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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To maintain synaptic transmission during intense neuronal activities, the synaptic vesicle (SV) pool at release sites is effectively replenished by recruitment of SVs from the reserve pool and/or by endocytosis. The authors have studied dynamics of SVs using a fluorescence dye, FM1-43, which is incorporated into SVs during endocytosis and released by exocytosis. Drosophila is one of the most suitable preparations for genetic and pharmacological analyses, and this provides a useful model system. The authors found at the neuromuscular junctions of Drosophila that exocytosis and endocytosis of SVs are triggered by Ca(2+) influx through distinct routes and that selective inhibition of exocytosis or endocytosis resulted in depression of synaptic transmission with a distinct time course. They identified two SV pools in a single presynaptic bouton. The exo/endo cycling pool (ECP) is loaded with FM1-43 during low-frequency stimulation and locates close to release sites in the periphery of boutons, whereas the reserve pool (RP) is loaded and unloaded only during high-frequency stimulation and resides primarily in the center of boutons. The size of ECP closely correlates with the quantal content of evoked release, suggesting that SVs in the ECP are primarily involved in synaptic transmission. SVs in the RP are recruited to synaptic transmission by a process involving the cAMP/PKA cascade during high-frequency stimulation. Cytochalasin D blocked this recruitment process, suggesting involvement of filamentous actin. Endocytosed SVs replenish the ECP during stimulation and the RP after tetanic stimulation. Replenishment of the ECP depends on Ca(2+) influx from external solutions, and that of the RP is initiated by Ca(2+) release from internal stores. Thus, SV dynamics is closely involved in modulation of synaptic efficacy and influences synaptic plasticity.
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PMID:Exocytosis and endocytosis of synaptic vesicles and functional roles of vesicle pools: lessons from the Drosophila neuromuscular junction. 1574 82

Synaptic scaling is a form of homeostatic plasticity that scales synaptic strengths up or down to compensate for prolonged changes in activity. It has been controversial whether this plasticity is expressed presynaptically, postsynaptically, or both. Here we describe in detail the homeostatic changes that take place at excitatory synapses in visual cortical cultures after 1 or 2 d of activity blockade. After 7-10 d in vitro, activity blockade significantly increased postsynaptic accumulation of synaptic AMPA receptors via proportional increases in glutamate receptor 1 (GluR1) and GluR2. Time-lapse imaging of enhanced green fluorescent protein-tagged AMPA receptors revealed that receptor accumulation increased progressively over 2 d of activity blockade and affected the entire population of imaged synapses. The strength of synaptic connections between pyramidal neurons was more than doubled after activity blockade without affecting short-term depression or the coefficient of variation of the postsynaptic responses. Furthermore, uptake of the fluorescent styryl dye FM1-43 (N-(3-triethylammoniumpropyl)-4-[4-(dibutylamino)styryl] pyridinium dibromide) by presynaptic terminals was not different at control and activity-blocked synapses. In addition to the increased accumulation of postsynaptic AMPA receptors, boosting of dendritic AMPA currents by sodium channels was increased by activity blockade. These data indicate that, at young neocortical synapses, synaptic scaling has a predominantly postsynaptic locus and functions as a gain control mechanism to regulate neuronal activity without affecting the dynamics of synaptic transmission.
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PMID:Postsynaptic expression of homeostatic plasticity at neocortical synapses. 1577 49

Recent studies using the styryl dye FM1-43 and two-photon microscopy to directly visualize transmitter release at CA3-CA1 excitatory synapses in the hippocampus have demonstrated that activity-dependent long-term potentiation (LTP) and long-term depression are associated with alterations in vesicular release. It is not known whether particular vesicle pools preferentially express these alterations or what second messenger cascades are involved. To address these questions, we selectively loaded FM1-43 into the rapidly recycling pool (RRP) of vesicles by use of a brief hypertonic shock to release and load the RRP. We demonstrate here that the induction of LTP can lead to a selective long-lasting enhancement in presynaptic release from the RRP, while reserve pool kinetics remain unchanged. LTP of RRP release was N-methyl-d-aspartate receptor-dependent and also required production of the intercellular messenger NO and activation of receptor tyrosine kinase. Measurement of FM1-43 stimulus-evoked uptake rates following induction of LTP confirmed that LTP produces more rapid recycling of vesicles released by electrical stimulation, consistent with an enhanced release probability from the RRP.
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PMID:Imaging LTP of presynaptic release of FM1-43 from the rapidly recycling vesicle pool of Schaffer collateral-CA1 synapses in rat hippocampal slices. 1630 88

