共查询到20条相似文献，搜索用时 31 毫秒
1.
Gerber SH Rah JC Min SW Liu X de Wit H Dulubova I Meyer AC Rizo J Arancillo M Hammer RE Verhage M Rosenmund C Südhof TC 《Science (New York, N.Y.)》2008,321(5895):1507-1510
During synaptic vesicle fusion, the soluble N-ethylmaleimide-sensitive factor-attachment protein receptor (SNARE) protein syntaxin-1 exhibits two conformations that both bind to Munc18-1: a "closed" conformation outside the SNARE complex and an "open" conformation in the SNARE complex. Although SNARE complexes containing open syntaxin-1 and Munc18-1 are essential for exocytosis, the function of closed syntaxin-1 is unknown. We generated knockin/knockout mice that expressed only open syntaxin-1B. Syntaxin-1B(Open) mice were viable but succumbed to generalized seizures at 2 to 3 months of age. Binding of Munc18-1 to syntaxin-1 was impaired in syntaxin-1B(Open) synapses, and the size of the readily releasable vesicle pool was decreased; however, the rate of synaptic vesicle fusion was dramatically enhanced. Thus, the closed conformation of syntaxin-1 gates the initiation of the synaptic vesicle fusion reaction, which is then mediated by SNARE-complex/Munc18-1 assemblies. 相似文献
2.
Schoch S Deák F Königstorfer A Mozhayeva M Sara Y Südhof TC Kavalali ET 《Science (New York, N.Y.)》2001,294(5544):1117-1122
SNAREs (soluble NSF-attachment protein receptors) are generally acknowledged as central components of membrane fusion reactions, but their precise function has remained enigmatic. Competing hypotheses suggest roles for SNAREs in mediating the specificity of fusion, catalyzing fusion, or actually executing fusion. We generated knockout mice lacking synaptobrevin/VAMP 2, the vesicular SNARE protein responsible for synaptic vesicle fusion in forebrain synapses, to make use of the exquisite temporal resolution of electrophysiology in measuring fusion. In the absence of synaptobrevin 2, spontaneous synaptic vesicle fusion and fusion induced by hypertonic sucrose were decreased approximately 10-fold, but fast Ca2+-triggered fusion was decreased more than 100-fold. Thus, synaptobrevin 2 may function in catalyzing fusion reactions and stabilizing fusion intermediates but is not absolutely required for synaptic fusion. 相似文献
3.
In vivo experience can occlude subsequent induction of long-term potentiation and enhance long-term depression of synaptic responses. Although a reduced capacity for synaptic strengthening may function to prevent excessive excitation, such an effect paradoxically implies that continued experience or training should not improve and may even degrade neural representations. In mice, we examined the effect of ongoing whisker stimulation on synaptic strengthening at layer 4-2/3 synapses in the barrel cortex. Although N-methyl-d-aspartate receptors were required to initiate strengthening, they subsequently suppressed further potentiation at these synapses in vitro and in vivo. Despite this transition, synaptic strengthening continued with additional sensory activity but instead required the activation of metabotropic glutamate receptors, suggesting a mechanism by which continued experience can result in increasing synaptic strength over time. 相似文献
4.
The defining morphological feature of chemical synapses is the vesicle cluster in the presynaptic nerve terminal. It has generally been assumed that vesicles closest to release sites are recruited first during nerve activity. We tested this by selectively labeling the "readily releasable" pool, those vesicles released first during physiological stimulation. The readily releasable vesicles were not clustered close to the presynaptic membrane but instead were dispersed almost randomly throughout the vesicle cluster. Thus, vesicles are not recruited according to proximity to release sites but are mobilized differently, perhaps by being peeled from the surface of the cluster. 相似文献
5.
