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PubMed2001

Independent receptors for diadenosine pentaphosphate and ATP in rat midbrain single synaptic terminals.

Diadenosine pentaphosphate (Ap5A) and adenosine 5'-triphosphate (ATP) stimulate a intrasynaptosomal calcium concentration [Ca(2+)](i) increase via specific purinergic receptors in rat midbrain synaptosomes, although nothing is known about their distribution in presynaptic terminals. A microfluorimetric technique to measure [Ca(2+)](i) increase using the dye FURA-2AM, has permitted study of the presence of dinucleotide and P2X receptors in independent isolated synaptic terminals. Our results demonstrate the existence of three populations of synaptosomes: one with dinucleotide receptors (12%), another with P2X receptors (20%) and a third with both (14%). It has been possible to demonstrate that the activation of these receptors occurs only in the presence of extracellular Ca(2+) and that it is also coupled with voltage-dependent Ca(2+) channels. Finally 54% of the synaptosomes that responded to K(+) did not present any calcium increase mediated by the nucleotides used. In summary, ATP and dinucleotides exhibit specific ionotropic receptors that can coexist or not on the same synaptic terminal.

Animals↗
PubMed2001

Presynaptic imaging techniques.

Understanding the detailed molecular events that support chemical synaptic transmission requires high-resolution methods that provide quantitative information combined with molecular specificity. In recent years, many new technological approaches, including genetically encoded fluorescent indicators, ultra-thin sectioning, and live-cell imaging have been brought to bear on understanding the cell biology and physiology of presynaptic terminals.

Animals↗
PubMed1977

Electron microscopic identification of postsynaptic dorsal root terminals: a possible substrate of dorsal root potentials in the frog spinal cord.

Dorsal root fibers were labeled with cobaltous chloride iontophoresis for electron microscopic investigations. In the base of the dorsal horn, where most of the coarser collaterals of dorsal root fibers terminate, many dorsal root terminals were found in postsynaptic relation to synapsing profiles. According to their morphological characteristics, three kinds of presynaptic terminals could be discerned in these complex synapses: axon terminals with spheric vesicles, axon terminals with flattered vesicles and presynaptic dendrites. These latter terminals contained relatively few flattened vesicles accumulated adjacent to a short synaptic articulation surface, and they were rich in cytoplasmic organelles. The functional significance of these structural specializations in the mediation of dorsal root potentials and recurrent inhibition is discussed.

Animals↗
PubMed1998

Immunohistochemical localization of serotonin transporter in normal and colchicine treated rat brain.

Distribution of serotonin transporter (SET) was examined immunohistochemically in the rat brain using two specific polyclonal antibodies raised against oligopeptides corresponding with 15 amino acids of carboxyl terminus and 14 amino acids of amino terminus of rat SET. The distribution and density of SET immunoreactive varicose fibers were quite similar to those of serotonin immunoreactive fibers, however no neuronal cell bodies in the brainstem raphe nuclei was stained in normal rat brain. Electron microscopic study showed that SET immunoreactivity was predominantly localized in the presynaptic terminals. After intraventricular infusion of colchicine, neuronal perikarya of dorsal, median, and pontine raphe nuclei became visible. These results suggest that SET is likely present at the synaptic terminals of serotonergic neurons and such localization may be in good agreement with its pharmacological action which includes reuptake of serotonin at presynaptic nerve terminals.

Animals↗
PubMed2006

Localization of diacylglycerol lipase-alpha around postsynaptic spine suggests close proximity between production site of an endocannabinoid, 2-arachidonoyl-glycerol, and presynaptic cannabinoid CB1 receptor.

