate new targets in the imaginal legs. Here we have used biocytin staining, immunocytochemistry, and confocal microscopy to follow the fates of the peripheral processes and presynaptic terminals of the leg motoneurons. Although the most distal processes of the motor nerves retract following the degeneration of larval leg muscles, the axon terminals always retain close association with the muscle remnants and the anlagen of the new adult muscles. As the imaginal muscles differentiate and enlarge, the motor terminals expand to form adult presynaptic terminals. An antibody to the presynaptic protein, synaptotagmin, revealed its localization to the terminal varicosities in both larval and adult stages but distribution within pre-terminal branches during adult development. Electrophysiological methods revealed that functional neuromuscular transmission first occurs quite early during metamorphosis, before the differentiation of contractile elements in the muscle fibers.

Animals↗
PubMed1998

Effects of mitochondrion on calcium transients at intact presynaptic terminals depend on frequency of nerve firing.

The rate and the total amount of Ca2+ elevation in the presynaptic terminals of bullfrog sympathetic ganglia depend on the firing frequency of the terminals. Carbonyl cyanide m-chlorophenylhydrazone (CCCP), a mitochondrial uncoupler, was used for testing whether mitochondrial Ca2+ uptake is one of the mechanisms that underlie this frequency dependence. Fura-2 fluorimetry was used for measurement of intraterminal Ca2+. When stimulations of different durations (30 and 1.5 s) and frequencies (4 and 20 Hz) evoked Ca2+ transients with similar peak amplitudes (264 +/- 22 nM vs. 251 +/- 18 nM, means +/- SE), CCCP augmented the responses to the 4-Hz stimulation 8.9 times more strongly than it did the responses to the 20-Hz stimulation (249.7 +/- 81.5% vs. 25.3 +/- 10.2%). When stimulations delivered at the two frequencies had the same durations (1.5, 3, 6, 10, 20, and 30 s), CCCP enlarged the responses to the 4-Hz stimulations up to 4.2 times more than it did the responses to the 20-Hz stimulations. When the same number of stimuli (120) was delivered at the two frequencies, the effects of CCCP on the responses evoked by the 4-Hz train were again 6.8 times stronger than its effects on the responses to the 20-Hz stimulation. Therefore neither the peak amplitudes of the responses nor the durations of the stimulations dictated the extent to which the mitochondria modulated the peak [Ca2+]i. Instead, the extent of the modulation was governed by the frequency of stimulation. Specifically, the less frequent the Ca2+ influx, the stronger the mitochondrial modulation. Also, during nerve firing Ca2+ release from the ryanodine-sensitive store had a higher potential to influence the [Ca2+]i transients than did Ca2+ removal by the mitochondria for the first 6 s of the responses. On cessation of stimulation, CCCP reduced the initial rapid rate of Ca2+ decay. Thus uptake by the mitochondria was an important mechanism for Ca2+ removal after repetitive firing at the presynaptic terminals.

Action Potentials↗
PubMed1985

Protein kinase C activation leading to protein F1 phosphorylation may regulate synaptic plasticity by presynaptic terminal growth.

It has recently been proposed by the author that protein kinase C regulates the expression of synaptic plasticity. In the present review it is suggested that this regulation involves a growth of presynaptic terminals. This proposal was based on the discovery that one of the substrates of protein kinase C, protein F1 (molecular mass = 47 kDa, pI = 4.5) is increased in its phosphorylation 5 min, 1 hr, and 3 days following long-term potentiation (LTP) in the intact hippocampal formation. No other phosphoprotein studied was altered by LTP. The amplitude or persistence of synaptic plasticity was directly related to the extent of protein F1 phosphorylation. As a critical control, it was shown that protein F1 was unaltered following synaptic activation that did not alter synaptic strength. Protein F1 in the hippocampus was also altered in its phosphorylation after an experience involving memory of a spatial environment. Phosphorylation F1 may thus participate in both neurophysiological and behavioral events that evoke plasticity. The identification of the F1 substrate has recently been sought. The physical characteristics of protein F1 (mol wt., isoelectric point) indicate that it is the same as the B-50 protein and the growth protein, GAP-43. Protein F1 is then a brain-specific, synaptically enriched phosphoprotein. Recent evidence indicates that protein F1 is present in high concentration in growth cones of late embryonic rat brain in which postsynaptic specializations are not detected, suggesting a presynaptic locus. With respect to the identity of the F1 kinase, we have shown that protein F1, like B-50, is a substrate for protein kinase C, a Ca2+/phospholipid-dependent kinase. Activation of this enzyme by tumor-promoting phorbol esters can trigger cell growth and neurite extension. Recent evidence indicates a presynaptic localization of the enzyme. On the basis of the colocalization of enzyme and substrate in the presynaptic terminal it is proposed that protein kinase C control of the phosphorylation state of protein F1 may regulate the expression of synaptic plasticity via presynaptic terminal growth.