Bruchpilot promotes active zone assembly, Ca2+ channel clustering, and vesicle release 总被引：1，自引：0，他引：1
Kittel RJ Wichmann C Rasse TM Fouquet W Schmidt M Schmid A Wagh DA Pawlu C Kellner RR Willig KI Hell SW Buchner E Heckmann M Sigrist SJ 《Science (New York, N.Y.)》2006,312(5776):1051-1054
The molecular organization of presynaptic active zones during calcium influx-triggered neurotransmitter release is the focus of intense investigation. The Drosophila coiled-coil domain protein Bruchpilot (BRP) was observed in donut-shaped structures centered at active zones of neuromuscular synapses by using subdiffraction resolution STED (stimulated emission depletion) fluorescence microscopy. At brp mutant active zones, electron-dense projections (T-bars) were entirely lost, Ca2+ channels were reduced in density, evoked vesicle release was depressed, and short-term plasticity was altered. BRP-like proteins seem to establish proximity between Ca2+ channels and vesicles to allow efficient transmitter release and patterned synaptic plasticity. 相似文献
6.
Verhage M Maia AS Plomp JJ Brussaard AB Heeroma JH Vermeer H Toonen RF Hammer RE van den Berg TK Missler M Geuze HJ Südhof TC 《Science (New York, N.Y.)》2000,287(5454):864-869
Brain function requires precisely orchestrated connectivity between neurons. Establishment of these connections is believed to require signals secreted from outgrowing axons, followed by synapse formation between selected neurons. Deletion of a single protein, Munc18-1, in mice leads to a complete loss of neurotransmitter secretion from synaptic vesicles throughout development. However, this does not prevent normal brain assembly, including formation of layered structures, fiber pathways, and morphologically defined synapses. After assembly is completed, neurons undergo apoptosis, leading to widespread neurodegeneration. Thus, synaptic connectivity does not depend on neurotransmitter secretion, but its maintenance does. Neurotransmitter secretion probably functions to validate already established synaptic connections. 相似文献
7.
Factors that regulate synaptic specificity were investigated with Aplysia buccal and bag cell neurons in primary cell culture. In the presence of fetal calf serum electrical synapses are formed between buccal-buccal or bag-bag cell pairs, but not between buccal-bag cell pairs. Instead, buccal neurons make inhibitory chemical synapses on bag cells. However, in the presence of nanomolar concentrations of the lectin concanavalin A this pattern changes, such that more than 75 percent of buccal-bag pairs exhibit electrical synapses and the frequency of occurrence of buccal-bag chemical synapses is reduced. Such changes in synaptic specificity may be important in determining the types of synapses formed during neuronal development and neurite regeneration. 相似文献
8.
Stereotyped synaptic connectivity can arise both by precise recognition between appropriate partners during synaptogenesis and by selective synapse elimination. The molecular mechanisms that underlie selective synapse removal are largely unknown. We found that stereotyped developmental elimination of synapses in the Caenorhabditis elegans hermaphrodite-specific motor neuron (HSNL) was mediated by an E3 ubiquitin ligase, a Skp1-cullin-F-box (SCF) complex composed of SKR-1 and the F-box protein SEL-10. SYG-1, a synaptic adhesion molecule, bound to SKR-1 and inhibited assembly of the SCF complex, thereby protecting nearby synapses. Thus, subcellular regulation of ubiquitin-mediated protein degradation contributes to precise synaptic connectivity through selective synapse elimination. 相似文献
9.
Driving AMPA receptors into synapses by LTP and CaMKII: requirement for GluR1 and PDZ domain interaction 总被引：1，自引：0，他引：1
Hayashi Y Shi SH Esteban JA Piccini A Poncer JC Malinow R 《Science (New York, N.Y.)》2000,287(5461):2262-2267
To elucidate mechanisms that control and execute activity-dependent synaptic plasticity, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPA-Rs) with an electrophysiological tag were expressed in rat hippocampal neurons. Long-term potentiation (LTP) or increased activity of the calcium/calmodulin-dependent protein kinase II (CaMKII) induced delivery of tagged AMPA-Rs into synapses. This effect was not diminished by mutating the CaMKII phosphorylation site on the GluR1 AMPA-R subunit, but was blocked by mutating a predicted PDZ domain interaction site. These results show that LTP and CaMKII activity drive AMPA-Rs to synapses by a mechanism that requires the association between GluR1 and a PDZ domain protein. 相似文献
10.