2-arachidonoyl-glycerol (2-AG) is an endocannabinoid that is released from postsynaptic neurons, acts retrogradely on presynaptic cannabinoid receptor CB1, and induces short- and long-term suppression of transmitter release. To understand the mechanisms of the 2-AG-mediated retrograde modulation, we investigated subcellular localization of a major 2-AG biosynthetic enzyme, diacylglycerol lipase-alpha (DAGLalpha), by using immunofluorescence and immunoelectron microscopy in the mouse brain. In the cerebellum, DAGLalpha was predominantly expressed in Purkinje cells. DAGLalpha was detected on the dendritic surface and occasionally on the somatic surface, with a distal-to-proximal gradient from spiny branchlets toward somata. DAGLalpha was highly concentrated at the base of spine neck and also accumulated with much lower density on somatodendritic membrane around the spine neck. However, DAGLalpha was excluded from the main body of spine neck and head. In hippocampal pyramidal cells, DAGLalpha was also accumulated in spines. In contrast to the distribution in Purkinje cells, DAGLalpha was distributed in the spine head, neck, or both, whereas somatodendritic membrane was labeled very weakly. These results indicate that DAGLalpha is essentially targeted to postsynaptic spines in cerebellar and hippocampal neurons, but its fine distribution within and around spines is differently regulated between the two neurons. The preferential spine targeting should enable efficient 2-AG production on excitatory synaptic activity and its swift retrograde modulation onto nearby presynaptic terminals expressing CB1. Furthermore, different fine localization within and around spines suggests that the distance between postsynaptic 2-AG production site and presynaptic CB1 is differentially controlled depending on neuron types.

Animals↗
PubMed2002

The neural basis of functional brain imaging signals.

The haemodynamic responses to neural activity that underlie the blood-oxygen-level-dependent (BOLD) signal used in functional magnetic resonance imaging (fMRI) of the brain are often assumed to be driven by energy use, particularly in presynaptic terminals or glia. However, recent work has suggested that most brain energy is used to power postsynaptic currents and action potentials rather than presynaptic or glial activity and, furthermore, that haemodynamic responses are driven by neurotransmitter-related signalling and not directly by the local energy needs of the brain. A firm understanding of the BOLD response will require investigation to be focussed on the neural signalling mechanisms controlling blood flow rather than on the locus of energy use.

Action Potentials↗
PubMed2003

Brief presynaptic bursts evoke synapse-specific retrograde inhibition mediated by endogenous cannabinoids.

Many types of neurons can release endocannabinoids that act as retrograde signals to inhibit neurotransmitter release from presynaptic terminals. Little is known, however, about the properties or role of such inhibition under physiological conditions. Here we report that brief bursts of presynaptic activity evoked endocannabinoid release, which strongly inhibited parallel fiber-to-Purkinje cell synapses in rat cerebellar slices. This retrograde inhibition was triggered by activation of either postsynaptic metabotropic or ionotropic glutamate receptors and was restricted to synapses activated with high-frequency bursts. Thus, endocannabinoids allow neurons to inhibit specific synaptic inputs in response to a burst, thereby dynamically fine-tuning the properties of synaptic integration.

Animals↗
PubMed1998

Post-translational processing and turnover kinetics of presynaptically targeted amyloid precursor superfamily proteins in the central nervous system.

The amyloid precursor superfamily is composed of three highly conserved transmembrane glycoproteins, the amyloid precursor protein (APP) and amyloid precursor-like proteins 1 and 2 (APLP1, APLP2), whose functions are unknown. Proteolytic cleavage of APP yields the betaA4 peptide, the major component of cerebral amyloid in Alzheimer's disease. Here we show that five post-translationally modified, full-length species of APP and APLP2 (but not APLP1) arrive at the mature presynaptic terminal in the fastest wave of axonal transport and are subsequently rapidly cleared (mean half-life of 3.5 h). Rapid turnover of presynaptic APP and APLP2 occurs independently of visual activity. Turnover of the most rapidly arriving APP species was accompanied by a delayed accumulation of a 120-kDa, APP fragment lacking the C terminus, consistent with presynaptic APP turnover via constitutive proteolysis. Turnover of APLP2 was not accompanied by detectable APLP2 fragment peptides, suggesting either that APLP2 either is more rapidly degraded than is APP or is retrogradely transported shortly after reaching the terminus. A single 150-kDa APLP2 species containing the Kunitz protease inhibitor domain is the major amyloid precursor superfamily protein transported to the presynapse. Presynaptic APP and APLP2 are sialylated and N- and O-glycosylated, and some also carry chondroitin sulfate glycosaminoglycan and/or dermatan sulfate glycosaminoglycan. The rapid kinetics for turnover of APP and APLP2 predict a sensitive balance of synthesis, transport, and elimination rates that may be critical to normal neuronal functions and metabolic fates of these proteins.

