Frontiers in Synaptic Neuroscience最新文献

{"title":"Organization of Presynaptic Autophagy-Related Processes.","authors":"Eckart D Gundelfinger, Anna Karpova, Rainer Pielot, Craig C Garner, Michael R Kreutz","doi":"10.3389/fnsyn.2022.829354","DOIUrl":"10.3389/fnsyn.2022.829354","url":null,"abstract":"<p><p>Brain synapses pose special challenges on the quality control of their protein machineries as they are far away from the neuronal soma, display a high potential for plastic adaptation and have a high energy demand to fulfill their physiological tasks. This applies in particular to the presynaptic part where neurotransmitter is released from synaptic vesicles, which in turn have to be recycled and refilled in a complex membrane trafficking cycle. Pathways to remove outdated and damaged proteins include the ubiquitin-proteasome system acting in the cytoplasm as well as membrane-associated endolysosomal and the autophagy systems. Here we focus on the latter systems and review what is known about the spatial organization of autophagy and endolysomal processes within the presynapse. We provide an inventory of which components of these degradative systems were found to be present in presynaptic boutons and where they might be anchored to the presynaptic apparatus. We identify three presynaptic structures reported to interact with known constituents of membrane-based protein-degradation pathways and therefore may serve as docking stations. These are (i) scaffolding proteins of the cytomatrix at the active zone, such as Bassoon or Clarinet, (ii) the endocytic machinery localized mainly at the peri-active zone, and (iii) synaptic vesicles. Finally, we sketch scenarios, how presynaptic autophagic cargos are tagged and recruited and which cellular mechanisms may govern membrane-associated protein turnover in the presynapse.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2022-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8968026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43918349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: Synaptic Diseases: From Biology to Potential Therapy","authors":"Hansen Wang, R. Balice-Gordon","doi":"10.3389/fnsyn.2022.846099","DOIUrl":"https://doi.org/10.3389/fnsyn.2022.846099","url":null,"abstract":"Mutations in genes encoding synaptic or synapse-related proteins that affect the structure and/or function of synapses are responsible for various forms of synaptopathies, including neurodevelopmental, neurodegenerative and psychiatric diseases (Lepeta et al., 2016; Lima Caldeira et al., 2019; Bonnycastle et al., 2021; Germann et al., 2021). Understanding how disease causing genes affect synapse structure and function, and cause circuit and behavioral dysfunction, has been a focus of neuroscience research over several decades. Many challenges remain to be addressed, from identifying rare disease-associated genes, defining the molecular and cellular mechanisms by which the genetic mutations confer disease risk and manifest as phenotypes, understanding how thesemutations affect circuit function, plasticity and behavior, to whether therapeutic interventions can restore function. Studying the pathophysiologic mechanisms underlying synaptopathies will lead to a better understanding of the molecular and cellular mechanisms that govern normal nervous system function, and may eventually help to discover impactful therapeutics (Wang and Doering, 2015; Lepeta et al., 2016; Lima Caldeira et al., 2019; Carroll et al., 2021). This Research Topic has focused on advances in studying common synaptopathies, collecting 31 research and review articles ranging from new insights into fundamental synapse biology to potential therapeutic strategies. Here we summarize each of these articles as a guide to the Research Topic, and highlight the many new research questions stimulated by the work.","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2022-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47757253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Synaptic Extracellular Matrix: Long-Lived, Stable, and Still Remarkably Dynamic","authors":"T. Dankovich, S. Rizzoli","doi":"10.3389/fnsyn.2022.854956","DOIUrl":"https://doi.org/10.3389/fnsyn.2022.854956","url":null,"abstract":"In the adult brain, synapses are tightly enwrapped by lattices of the extracellular matrix that consist of extremely long-lived molecules. These lattices are deemed to stabilize synapses, restrict the reorganization of their transmission machinery, and prevent them from undergoing structural or morphological changes. At the same time, they are expected to retain some degree of flexibility to permit occasional events of synaptic plasticity. The recent understanding that structural changes to synapses are significantly more frequent than previously assumed (occurring even on a timescale of minutes) has called