The extent to which synaptic activity can signal a sensory stimulus limits the information available to a neuron. We determined the contribution of individual synapses to sensory representation by recording excitatory postsynaptic currents (EPSCs) in cerebellar granule cells during a time-varying, quantifiable vestibular stimulus. Vestibular-sensitive synapses faithfully reported direction and velocity, rather than position or acceleration of whole-body motion, via bidirectional modulation of EPSC frequency. The lack of short-term synaptic dynamics ensured a highly linear relationship between velocity and charge transfer, and as few as 100 synapses provided resolution approaching psychophysical limits. This indicates that highly accurate stimulus representation can be achieved by small networks and even within single neurons. 相似文献
11.
The hypothesis that learning occurs through long-term potentiation (LTP)- and long-term depression (LTD)-like mechanisms is widely held but unproven. This hypothesis makes three assumptions: Synapses are modifiable, they modify with learning, and they strengthen through an LTP-like mechanism. We previously established the ability for synaptic modification and a synaptic strengthening with motor skill learning in horizontal connections of the rat motor cortex (MI). Here we investigated whether learning strengthened these connections through LTP. We demonstrated that synapses in the trained MI were near the ceiling of their modification range, compared with the untrained MI, but the range of synaptic modification was not affected by learning. In the trained MI, LTP was markedly reduced and LTD was enhanced. These results are consistent with the use of LTP to strengthen synapses during learning. 相似文献
12.
The mechanisms underlying experience-dependent plasticity in the brain may depend on the AMPA subclass of glutamate receptors (AMPA-Rs). We examined the trafficking of AMPA-Rs into synapses in the developing rat barrel cortex. In vivo gene delivery was combined with in vitro recordings to show that experience drives recombinant GluR1, an AMPA-R subunit, into synapses formed between layer 4 and layer 2/3 neurons. Moreover, expression of the GluR1 cytoplasmic tail, a construct that inhibits synaptic delivery of endogenous AMPA-Rs during long-term potentiation, blocked experience-driven synaptic potentiation. In general, synaptic incorporation of AMPA-Rs in vivo conforms to rules identified in vitro and contributes to plasticity driven by natural stimuli in the mammalian brain. 相似文献
13.
Synaptic morphology and differences in sensitivity 总被引：1，自引：0，他引：1
A relation between synaptic morphology and physiology was observed in an in vitro preparation of a sense organ (the ampulla of Lorenzini), in which activity was monitored from the primary afferent neurons before electron microscopic examination of the afferent synapses. The depth of the postsynaptic trough decreased as prefixation sensitivity of the sense organ decreased. This relation and other ultrastructural differences suggest that physiological properties of synapses are influenced by morphological features. Thus, synapses might be morphologically dynamic to modulate synaptic efficacy in relatively long-term phenomena. 相似文献
14.
The mushroom bodies of the Drosophila brain are important for olfactory learning and memory. To investigate the requirement for mushroom body signaling during the different phases of memory processing, we transiently inactivated neurotransmission through this region of the brain by expressing a temperature-sensitive allele of the shibire dynamin guanosine triphosphatase, which is required for synaptic transmission. Inactivation of mushroom body signaling through alpha/beta neurons during different phases of memory processing revealed a requirement for mushroom body signaling during memory retrieval, but not during acquisition or consolidation. 相似文献
15.
Interaction of brain synaptic vesicles induced by endogenous Ca2+ -dependent phospholipase A2 总被引：2，自引：0，他引：2
Endogenous phospholipase A2 activity of brain synaptic vesicles was Ca2+ -dependent and was increased by prostaglandin F2 alpha, calmodulin, adenosine 3', 5' -monophosphate, and adenosine triphosphate, whereas the activity was inhibited by prostaglandin E2 in the absence or presence of calmodulin. Light-scattering measurements demonstrated that stimulation of the enzyme's activity correlated with the induction of vesicle-vesicle aggregation. The effects of these compounds on endogenous synaptic vesicle phospholipase A2 activity may imply a common end point of their purported neuromodulatory actions, and indicate that synaptic vesicle phospholipase A2 may play a central role in presynaptic neurotransmission. 相似文献
16.