Alzheimer Disease↗
PubMed2001

Ultra rapid calcium events in electrically stimulated frog nerve terminals.

Fast calcium events occurring in cytoplasmic organelles after a single electrical stimulus were investigated by electron spectroscopic imaging (an electron microscope technique that reveals total calcium with high sensitivity and spatial resolution) in quick frozen presynaptic terminals of the frog neuromuscular junction. In resting preparations synaptic vesicles showed a prominent calcium signal whereas mitochondria were mostly negative and only some of the cisternae of the endoplasmic reticulum were clearly positive. In preparations quick frozen 10 ms after the application to the nerve of a single, supramaximal electric stimulus, no obvious change was observed in synaptic vesicles, while calcium levels rose to high values in the endoplasmic reticulum cisternae and in the matrix of mitochondria. Voltage-induced influx of Ca(2+) within synaptic terminals appears therefore to induce an extremely rapid uptake into selected organelles. The possible physiological role of this response is discussed.

Animals↗
PubMed1994

Multiple subtypes of voltage-gated calcium currents in the Edinger-Westphal nucleus.

Avian Edinger-Westphal (EW) neurons provide a unique opportunity to compare electrophysiologically the membranes of cell bodies and terminals in the same population of neurons. Axons that originate from neurons in the lateral region of the EW nucleus form a morphologically distinct presynaptic terminal, known as a calyx, on ciliary ganglion neurons. Several studies have shown that calyciform terminals in the ciliary ganglion exhibit predominantly N-type, high-voltage-activated (HVA) calcium channels. The goal of this study was to characterize and compare the calcium currents expressed in EW cell somas with those reported in the terminals. Whole-cell patch-clamp techniques were used to record from cell bodies in the lateral EW nucleus in slice preparations. Slices were obtained from embryonic day 16 chicks, matching the age of the embryos in which calyces were studied. Recordings were localized to the lateral region of the EW nucleus using Lucifer yellow fills. Voltage-step commands from -70 to 0 mV produced calcium currents with both a sustained and an inactivating component. Depolarization steps to 0 mV from a holding potential of -40 mV eliminated the inactivating component. These recordings suggested the presence of both LVA and HVA calcium currents. Application of 0.1 mM NiCl2 produced a reversible decrease in the amplitude of the whole-cell calcium current, preferentially affecting the inactivating component. The Ni2+(-)sensitive current activated and inactivated rapidly in a voltage-dependent manner. Treatment with 0.1 mM cadmium chloride caused a reversible reduction in the amplitude of the calcium current.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

Synaptic structural complexity as a factor enhancing probability of calcium-mediated transmitter release.

1. In a model synaptic system, the excitatory neuromuscular junction of the freshwater crayfish, the nerve terminals possess synapses that vary in structural complexity, with numbers of active zones ranging from zero to five. Active zones on individual synapses show a wide range of separation distances. We tested the hypothesis that two active zones of a single synapse in close proximity can enhance the localized increase in free calcium ion concentration, thus enhancing the probability of neurotransmission at that synapse. We evaluated the increase in calcium ion concentration as a function of distance between adjacent active zones. 2. To test this hypothesis, a reaction-diffusion model for Ca2+ entering the presynaptic terminals was used. This test was used because 1) present measurement techniques are inadequate to resolve quantitatively the highly localized, transient calcium microdomains at synaptic active zones; and 2) there is presently no suitable preparation for physiological recording from isolated synapses with varying distances between active zones. Included in the model were intracellular buffer and a typical distribution of voltage-activated Ca2+ channels for an active zone, estimated from freeze-fracture micrographs. 3. The model indicated that localized Ca2+ clouds from discrete active zones can overlap to create spatial enhancement of Ca2+ concentration. The degree of interaction between two active zones depends on the distance between them. When two typical active zones are separated by < or = 200 nm, the maximum intracellular Ca2+ concentration ([Ca2+]i) is greater at 1) the midpoint between them, and 2) the center of each one, than at the corresponding positions for a single isolated active zone. Enhanced [Ca2+]i at the edge of the active zone where "docked" synaptic vesicles occur would be expected to have an effect on transmitter release. 4. When the model includes no intracellular buffer, the increase in [Ca2+]i is a linear function of calcium channel current, but is a nonlinear function of the number of conducting calcium channels in an active zone. With immobile buffer included, the increase in [Ca2+]i is nonlinear with respect to both channel current and number of conducting channels. 5. Inclusion of immobile buffer in the model provides "released" residual calcium that slowly accumulates during a train of current pulses. Released residual calcium accumulates more rapidly at paired active zones separated by < or = 200 nm that at single isolated active zones. 6. We propose that the probability of release is enhanced at synapses with closely associated active zones. Synapses of this type ("complex" synapses) could be selectively recruited when the neuron is active at low frequencies. At higher frequencies of neuronal activity, more distant active zones may interact and acquire a greater probability of releasing quanta. This would provide the nerve terminal with one component of a mechanism for frequency facilitation, because the number of quanta released by the terminal as a whole would increase with frequency. Thus variation in synaptic complexity in a nerve terminal provides a mechanism for short-term plasticity of transmitter release.

