FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2078698296> ?p ?o ?g. }

• W2078698296 endingPage "346" @default.
• W2078698296 startingPage "345" @default.
• W2078698296 abstract "Nascent synaptic networks have a high incidence of silent synapses. In this issue of Neuron, Shen et al. show that a brief burst of action potentials rapidly awaken silent synapses by increasing the availability of synaptic vesicles for fusion through BDNF-triggered presynaptic actin remodeling mediated by the small GTPase Cdc42. Nascent synaptic networks have a high incidence of silent synapses. In this issue of Neuron, Shen et al. show that a brief burst of action potentials rapidly awaken silent synapses by increasing the availability of synaptic vesicles for fusion through BDNF-triggered presynaptic actin remodeling mediated by the small GTPase Cdc42. All-or-nothing changes in signal strength have been a favorite of electrophysiologists. Action potential generation, quantal neurotransmitter release, and ion channel openings are typical examples of all-or-nothing signaling events that form the basis of information processing and signal transmission in the nervous system. As exemplified by the modern digital technology, this form of signaling allows unambiguous information storage, transmission, and signal detection. In contrast, more graded changes in signal amplitudes are harder to store, transmit, and detect with high fidelity and, therefore, more prone to noise and errors. In the last decade, an elegant set of studies showed that changes in synaptic strength during long-term plasticity also occur in an all-or-nothing manner (Malinow and Malenka, 2002Malinow R. Malenka R.C. Annu. Rev. Neurosci. 2002; 25: 103-126Crossref PubMed Scopus (2059) Google Scholar, Bagal et al., 2005Bagal A.A. Kao J.P. Tang C.M. Thompson S.M. Proc. Natl. Acad. Sci. USA. 2005; 102: 14434-14439Crossref PubMed Scopus (135) Google Scholar). Evidence from the experiments by Shen et al., 2006Shen W. Wu B. Zhang Z. Dou Y. Rao Z. Chen Y. Duan S. Neuron. 2006; 50 (this issue): 401-414Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar published in this issue of Neuron brings a clear mechanistic insight to this type of off/on switching, which occurs during early synaptic development contributing to the plasticity of synaptic networks. Recent studies have provided four distinct models to account for rapid switching of silent synapses into functional ones. The first model postulates that prior to activation, the site of the future synapse may lack structural synaptic components (synaptic vesicles, Ca2+ channels, fusion machinery, etc.). Therefore, stimulation not only renders a pre-existing synapse functional but actually triggers its de novo assembly (Friedman et al., 2000Friedman H.V. Bresler T. Garner C.C. Ziv N.E. Neuron. 2000; 27: 57-69Abstract Full Text Full Text PDF PubMed Scopus (427) Google Scholar, Zhai et al., 2001Zhai R.G. Vardinon-Friedman H. Cases-Langhoff C. Becker B. Gundelfinger E.D. Ziv N.E. Garner C.C. Neuron. 2001; 29: 131-143Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar). The second model proposes that a fully functional presynaptic terminal may exist, but the postsynaptic site may not possess AMPA receptors although it contains NMDA receptors. Evidence for these types of synapses have been observed in developing Xenopus neurons (Wu et al., 1996Wu G. Malinow R. Cline H.T. Science. 1996; 274: 972-976Crossref PubMed Scopus (456) Google Scholar). According to this scenario, activity induces the insertion of functional AMPA receptors, similar to what occurs in mature synapses, making silent synapses functional under physiological conditions. A third model possesses the same apparent features of an NMDA-only synapse, but the NMDA-only nature of these synapses is explained by a presynaptic anomaly not by lack of postsynaptic AMPA receptors. This model involves the regulation of synaptic vesicle fusion pore dynamics (Renger et al., 2001Renger J.J. Egles C. Liu G. Neuron. 2001; 29: 469-484Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar, Choi et al., 2003Choi S. Klingauf J. Tsien R.W. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2003; 358: 695-705Crossref PubMed Scopus (69) Google Scholar). According to this scheme, activation of postsynaptic AMPA or NMDA receptors can be determined by the kinetics of fusion pore opening and the release profile of glutamate. In young nerve terminals, neurotransmitter release occurs through a narrow fusion pore leading to exclusive activation of NMDA receptors as they have a higher affinity for glutamate. Synapse maturation in turn leads to an increase in preponderance of full fusion events, thus activating NMDA as well as AMPA receptors. The fourth model suggests that immature synapses may contain synaptic vesicle clusters; however, they do not readily respond to action potential stimulation but rather require a more intense stimulation to release neurotransmitters (Mozhayeva et al., 2002Mozhayeva M.G. Sara Y. Liu X. Kavalali E.T. J. Neurosci. 2002; 22: 654-665Crossref PubMed Google Scholar). This model suggests a full presynaptic neurotransmitter failure because of some inadequacy in fusion competence or localization of synaptic vesicles. In these presynaptically “mute” synapses, any apparent activation of NMDA receptors (but not AMPA) during action potential stimulation would be attributed to spill over of neurotransmitter from adjacent active nerve terminals because NMDA receptors have a much higher affinity for glutamate (Kullmann and Asztely, 1998Kullmann D.M. Asztely F. Trends Neurosci. 1998; 21: 8-14Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar). In this issue of Neuron, Shen and colleagues perform a comprehensive analysis of silent synapses by carrying out a phenomenal number of paired recordings in developing hippocampal cultures. Their results provide a fresh look at these silent synapses and their switching to active ones. The authors uncover a presynaptic mechanism that enables rapid conversion of nonfunctional synapses to functional ones. Although most of the recording pairs display no synaptic responses, a brief theta bursting stimulation was able to convert up to 16% of these contacts to functional synapses. These “unsilenced” synapses previously contain synaptic vesicle markers and potentially other exocytosis apparatus. During the process of unsilencing, synaptic vesicles previously hesitant to exocytose and recycle, start to fuse and recycle the styryl dye FM4-64. Closer examination of these putative silent synapses by immunocytochemistry and electronmicrocopy reveals abundant synaptic vesicle clusters, arguing against the de novo synapse assembly model mentioned above. In mature cultures, the success rate of theta-burst induction dramatically decreases, suggesting that most synapses were already unsilenced. The conversion of silent synapses requires the activation of NMDA receptors as judged by its sensitivity to APV. Once converted, synapses exhibit both NMDA and AMPA responses. Surprisingly, in contrast to the second and third silent synapse models discussed above the authors do not encounter NMDA responses prior to the synapse awakening. Nevertheless, unsilencing is still sensitive to APV. This APV sensitivity can be due to some NMDA receptor activity below the detection threshold or alternatively may originate from potential presynaptic NMDA receptors. The probable role of postsynaptic NMDA receptors in this process is consistent with the requirement for postsynaptic Ca2+ signaling as dialysis of the postsynaptic cell with the fast Ca2+ chelator BAPTA abolishes conversion. Interestingly, presynaptic EGTA is also effective in preventing unsilencing, implicating a potential retrograde signal mediating the unsilencing process. Accordingly, the authors test the involvement of BDNF as a retrograde factor and show that the conversion requires endogenous BDNF because incubation with an antibody against BDNF or interference with the tyrosine kinase B receptor (TrkB, receptor for BDNF) signaling impairs the activity-dependent unsilencing process. What then are the downstream targets of BDNF signaling in the presynaptic terminal? To address this question, the authors examine the small GTPase Cdc42, a critical regulator of cytoskeletal rearrangements, in response to tyrosine kinase activation. The authors found that a general inhibitor of small GTPases, as well as a dominant negative inhibitor of Cdc42 signaling, abolishes the theta-burst-induced conversion of silent synapses to functional synapses. Moreover, the action of BDNF was also blocked by the same maneuvers verifying the role of BDNF as the trigger of this cascade. In contrast, mature synapses or already functional synapses were not affected by manipulations interfering with Cdc42 signaling. However, in some cell