Postsynaptic alterations have been suggested to account for NMDA receptor (NMDAR)-dependent long-term depression (LTD) and long-term potentiation of synaptic strength, although there is substantial evidence supporting changes in presynaptic release. Direct chemical activation of either NMDA or group I metabotropic glutamate receptor (mGluR1) elicits LTD of similar magnitudes, but it is unknown whether they share common expression mechanisms. Using dual-photon laser-scanning microscopy of FM1-43 [N-(3-triethylammoniumpropyl)-4-(4-(dibutylamino)styryl)pyridinium dibromide] to directly visualize presynaptic vesicular release from the rapidly recycling vesicle pool (RRP) at Schaffer collateral terminals in field CA1 of rat hippocampal slices, we found that a persistent reduction in vesicular release from the RRP is induced by NMDA-LTD but not by mGluR1-LTD. Variance-mean analyses of Schaffer collateral release probability (P(r)) at varying extracellular calcium concentrations confirmed that NMDA-LTD was associated with reduced P(r), whereas mGluR1-LTD was not. Pharmacological isolation of NMDAR-dependent and mGluR-dependent forms of stimulus-evoked LTD revealed that both are composed of a combination of presynaptic and postsynaptic alterations. However, when group I mGluR-dependent LTD was isolated by combining an NMDAR blocker with a group II mGluR antagonist, this form of LTD was purely postsynaptic. The nitric oxide synthase inhibitor N omega-nitro-L-arginine blocked the induction of NMDA-LTD but did not alter mGluR-LTD, consistent with a selective role for nitric oxide as a retrograde messenger mediating NMDA-LTD. These data demonstrate that single synapses can express multiple forms of LTD with different sites of expression, that NMDA-LTD is a combination of presynaptic and postsynaptic alterations, but that group I mGluR-LTD appears to be expressed entirely postsynaptically.
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PMID:NMDA-dependent, but not group I metabotropic glutamate receptor-dependent, long-term depression at Schaffer collateral-CA1 synapses is associated with long-term reduction of release from the rapidly recycling presynaptic vesicle pool. 1702 Nov 82

The mechanism by which synaptic vesicles (SVs) are recruited to the release site is poorly understood. One candidate mechanism for trafficking of SVs is the myosin-actin motor system. Myosin activity is modulated by myosin light chain kinase (MLCK), which in turn is activated by calmodulin. Ca(2+) signaling in presynaptic terminals, therefore, may serve to regulate SV mobility along actin filaments via MLCK. Previous studies in different types of synapses have supported such a hypothesis. Here, we further investigated the role of MLCK in neurotransmitter release at glutamatergic synapses in cultured hippocampal neurons by examining the effects of two MLCK inhibitors, 1-(5-iodonaphthalene-1-sulfonyl)-1H-hexahydro-1,4-diazepine.HCl (ML-7) and wortmannin. Bath application of ML-7 enhanced short-term depression of EPSCs to repetitive stimulation, whereas it reduced presynaptic release probability. However, ML-7 also inhibited action potential amplitude and voltage-gated Ca(2+) channel currents. These effects were not mimicked by wortmannin, suggesting that ML-7 was not specific to MLCK in hippocampal neurons. When SV exocytosis was directly triggered by a Ca(2+) ionophore, calcimycin, to bypass voltage-gated Ca(2+) channels, ML-7 had no effect on neurotransmitter release. Furthermore, when SV exocytosis elicited by electrical field stimulation was monitored by styryl dye, FM1-43 [N-(3-triethylammoniumpropyl)-4-(4-(dibutylamino)styryl)pyridinium dibromide], the unloading kinetics of the dye was not altered in the presence of wortmannin. These data indicate that MLCK is not a major regulator of presynaptic SV trafficking during repetitive exocytosis at hippocampal synapses.
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PMID:Myosin light chain kinase is not a regulator of synaptic vesicle trafficking during repetitive exocytosis in cultured hippocampal neurons. 1709 82