Animals↗
PubMed1992

Microdomains of high calcium concentration in a presynaptic terminal.

Increases in intracellular calcium concentration are required for the release of neurotransmitter from presynaptic terminals in all neurons. However, the mechanism by which calcium exerts its effect is not known. A low-sensitivity calcium-dependent photoprotein (n-aequorin-J) was injected into the presynaptic terminal of the giant squid synapse to selectively detect high calcium concentration microdomains. During transmitter release, light emission occurred at specific points or quantum emission domains that remained in the same place during protracted stimulation. Intracellular calcium concentration microdomains on the order of 200 to 300 micromolar occur against the cytoplasmic surface of the plasmalemma during transmitter secretion, supporting the view that the synaptic vesicular fusion responsible for transmitter release is triggered by the activation of a low-affinity calcium-binding site at the active zone.

Aequorin↗
PubMed1990

Chronic maintenance of presynaptic terminals in gliotic hippocampus following ischemia.

Following brief cerebral ischemia, neurons are selectively damaged and die, whereas glial cells and blood vessels survive. This phenomenon of selective vulnerability is well illustrated in the hippocampal CA1 region. Five min of forebrain ischemia in the Mongolian gerbil produced selective neuronal necrosis in the hippocampal CA1 sector. After destruction and loss of CA1 neurons, a remarkable glial reaction (gliosis) was seen. The thickness of the CA1 subfield remained unchanged until 1 month after ischemia and then gradually shrank over several months. Ultrastructural observation of this region revealed persistent maintenance of presynaptic structures. Numerous presynaptic terminals containing synaptic vesicles were scattered throughout the gliotic scar tissue. These presynaptic terminals were apposed to degenerative structures which seemed most likely to be remnants of dendrites. In another group of animals, at one month following ischemic damage in the CA1 sector, the CA3 neurons were destroyed by kainic acid injection. In these animals, numerous degenerating presynaptic boutons were seen in the CA1 sector when fixed 4 days following kainate injection. These results indicate that even in gliotic tissue, presynaptic terminals can survive and maintain their structural characteristics although neuronal cell bodies are almost absent.

Animals↗
PubMed1990

Alzheimer patients and Down patients: abnormal presynaptic terminals are related to cerebral preamyloid deposits.

In Alzheimer's disease, in Down syndrome and in normal aging, scattered deposits of amyloid fibril precursors occur in both cerebral cortex and subcortical grey structures. Within such preamyloid deposits, no degenerating neurites with paired helical filaments have ever been observed. This study, carried out on brains from Alzheimer patients and Down patients, reports on the relationship between preamyloid deposits and neuritic changes. These changes were represented by presynaptic terminal swellings immunolabeled by antisynaptophysin and antiubiquitin antibodies, not by Alz50. These findings support the view that the deposition of amyloid fibril precursors in the neuropil is closely related to presynaptic terminals, although whether the former precedes or follows the development of presynaptic terminal changes is still undetermined.

Adult↗
PubMed2000

Receptors with opposing functions are in postsynaptic microdomains under one presynaptic terminal.

Fast excitatory synaptic transmission through vertebrate autonomic ganglia is mediated by postsynaptic nicotinic acetylcholine receptors (nAChRs). We demonstrate a unique postsynaptic receptor microheterogeneity on chick parasympathetic ciliary ganglion neurons-under one presynaptic terminal, nAChRs and glycine receptors formed separate but proximal clusters. Terminals were loaded with [3H]glycine via the glycine transporter-1 (GlyT-1), which localized to the cholinergic presynaptic terminal membrane; depolarization evoked [3H]glycine release that was calcium independent and blocked by the GlyT-1 inhibitor sarcosine. Ganglionic synaptic transmission mediated by nAChRs was attenuated by glycine. Coexistence of separate clusters of receptors with opposing functions under one terminal contradicts Dale's principle and provides a new mechanism for modulating synaptic activity in vivo.

Amino Acid Transport Systems, Neutral↗
PubMed1972

Calcium transient in presynaptic terminal of squid giant synapse: detection with aequorin.

Microinjection of aequorin, a bioluminescent protein sensitive tocalcium, into the presynaptic terminal of the squid giant synapse demnonstrated an increase in intracellular calcium ion concentration during repetitive synaptic transmission. Although no light flashes synchronous with individual presynaptic : tion potentials were detected, the results are considered consistent with the hypothesis that entry of calcium into the presynaptic terminal triggers release of e synaptic transmitter substance.