pairs, which exhibited functional transmission, the amplitude of synaptic responses increased after theta-burst stimulation in a Cdc42-dependent manner. This observation suggests that a single cell may make functional as well as silent contacts, which can be unsilenced independently. Taken together, a major strength of this study stems from its ability to bring together several disparate earlier observations including presynaptically silent synapses, the role of BDNF and TrkB signaling in synaptic function and synaptogenesis, maturation of vesicle pool organization, and the role of actin cytoskeleton during synapse maturation in a single coherent model. The authors propose that silent synapse conversion requires already existing vesicles by increasing physical docking and presumably synaptic vesicle recycling. Synaptic vesicle recycling in nascent synapses is known to be susceptible to actin depolymerization, whereas mature synapses are far less sensitive to manipulations that alter actin (Zhang and Benson, 2001Zhang W. Benson D.L. J. Neurosci. 2001; 21: 5169-5181Crossref PubMed Google Scholar). To examine the link between activity and actin polymerization, Shen and colleagues first demonstrate an increase in actin polymerization at presynaptic terminals after theta-burst stimulation. In addition, they establish that F-actin accumulation in synapses share the same signaling pathway as stimulus induced unsilencing because inhibition of either BDNF or Cdc42 prevents morphological change in the nerve terminals. Is this signaling required for all forms of synapse maturation? What happens to these synapses if they are not somehow awakened? The answer to these questions comes from recent genetic evidence. In the absence of TrkB signaling, a central component of the unsilencing process, preexisting clusters may disassemble and some of the synapses may never form. In a mutant mouse model in which TrkB is ablated either in presynaptic or in both presynaptic and postsynaptic cells at early or late developmental time points in the hippocampal CA1 region, synapse numbers were significantly reduced (Luikart et al., 2005Luikart B.W. Nef S. Virmani T. Lush M.E. Liu Y. Kavalali E.T. Parada L.F. J. Neurosci. 2005; 25: 3774-3786Crossref PubMed Scopus (130) Google Scholar). Ablation of TrkB after synapse formation did not affect synapse numbers. In these genetic experiments, loss of TrkB signaling only afflicts a fraction of the total number of synapses, presumably the ones that are most labile to activity in their formation, as well as elimination (Zito and Svoboda, 2002Zito K. Svoboda K. Neuron. 2002; 35: 1015-1017Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar) consistent with the observations in the current study. Several questions remain. Arguably the most pressing issue is the precise role of NMDA receptors in this process. Are they only postsynaptic triggers of subsequent signaling events? Or do they also play a presynaptic role in reorganization of the synaptic vesicle recycling apparatus? Another important issue is to better understand the mechanistic details of actin dependent reorganization of synaptic vesicle pools during development. To address this question, we need to obtain a better grasp of the synaptic-vesicle-associated molecules that interact with actin as well as the nature of synaptic-vesicle-docking and active-zone molecules involved. Lastly, now that we possess a wealth of information on the sequence of events that underlie synapse assembly and maturation, it is time to test whether synapse elimination and synapse degeneration are simply governed by the reversibility of the same molecular and cellular events. Activity-Induced Rapid Synaptic Maturation Mediated by Presynaptic Cdc42 SignalingShen et al.NeuronMay 04, 2006In BriefMaturation of presynaptic transmitter secretion machinery is a critical step in synaptogenesis. Here we report that a brief train of presynaptic action potentials rapidly converts early nonfunctional contacts between cultured hippocampal neurons into functional synapses by enhancing presynaptic glutamate release. The enhanced release was confirmed by a marked increase in the number of depolarization-induced FM4-64 puncta in the presynaptic axon. This rapid presynaptic maturation can be abolished by treatments that interfered with presynaptic BDNF and Cdc42 signaling or actin polymerization. Full-Text PDF Open Archive" @default.