Synaptic communication requires an efficient coupling of vesicle fusion to release neurotransmitter and vesicle retrieval to repopulate the synapse. In synapses of the CNS many proteins involved in exocytosis, endocytosis and refilling of vesicles have been identified. However, little is known about the organization and functioning of synaptic contacts in the enteric nervous system (ENS). We used fluorescent antibodies against presynaptic proteins (synaptobrevin, synaptophysin, synaptotagmin and bassoon) to identify synaptic contacts not only in guinea-pig enteric ganglia but also in the interconnecting fiber strands. Staining patterns were not altered by colchicine (100 microM), ruling out a contribution of protein transport at the time of fixation. Active release sites at fiber intersections and around neuronal cell bodies were labeled with FM1-43 (10 microM) by high K+ or electric field stimulation (EFS). During a second round of EFS, vesicles were reused, as reflected by dye loss. Destaining rates increased with stimulus frequency (2-30 Hz), reaching a maximum at about 15 Hz, likely caused by synaptic depression at higher frequencies. Tetrodotoxin (TTX, 1 microM) as well as nominally zero external Ca2+ (2 mM EGTA) prevented all destaining. The readily releasable pool (RRP, a subset of vesicles docked at the membrane and ready to fuse upon [Ca2+]i increase) can be specifically released by a hypertonic challenge (500 mM sucrose). We measured this pool to be approximately 27% of the total recycling pool, remarkably similar to synapses in the CNS. In whole-mount preparations, FM1-43 also reliably labeled active release sites in ganglia, fiber strands and in muscle bundles. The staining pattern indicated that the presynaptic antibodies mainly labeled active sites. The presence of numerous release sites suggests information processing capability within interconnecting fibers. With FM imaging, enteric synaptic function can be monitored independent of any postsynaptic modulation. Although electron microscopy data suggest that ENS synapses may not be as specialized as hippocampal synapses, remarkably similar release properties were measured.
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PMID:Spatial organization and dynamic properties of neurotransmitter release sites in the enteric nervous system. 1719 3

We employed optical detection of the lipophylic dye FM1-43 and focal recordings of quantal release to investigate how synapsin affects vesicle cycling at the neuromuscular junction of synapsin knockout (Syn KO) Drosophila. Loading the dye employing high K+ stimulation, which presumably involves the recycling pool of vesicles in exo/endocytosis, stained the periphery of wild type (WT) boutons, while in Syn KO the dye was redistributed towards the center of the bouton. When endocytosis was promoted by cyclosporin A pretreatment, the dye uptake was significantly enhanced in WT boutons, and the entire boutons were stained, suggesting staining of the reserve vesicle pool. In Syn KO boutons, the same loading paradigm produced fainter staining and significantly faster destaining. When the axon was stimulated electrically, a distinct difference in dye loading patterns was observed in WT boutons at different stimulation frequencies: a low stimulation frequency (3 Hz) produced a ring-shaped staining pattern, while at a higher frequency (10 Hz) the dye was redistributed towards the center of the bouton and the fluorescence intensity was significantly increased. This difference in staining patterns was essentially disrupted in Syn KO boutons, although synapsin did not affect the rate of quantal release. Stimulation of the nerve in the presence of bafilomycin, the blocker of the transmitter uptake, produced significantly stronger depression in Syn KO boutons. These results, taken together, suggest that synapsin maintains the reserve pool of vesicles and segregation between the recycling and reserve pools, and that it mediates mobilization of the reserve pool during intense stimulation.
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PMID:Synapsin maintains the reserve vesicle pool and spatial segregation of the recycling pool in Drosophila presynaptic boutons. 1790 36