Action Potentials↗
PubMed1997

Dynamic responses of presynaptic terminal membrane pools following KCl and sucrose stimulation.

The cholinergic presynaptic terminals of Torpedo electric organ have been examined morphometrically following stimulation by KCI and sucrose. The objective was to confirm correlations predicted by the vesicle hypothesis between miniature end-plate potentials (MEPPs) and morphometric changes in terminal ultrastructure. Both secretegogues generated high frequencies of MEPPs and also distinctive though differing ultrastructural changes. The synaptic vesicles show classes of 68 and 90 nm diameters and both store acetylcholine (ACh). KCl stimulation depleted the 90 nm class first whereas sucrose reversed the order of depletion. Very few instances of actual vesicle fusion were seen. Dose-response correlations between vesicle density and secretegogue strength (mM) and duration were higher with sucrose. Both secretegogues produced declines in vesicle numbers and densities and yielded multimodal distributions of large vesicles with an average 160 nm mean diameter. No meaningful correlations were detected between numbers of MEPPs and vesicles and little evidence was found to indicate that vesicles were fusing to terminal plasma membrane in numbers approximating MEPP release. Linear regression analysis was used to quantitatively examine relationships between the vesicle membrane pool and other pools of the putative exo/endocytotic pathway. Correlation coefficients between vesicle and terminal plasma membrane pools were non-significant and of positive sign, indicating independent, similar responses. Non-significant, negative coefficients were obtained when vacuole and 160 nm vesicle membrane values were included. These tests further argue against claims that vesicles are actively fusing with the plasma membrane. These conflicting findings for both secretegogues preclude meaningful correlations between vesicle changes and numbers of MEPPs generated and again emphasize the difficulty of validating the vesicle hypothesis by ultrastructural means. On the other hand, the study shows that vesicular, vacuolar and terminal membrane pools are dynamically changing during transmitter release, presumably interacting with cytosolic membrane constituents. A dynamical release process therefore has been proposed to account for the two classes of MEPPs, the rapid changes in class ratio and the mutable characteristics of the bell-MEPP that presently challenge the quantal-vesicular claims of prepackaged, immutable, exocytotically released packets of transmitter. This model features a state for each MEPP class with class and size determined at moment of release. For example, a single flicker of a channel would generate the sub-MEPP (defined subunit of an MEPP) and 7-20 flickering channels would generate the bell-MEPP.

Animals↗
PubMed1997

Ca2+ -activated K+ current at presynaptic terminals of goldfish retinal bipolar cells.

Properties of the Ca2+ -activated K+ current (I[K(Ca)]) were investigated in bipolar cells isolated from the goldfish retina. Pharmacological experiments and single channel current recordings demonstrated that I[K(Ca)] represented currents through BK channels, which were confined mostly to the presynaptic terminal. The ensemble noise analysis of I[K(Ca)], which was evoked following the activation of presynaptic Ca2+ current, revealed that the single channel conductance and open probability (P(o)) were approximately 50 pS ([K+]o = 2.6 mM, [K+]i = 140 mM) and 0.6 at 0 mV, respectively. To estimate [Ca2+]i at the cytosolic side of BK channels, activation of I[K(Ca)] was examined in Ca2+-loaded bipolar cells bathed in Co2+ solution. [Ca2+]i was monitored using furaptra fluorimetry. It was found that [Ca2+]i ranged between 10 and 20 microM when P(o) was 0.6. A high concentration of BAPTA ( > 20 mM) was required to suppress I[K(Ca)]. Under this condition, channel number was reduced without changing P(o). Therefore, it is likely that some BK channels are co-localized with Ca2+ channels in presynaptic terminals of retinal bipolar cells.

Animals↗
PubMed1990

Cytoplasmic matrix proteins in central nervous system presynaptic terminals: turnover and effects of osmotic lysis.

Cytomatrix proteins, of primary functional importance in central nervous system neuron terminals, are provided to their site of action in the terminal by axonal transport. Slow component b (SCb) of axonal transport has been proposed to be the biochemical counterpart of the moving cytoplasmic matrix, or cytomatrix, in axons. In the current study, axonally transported SCb proteins destined for neuron terminals were pulse-radiolabeled with [35S]methionine in guinea pig retinal ganglion cells. After SCb proteins reached the terminals in the superior colliculi, synaptosomes were prepared to distinguish between SCb proteins in the preterminal axons and those of the presynaptic terminals. Study of the initial entry and turnover of individual SCb proteins in presynaptic terminals revealed different residence times of certain SCb proteins in comparison with their cohorts. Preliminary information about the structural relationships of the proteins comprising the presynaptic cytomatrix was obtained by examining the solubility of individual SCb proteins relative to other SCb proteins, or membranes from osmotically lysed terminals. Last, treatment of those radiolabeled synaptosomes with varying concentrations of salts was performed to determine possible effects on observed structural relationships.