Pinto S Roseberry AG Liu H Diano S Shanabrough M Cai X Friedman JM Horvath TL 《Science (New York, N.Y.)》2004,304(5667):110-115
The fat-derived hormone leptin regulates energy balance in part by modulating the activity of neuropeptide Y and proopiomelanocortin neurons in the hypothalamic arcuate nucleus. To study the intrinsic activity of these neurons and their responses to leptin, we generated mice that express distinct green fluorescent proteins in these two neuronal types. Leptin-deficient (ob/ob) mice differed from wild-type mice in the numbers of excitatory and inhibitory synapses and postsynaptic currents onto neuropeptide Y and proopiomelanocortin neurons. When leptin was delivered systemically to ob/ob mice, the synaptic density rapidly normalized, an effect detectable within 6 hours, several hours before leptin's effect on food intake. These data suggest that leptin-mediated plasticity in the ob/ob hypothalamus may underlie some of the hormone's behavioral effects. 相似文献
17.
Guanosine 5'-triphosphate (GTP)-binding proteins (G proteins) are involved in exocytosis, endocytosis, and recycling of vesicles in yeast and mammalian secretory cells. However, little is known about their contribution to fast synaptic transmission. We loaded guanine nucleotide analogs directly into a giant nerve terminal in rat brainstem slices. Inhibition of G-protein activity had no effect on basal synaptic transmission, but augmented synaptic depression and significantly slowed recovery from depression. A nonhydrolyzable GTP analog blocked recovery of transmission from activity-dependent depression. Neither effect was accompanied by a change in presynaptic calcium currents. Thus, G proteins contribute to fast synaptic transmission by refilling synaptic vesicles depleted after massive exocytosis. 相似文献
18.
Use-dependent forms of synaptic plasticity have been extensively characterized at chemical synapses, but a relationship between natural activity and strength at electrical synapses remains elusive. The thalamic reticular nucleus (TRN), a brain area rich in gap-junctional (electrical) synapses, regulates cortical attention to the sensory surround and participates in shifts between arousal states; plasticity of electrical synapses may be a key mechanism underlying these processes. We observed long-term depression resulting from coordinated burst firing in pairs of coupled TRN neurons. Changes in gap-junctional communication were asymmetrical, indicating that regulation of connectivity depends on the direction of use. Modification of electrical synapses resulting from activity in coupled neurons is likely to be a widespread and powerful mechanism for dynamic reorganization of electrically coupled neuronal networks. 相似文献
19.
Molecular dependence of vesicular endocytosis was investigated with capacitance measurements at the calyx of Held terminal in brainstem slices. Intraterminal loading of botulinum toxin E revealed that the rapid capacitance transient implicated as "kiss-and-run" was unrelated to transmitter release. The release-related capacitance change decayed with an endocytotic time constant of 10 to 25 seconds, depending on the magnitude of exocytosis. Presynaptic loading of the nonhydrolyzable guanosine 5'-triphosphate (GTP) analog GTPgS or dynamin-1 proline-rich domain peptide abolished endocytosis. These compounds had no immediate effect on exocytosis, but caused a use-dependent rundown of exocytosis. Thus, the guanosine triphosphatase dynamin-1 is indispensable for vesicle endocytosis at this fast central nervous system (CNS) synapse. 相似文献
20.
El-Husseini AE Schnell E Chetkovich DM Nicoll RA Bredt DS 《Science (New York, N.Y.)》2000,290(5495):1364-1368
PSD-95 is a neuronal PDZ protein that associates with receptors and cytoskeletal elements at synapses, but whose function is uncertain. We found that overexpression of PSD-95 in hippocampal neurons can drive maturation of glutamatergic synapses. PSD-95 expression enhanced postsynaptic clustering and activity of glutamate receptors. Postsynaptic expression of PSD-95 also enhanced maturation of the presynaptic terminal. These effects required synaptic clustering of PSD-95 but did not rely on its guanylate kinase domain. PSD-95 expression also increased the number and size of dendritic spines. These results demonstrate that PSD-95 can orchestrate synaptic development and are suggestive of roles for PSD-95 in synapse stabilization and plasticity. 相似文献