• W2078698296 created "2016-06-24" @default.
• W2078698296 creator A5038903346 @default.
• W2078698296 creator A5059395438 @default.
• W2078698296 date "2006-05-01" @default.
• W2078698296 modified "2023-09-28" @default.
• W2078698296 title "Presynaptic Unsilencing: Searching for a Mechanism" @default.
• W2078698296 cites W1969600766 @default.
• W2078698296 cites W2031130044 @default.
• W2078698296 cites W2033907545 @default.
• W2078698296 cites W2041794060 @default.
• W2078698296 cites W2050389368 @default.
• W2078698296 cites W2053287773 @default.
• W2078698296 cites W2075603142 @default.
• W2078698296 cites W2077516634 @default.
• W2078698296 cites W2092326283 @default.
• W2078698296 cites W2097738233 @default.
• W2078698296 cites W2098434647 @default.
• W2078698296 cites W2128574573 @default.
• W2078698296 cites W2157463295 @default.
• W2078698296 doi "https://doi.org/10.1016/j.neuron.2006.04.018" @default.
• W2078698296 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/16675387" @default.
• W2078698296 hasPublicationYear "2006" @default.
• W2078698296 type Work @default.
• W2078698296 sameAs 2078698296 @default.
• W2078698296 citedByCount "8" @default.
• W2078698296 countsByYear W20786982962013 @default.
• W2078698296 crossrefType "journal-article" @default.
• W2078698296 hasAuthorship W2078698296A5038903346 @default.
• W2078698296 hasAuthorship W2078698296A5059395438 @default.
• W2078698296 hasBestOaLocation W20786982961 @default.
• W2078698296 hasConcept C121332964 @default.
• W2078698296 hasConcept C15744967 @default.
• W2078698296 hasConcept C169760540 @default.
• W2078698296 hasConcept C188147891 @default.
• W2078698296 hasConcept C41008148 @default.
• W2078698296 hasConcept C46312422 @default.
• W2078698296 hasConcept C62520636 @default.
• W2078698296 hasConcept C89611455 @default.
• W2078698296 hasConceptScore W2078698296C121332964 @default.
• W2078698296 hasConceptScore W2078698296C15744967 @default.
• W2078698296 hasConceptScore W2078698296C169760540 @default.
• W2078698296 hasConceptScore W2078698296C188147891 @default.
• W2078698296 hasConceptScore W2078698296C41008148 @default.
• W2078698296 hasConceptScore W2078698296C46312422 @default.
• W2078698296 hasConceptScore W2078698296C62520636 @default.
• W2078698296 hasConceptScore W2078698296C89611455 @default.
• W2078698296 hasIssue "3" @default.
• W2078698296 hasLocation W20786982961 @default.
• W2078698296 hasLocation W20786982962 @default.
• W2078698296 hasOpenAccess W2078698296 @default.
• W2078698296 hasPrimaryLocation W20786982961 @default.
• W2078698296 hasRelatedWork W1968702859 @default.
• W2078698296 hasRelatedWork W1978627301 @default.
• W2078698296 hasRelatedWork W1981082198 @default.
• W2078698296 hasRelatedWork W1987137857 @default.
• W2078698296 hasRelatedWork W1993305689 @default.
• W2078698296 hasRelatedWork W2152412393 @default.
• W2078698296 hasRelatedWork W2369566408 @default.
• W2078698296 hasRelatedWork W2562980820 @default.
• W2078698296 hasRelatedWork W2748952813 @default.
• W2078698296 hasRelatedWork W2899084033 @default.
• W2078698296 hasVolume "50" @default.
• W2078698296 isParatext "false" @default.
• W2078698296 isRetracted "false" @default.
• W2078698296 magId "2078698296" @default.
• W2078698296 workType "article" @default.