Animals↗
PubMed1990

[A statistical assessment of the membrane area and of the number of active zones in presynaptic terminals].

Geometrical features of electron microgram profiles of presynaptic terminals (PTs) in the dorsal horn of the cat spinal cord were studied. The statistical approach which has permitted estimating the surface area of the closed membrane on the basis of parameters of its plane random sections is described. Mean surface area of the plasma membrane of observed PTs is estimated. The probability estimate of the mean number of active zones per each presynaptic bouton is considered. The obtained quantitative data are discussed for the possibility to describe physical processes occurring in presynapses.

Animals↗
PubMed2001

Endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals.

Endogenous cannabinoids are considered to function as diffusible and short-lived modulators that may transmit signals retrogradely from postsynaptic to presynaptic neurons. To evaluate this possibility, we have made a paired whole-cell recording from cultured hippocampal neurons with inhibitory synaptic connections. In about 60% of pairs, a cannabinoid agonist greatly reduced the release of the inhibitory neurotransmitter GABA from presynaptic terminals. In most of such pairs but not in those insensitive to the agonist, depolarization of postsynaptic neurons and the resultant elevation of intracellular Ca2+ concentration caused transient suppression of inhibitory synaptic currents, which is mainly due to reduction of GABA release. This depolarization-induced suppression was completely blocked by selective cannabinoid antagonists. Our results reveal that endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals to cause the reduction of transmitter release.

Action Potentials↗
PubMed1998

Frontotemporal dementia: neuropil spheroids and presynaptic terminal degeneration.

We compared the neuropathological changes of 6 patients with clinically diagnosed lobar dementia. In the 4 patients with histopathology consistent with frontotemporal dementia (FTD), moderate neuronal loss contrasted with marked cortical and subcortical gliosis. We found silver-positive, carbohydrate-rich, spheroidal enlargements of presynaptic terminals within the neuropil of specific central nervous system regions. The spheroids were immunopositive for the cytoskeletal proteins tau, the high molecular weight neurofilament subunit (NF-H), and beta-tubulin. No abnormal tau phosphorylation and only rare ubiquitin immunoreactivity were detected in these structures. Carbohydrate modifications, including advanced glycation end products within the spheroid matrix, were confirmed by lectin binding, and by anti-pentosidine immunoreactivity, an indicator of oxidative stress. Ultrastructurally, the spheroids consisted of unmyelinated, membrane-enclosed structures filled with randomly arrayed pairs of filaments, approximately 8 to 10 nm in diameter, that were sparsely labeled with antibodies to unmodified tau (T14) and NF-H. Despite clinical overlap, the central nervous systems of our FTD patients are distinguishable from those of other patients with other lobar dementias, including Pick's disease and corticobasal degeneration, by the absence of abnormally phosphorylated neuronal or glial tau inclusions. The neuropil spheroids are dystrophic changes of certain selectively vulnerable presynaptic terminals, suggesting a retrograde degenerative process in FTD.

Adult↗
PubMed1992

The characteristics of blood-brain barrier in three different conditions--infarction, selective neuronal death and selective loss of presynaptic terminals--following cerebral ischemia.

We investigated the extravasation of serum albumin using immunohistochemistry in three different conditions, i.e., infarction, selective neuronal death and selective loss of presynaptic terminals following cerebral ischemia in gerbils. In selective neuronal death, which is typically found in the CA1 neurons of the hippocampus after 5-min bilateral cerebral ischemia, selective damage of postsynaptic components with intact presynaptic sites was demonstrated by immunohistochemical examination for microtubule-associated protein 2 and synapsin I, and albumin extravasation did not become apparent before postsynaptic structures were destroyed. In cerebral infarction, which was consistently observed in the thalamus after 15-min forebrain ischemia, massive albumin extravasation was visible early after ischemia due probably to the ischemic endothelial necrosis. In selective loss of presynaptic terminals, which was detected at the molecular layer of the dentate gyrus in the contralateral, nonischemic hippocampus after unilateral cerebral ischemia, immunoreaction for albumin was not visualized. Since endothelium and glial cells were intact in morphological aspects in selective damage of both pre- and postsynaptic sites, it was thought that extravasation was facilitated by the stimulation of endothelial cells and glial cells with unknown factors that were induced by the destruction of post- but not presynaptic elements.