Animals↗
PubMed2002

Interaction between metabotropic glutamate receptor 7 and alpha tubulin.

Metabotropic glutamate receptors (mGluRs) mediate a variety of responses to glutamate in the central nervous system. A primary role for group-III mGluRs is to inhibit neurotransmitter release from presynaptic terminals, but the molecular mechanisms that regulate presynaptic trafficking and activity of group-III mGluRs are not well understood. Here, we describe the interaction of mGluR7, a group-III mGluR and presynaptic autoreceptor, with the cytoskeletal protein, alpha tubulin. The mGluR7 carboxy terminal (CT) region was expressed as a GST fusion protein and incubated with rat brain extract to purify potential mGluR7-interacting proteins. These studies yielded a single prominent mGluR7 CT-associated protein of 55 kDa, which subsequent microsequencing analysis revealed to be alpha tubulin. Coimmunoprecipitation assays confirmed that full-length mGluR7 and alpha tubulin interact in rat brain as well as in BHK cells stably expressing mGluR7a, a splice variant of mGluR7. In addition, protein overlay experiments showed that the CT domain of mGluR7a binds specifically to purified tubulin and calmodulin, but not to bovine serum albumin. Further pull-down studies revealed that another splice variant mGluR7b also interacts with alpha tubulin, indicating that the binding region is not localized to the splice-variant regions of either mGluR7a (900-915) or mGluR7b (900-923). Indeed, deletion mutagenesis experiments revealed that the alpha tubulin-binding site is located within amino acids 873-892 of the mGluR7 CT domain, a region known to be important for regulation of mGluR7 trafficking. Interestingly, activation of mGluR7a in cells results in an immediate and significant decrease in alpha tubulin binding. These data suggest that the mGluR7/alpha tubulin interaction may provide a mechanism to control access of the CT domain to regulatory molecules, or alternatively, that this interaction may lead to morphological changes in the presynaptic membrane in response to receptor activation.

Amino Acid Sequence↗
PubMed1999

Prostaglandin E2 inhibits spontaneous inhibitory postsynaptic currents in rat supraoptic neurones via presynaptic EP receptors.

Prostaglandin E2 (PGE2) has been implicated in the excitatory regulation of magnocellular neurones in the supraoptic nucleus (SON). We have recently reported that PGE2 excited SON neurones by directly activating postsynaptic PGE2 receptors (EP receptors) of a subclass other than EP1-3, but did not affect excitatory postsynaptic currents (EPSCs). In the present study, we examined presynaptic effects of PGE2 on rat SON neurones by measuring spontaneous inhibitory postsynaptic currents (IPSCs) by a slice patch-clamp technique. PGE2 inhibited spontaneous IPSCs in a dose-dependent and reversible manner. PGE2 selectively suppressed the frequency of IPSCs without affecting the amplitude of IPSCs in the presence of tetrodotoxin, a blocker of Na+ channels, indicating that the effects were presynaptic. The inhibitory effects of PGE2 on the frequency of IPSCs were mimicked by the EP1/EP3 agonists, 17PT-PGE2 and sulprostone, and the EP2/EP3 agonist, misoprostol, whereas the EP2 agonist, butaprost, or the FP agonist, fluprostenol, had little effect. The effects of PGE2 on IPSCs were unaffected by the selective EP1 antagonist, SC-51322. They were unaffected also by antagonists of GABAB and alpha2 adrenergic receptors, which are present at presynaptic terminals of GABA neurones in the SON and cause suppression of spontaneous IPSCs. The inhibitor of PG synthesis, indomethacin, had little effect on spontaneous IPSCs and on the inhibitory effects of PGE2 as well as of the GABAB agonist, baclofen, and noradrenaline. These results suggest that PGE2 inhibits release of GABA from the GABAergic terminals innervating SON neurones by activating presynaptic EP receptors, presumably of the EP3 subclass, and that such a presynaptic mechanism may play a role in the excitatory regulation of SON neurones by PGE2.