Cyclic AMP signaling plays a central role in regulating activity at a number of synapses in the brain. We showed previously that pairing activation of receptors that inhibit adenylate cyclase (AC) and reduce the concentration of cyclic AMP, with elevation of the concentration of cyclic GMP is sufficient to elicit a presynaptically expressed form of LTD at Schaffer collateral-CA1 synapses in the hippocampus. To directly test the role of AC inhibition and G-protein signaling in LTD at these synapses, we utilized transgenic mice that express a mutant, constitutively active inhibitory G protein, Galpha(i2), in principal neurons of the forebrain. Transgene expression of Galpha(i2) markedly enhanced LTD and impaired late-phase LTP at Schaffer collateral synapses, with no associated differences in input/output relations, paired-pulse facilitation, or NMDA receptor-gated conductances. When paired with application of a type V phosphodiesterase inhibitor to elevate the concentration of intracellular cyclic GMP, constitutively active Galpha(i2) expression converted the transient depression normally caused by this treatment to an LTD that persisted after the drug was washed out. Moreover, this effect could be mimicked in control slices by pairing type V phosphodiesterase inhibitor application with application of a PKA inhibitor. Electrophysiological recordings of spontaneous excitatory postsynaptic currents and two-photon visualization of vesicular release using FM1-43 revealed that constitutively active Galpha(i2) tonically reduced basal release probability from the rapidly recycling vesicle pool of Schaffer collateral terminals. Our findings support the hypothesis that inhibitory G-protein signaling acts presynaptically to regulate release, and, when paired with elevations in the concentration of cyclic GMP, converts a transient cyclic GMP-induced depression into a long-lasting decrease in release.
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PMID:Galpha(i2) inhibition of adenylate cyclase regulates presynaptic activity and unmasks cGMP-dependent long-term depression at Schaffer collateral-CA1 hippocampal synapses. 1839 Nov 87

Glutamate receptor (GluR) delta2 selectively expressed in cerebellar Purkinje cells plays key roles in synapse formation, long-term depression and motor learning. We propose that GluRdelta2 regulates synapse formation by making a physical linkage between the active zone and postsynaptic density. To examine the issue, GluRdelta2-transfected 293T cells were cultured with cerebellar neurons. We found numerous punctate signals for presynaptic markers on the surface of 293T cells expressing GluRdelta2. The presynaptic specializations induced by GluRdelta2 were capable of exo- and endocytosis as indicated by FM1-43 dye labeling. Replacement of the extracellular N-terminal domain (NTD) of GluRdelta2 with that of the AMPA receptor GluRalpha1 abolished the inducing activity. The NTD of GluRdelta2 fused to the immunoglobulin constant region successfully induced the accumulation of presynaptic specializations on the surface of beads bearing the fusion protein. These results suggest that GluRdelta2 triggers presynaptic differentiation by direct interaction with presynaptic components through the NTD.
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PMID:The amino-terminal domain of glutamate receptor delta2 triggers presynaptic differentiation. 1900 Aug 99

We combined electron microscopy (EM), synaptic vesicle staining by fluorescent marker FM1-43, photoconversion of the dye into an electron dense product, and electrical recordings of synaptic responses to study the distribution of reserve and recycling vesicles and its dependence on stimulation in Drosophila motor boutons. We showed that, at rest, vesicles are distributed over the periphery of the bouton, with the recycling and reserve pools being intermixed and the central core of the bouton being devoid of vesicles. Continuous high-frequency stimulation followed by a resting period mobilized the reserve vesicles into the recycling pool and, most notably, produced an increase in vesicle abundance. Recordings of synaptic activity from the temperature-sensitive endocytosis mutant shibire during continuous stimulation until complete depression provided an independent estimate of the increase in vesicle abundance on intense stimulation. EM analysis demonstrated that continuous stimulation produced an increase in the vesicle density, whereas during a subsequent resting period, vesicles filled empty areas of the bouton, spreading toward its central core. Although the observed structural potentiation did not alter basal transmitter release, it produced an increased synaptic enhancement during high-frequency stimulation. The latter effect was not observed when the boutons were potentiated using high-frequency stimulation without a subsequent resting period. We concluded therefore that the newly formed vesicles replenish the reserve pool during a resting period following intense stimulation.
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PMID:Stimulation-induced formation of the reserve pool of vesicles in Drosophila motor boutons. 1927 47


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