Albumins↗
PubMed2001

Neuronal P2X7 receptors are targeted to presynaptic terminals in the central and peripheral nervous systems.

The ionotropic ATP receptor subunits P2X(1-6) receptors play important roles in synaptic transmission, yet the P2X(7) receptor has been reported as absent from neurons in the normal adult brain. Here we use RT-PCR to demonstrate that transcripts for the P2X(7) receptor are present in extracts from the medulla oblongata, spinal cord, and nodose ganglion. Using in situ hybridization mRNA encoding, the P2X(7) receptor was detected in numerous neurons throughout the medulla oblongata and spinal cord. Localizing the P2X(7) receptor protein with immunohistochemistry and electron microscopy revealed that it is targeted to presynaptic terminals in the CNS. Anterograde labeling of vagal afferent terminals before immunohistochemistry confirmed the presence of the receptor in excitatory terminals. Pharmacological activation of the receptor in spinal cord slices by addition of 2'- and 3'-O-(4-benzoylbenzoyl)adenosine 5'-triphosphate (BzATP; 30 microm) resulted in glutamate mediated excitation of recorded neurons, blocked by P2X(7) receptor antagonists oxidized ATP (100 microm) and Brilliant Blue G (2 microm). At the neuromuscular junction (NMJ) immunohistochemistry revealed that the P2X(7) receptor was present in motor nerve terminals. Furthermore, motor nerve terminals loaded with the vital dye FM1-43 in isolated NMJ preparations destained after application of BzATP (30 microm). This BzATP evoked destaining is blocked by oxidized ATP (100 microm) and Brilliant Blue G (1 microm). This indicates that activation of the P2X(7) receptor promotes release of vesicular contents from presynaptic terminals. Such a widespread distribution and functional role suggests that the receptor may be involved in the fundamental regulation of synaptic transmission at the presynaptic site.

Animals↗
PubMed1997

Electron microscopic serial analysis of GABA presynaptic terminals on the axon hillock and initial segment of labeled abducens motoneurons in the rat.

The aim of the present study was to provide a quantitative analysis of the synapses made onto the axon hillock and initial segment of rat abducens motoneurons retrogradely or intracellularly stained with HRP. GABA-immunoreactive terminals contacting these axons were visualized using a postembedding procedure. The presynaptic terminals contained either spherical or pleomorphic vesicles. gamma-Aminobutyric acid (GABA)-immunoreactive axon terminals, which belonged to this last category, were distributed both onto axon hillocks and the proximal part of initial segments. The percentage of axonal membrane covered by synapses ranged from 44.1 to 68.2%. A quantitative analysis performed on a series of ultrathin sectioned terminals contacting the axon of an intracellularly labeled motoneuron revealed a significant correlation between the length of membrane apposition of the terminals and their perimeter or surface area, and also between the area of membrane apposition and terminal volume. GABA-immunoreactive terminals had a mean perimeter and volume that were larger than those of unlabeled axon terminals. The number of active zones was correlated with the area of apposition. Some hypotheses concerning the functional role of the GABAergic innervation of this particular part of the neuron are discussed.

Abducens Nerve↗
PubMed1996

Type I brain hexokinase: axonal transport and membrane associations within central nervous system presynaptic terminals.

While studying the delivery of cytoplasmic proteins to the presynaptic terminals of CNS neurons, we discovered unique characteristics of one protein (p118) conveyed in slow component b (SCb) of axonal transport, the large group of proteins representing the cytoplasmic matrix. Alone among the SCb group, p118 coisolated with the synaptic junctional complex on biochemical fractionation of the radiolabeled synaptic regions. Purification and amino acid sequencing of this protein revealed it is most likely the guinea pig form of type I (brain) hexokinase (ATP:D-hexose 6-phosphotransferase, EC 2.7.1.1). Further biochemical treatments were consistent with this identity. The majority of type I brain hexokinase has been thought to be associated primarily with membranes, in particular the mitochondrial outer membrane. We found that the majority of type I hexokinase is transported toward the terminals at a rate at least 10 times slower than that exhibited by the maximal or average rate of mitochondria. This suggests that, in the axon, the enzyme exhibits transient or dynamic interactions with mitochondria that are moving more rapidly. It is not clear whether hexokinase binds exclusively to mitochondria, or also exhibits association with nonmitochondrial membranes. The unexpected enrichment of hexokinase during synaptic junctional complex purification may result from its strong association with the presynaptic membrane portion of the synapse.

Amino Acid Sequence↗