Alprostadil↗
PubMed2002

Functional identification of a cloned squid presynaptic voltage-dependent calcium channel.

We previously cloned a voltage-dependent Ca2+ channel alpha1 subunit LoCa(v)2 cDNA from the squid optic lobe. LoCa(v)2 is designated as a non-L-type voltage-dependent Ca2+ channel based on its amino acid sequence. We performed functional expression experiments of LoCa(v)2 in oocytes and characterized the expressed currents electrophysiologically and pharmacologically. The LoCa(v)2 current was high voltage-activated and the peak current was maximal at +20 mV and lasted for long during activation. The LoCa(v)2 current was not inhibited by the drugs and toxins examined except for omega-agatoxin IVA and PLTX-II. Omega-agatoxin IVA, which is a P-type channel blocker, moderately inhibited the LoCa(v)2 current at higher concentration. PLTX-II, which blocks insect presynaptic Ca2+ channel, inhibited the LoCa(v)2 current at lower concentration. Immunohistochemical investigation showed that the LoCa(v)2 protein may exist at presynaptic terminals in the squid optic lobe. These results suggest that LoCa(v)2 is an omega-agatoxin IVA and PLTX-II-sensitive presynaptic Ca2+ channel in the squid nervous system.

Animals↗
PubMed2002

Dopamine selectively reduces GABA(B) transmission onto dopaminergic neurones by an unconventional presynaptic action.

The functioning of midbrain dopaminergic neurones is closely involved in mental processes and movement. In particular the modulation of the inhibitory inputs on these cells might be crucial in controlling firing activity and dopamine (DA) release in the brain. Here, we report a concentration-dependent depressant action of dopamine on the GABA(B) IPSPs intracellularly recorded from dopaminergic neurones. Such effect was observed in spite of the presence of D(1)/D(2) dopamine receptor antagonists. A reduction of the GABA(B) IPSPs was also caused by noradrenaline (norepinephrine) and by L-beta-3,4-dihydroxyphenylalanine (L-DOPA), which is metabolically transformed into DA. The DA-induced depression of the IPSPs was partially antagonised by the alpha2 antagonists yohimbine and phentolamine. DA did not change the postsynaptic effects of the GABA(B) agonist baclofen, suggesting a presynaptic site of action. Furthermore, DA did not modulate the GABA(A)-mediated IPSP. The DA-induced depression of the GABA(B) IPSP occluded the depression produced by serotonin and was not antagonized by serotonin antagonists. The DA- and 5-HT-induced depression of the GABA(B) IPSP persisted when calcium and potassium currents were reduced in to the presynaptic terminals. These results describe an unconventional presynaptic, D(1) and D(2) independent action of DA on the GABA(B) IPSP. This might have a principal role in determining therapeutic/side effects of L-DOPA and antipsychotics and could be also involved in drug abuse.

4-Aminopyridine↗
PubMed1990

Paired individual and mean postsynaptic currents recorded in four-cell networks of Aplysia.

1. Presynaptic neurons B4 and B5 of Aplysia buccal ganglia produce similar inhibitory postsynaptic currents (PSCs) in several postsynaptic follower cells. Two previous papers have characterized the variability of synaptic current amplitude and decay time both for individual PSCs and also for mean values characterizing synapses and have compared PSC amplitude and time course at different synapses sharing a common presynaptic or postsynaptic neuron. 2. To distinguish similarity in synaptic current amplitude or decay introduced by a common pre- or postsynaptic neuron from similarity because of factors common to the particular ganglion or animal, paired synapses were analyzed in four-cell networks in which each of two identified presynaptic neurons produces similar PSCs in each of two postsynaptic cells. Pairing the same synaptic data by common presynaptic or postsynaptic neuron tests if the presynaptic or postsynaptic element partially specifies a parameter; cross-pairing controls for more global factors. Paired values of peak conductance gpeak and decay time constant tau were compared for both individual sequential PSCs and for averages characterizing synapses. Analyses of individual PSCs examine processes affecting synaptic plasticity on a time scale of seconds to minutes, while average values compare more slowly varying factors. 3. Peak amplitudes were compared between individual PSCs in each of 24 paired sets. Correlations of gpeak fluctuations were significantly larger for PSCs produced by the same presynaptic neuron than for postsynaptic or cross pairings (P less than 0.05), consistent with partially correlated fluctuations in transmitter release at different presynaptic terminals. 4. Firing rates of individual presynaptic neurons were modulated to induce variability of test PSCs. These manipulations altered synaptic peak amplitudes in paired postsynaptic neurons, although not to the same degree. Manipulation of a single presynaptic neuron modulated input from that neuron alone to common postsynaptic cells without any effect on input from the paired presynaptic neuron. When fluctuations in the amplitude of gpeak were examined in runs incorporating presynaptic modulation, correlations were strong for sets of PSCs sharing a common presynaptic neuron (R = 0.87), significantly greater (P less than 0.001) than for other pairings. 5. In contrast to the partial presynaptic specification of fluctuations of individual PSCs, values of synaptic amplitude and time course averaged over 21-132 PSCs at a given synapse reflect postsynaptic determinants. Mean values of gpeak characterizing synapses paired by common postsynaptic cell are highly similar (P = 0.0001), in contrast to the lack of similarity seen when the same data are presynaptically (P = 0.11) or cross (P = 0.36) paired.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Serotonergic modulation of swimming speed in the pteropod mollusc Clione limacina. I. Serotonin immunoreactivity in the central nervous system and wings.

Serotonin-immunoreactive somata in the pteropod mollusc Clione limacina were restricted to the cerebral and pedal ganglia. 10-14 pairs of cells were consistently found in the cerebral ganglia, including one large pair that had soma positions and axon branching patterns reminiscent of those of the metacerebral cells of other molluscs. Two clusters of somata were found on the midline near the cerebral commissure, one on the anterior-lateral margin and one posterior-laterally. A distinct paired cluster of up to nine somata was found on the dorso-lateral margin of the pedal ganglia, near the emergence of the pedal commissure. Up to five of these cells innervated the ipsilateral wing via the wing nerve. Dye-fills of these cells showed that they branch repeatedly in the ipsilateral wing and innervate the swim musculature. Double-labelling experiments indicated that the filled neurons were also serotonin-immunoreactive. Neurobiotin fills that were processed for electron microscopy revealed two types of terminals associated with the swim musculature: direct contacts and reactive terminals adjacent to non-labelled presynaptic terminals. Additional immunoreactive neurons in the pedal ganglia included the asymmetrical heart excitor neuron of the left pedal ganglion and up to nine ventral somata.

Animals↗
PubMed2003

Developmental switch from GABA to glycine release in single central synaptic terminals.

Early in postnatal development, inhibitory inputs to rat lateral superior olive (LSO) neurons change from releasing predominantly GABA to releasing predominantly glycine into the synapse. Here we show that spontaneous miniature inhibitory postsynaptic currents (mIPSCs) also change from GABAergic to glycinergic over the first two postnatal weeks. Many 'mixed' mIPSCs, resulting from co-release of glycine and GABA from the same vesicles, are seen during this transition. Immunohistochemistry showed that a large number of terminals contained both GABA and glycine at postnatal day 8 (P8). By P14, both the content of GABA in these mixed terminals and the contribution of GABA to the mixed mIPSCs had decreased. The content of glycine in terminals increased over the same period. Our results indicate that switching from GABAergic to glycinergic inputs to the LSO may occur at the level of a single presynaptic terminal. This demonstrates a new form of developmental plasticity at the level of a single central synapse.

Animals↗