for a mechanism that allows continual and energy-efficient remodeling of the extracellular matrix (ECM) at synapses. Here, we review recent evidence for such a process based on the constitutive recycling of synaptic ECM molecules. We discuss the key characteristics of this mechanism, focusing on its roles in mediating synaptic transmission and plasticity, and speculate on additional potential functions in neuronal signaling.","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2022-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41936499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiple Roles of Actin in Exo- and Endocytosis.","authors":"Ling-Gang Wu, Chung Yu Chan","doi":"10.3389/fnsyn.2022.841704","DOIUrl":"10.3389/fnsyn.2022.841704","url":null,"abstract":"<p><p>Cytoskeletal filamentous actin (F-actin) has long been considered a molecule that may regulate exo- and endocytosis. However, its exact roles remained elusive. Recent studies shed new light on many crucial roles of F-actin in regulating exo- and endocytosis. Here, this progress is reviewed from studies of secretory cells, particularly neurons and endocrine cells. These studies reveal that F-actin is involved in mediating all kinetically distinguishable forms of endocytosis, including ultrafast, fast, slow, bulk, and overshoot endocytosis, likely <i>via</i> membrane pit formation. F-actin promotes vesicle replenishment to the readily releasable pool most likely <i>via</i> active zone clearance, which may sustain synaptic transmission and overcome short-term depression of synaptic transmission during repetitive firing. By enhancing plasma membrane tension, F-actin promotes fusion pore expansion, vesicular content release, and a fusion mode called shrink fusion involving fusing vesicle shrinking. Not only F-actin, but also the F-actin assembly pathway, including ATP hydrolysis, N-WASH, and formin, are involved in mediating these roles of exo- and endocytosis. Neurological disorders, including spinocerebellar ataxia 13 caused by Kv3.3 channel mutation, may involve impairment of F-actin and its assembly pathway, leading in turn to impairment of exo- and endocytosis at synapses that may contribute to neurological disorders.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2022-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8931529/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40308176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hearing Loss Increases Inhibitory Effects of Prefrontal Cortex Stimulation on Sound Evoked Activity in Medial Geniculate Nucleus.","authors":"Chenae De Vis, Kristin M Barry, Wilhelmina H A M Mulders","doi":"10.3389/fnsyn.2022.840368","DOIUrl":"10.3389/fnsyn.2022.840368","url":null,"abstract":"<p><p>Sensory gating is the process whereby irrelevant sensory stimuli are inhibited on their way to higher cortical areas, allowing for focus on salient information. Sensory gating circuitry includes the thalamus as well as several cortical regions including the prefrontal cortex (PFC). Defective sensory gating has been implicated in a range of neurological disorders, including tinnitus, a phantom auditory perception strongly associated with cochlear trauma. Recently, we have shown in rats that functional connectivity between PFC and auditory thalamus, i.e., the medial geniculate nucleus (MGN), changes following cochlear trauma, showing an increased inhibitory effect from PFC activation on the spontaneous firing rate of MGN neurons. In this study, we further investigated this phenomenon using a guinea pig model, in order to demonstrate the validity of our finding beyond a single species and extend data to include data on sound evoked responses. Effects of PFC electrical stimulation on spontaneous and sound-evoked activity of single neurons in MGN were recorded in anaesthetised guinea pigs with normal hearing or hearing loss 2 weeks after acoustic trauma. No effect, inhibition and excitation were observed following PFC stimulation. The proportions of these effects were not different in animals with normal hearing and hearing loss but the magnitude of effect was. Indeed, hearing loss significantly increased the magnitude of inhibition for sound evoked responses, but not for spontaneous activity. The findings support previous observations that PFC can modulate MGN activity and that functional changes occur within this pathway after cochlear trauma. These data suggest hearing loss can alter sensory gating which may be a contributing factor toward tinnitus development.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8921694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46734421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synaptic Vesicle Recycling and the Endolysosomal System: A Reappraisal of Form and Function","authors":"D. Ivanova, M. Cousin","doi":"10.3389/fnsyn.2022.826098","DOIUrl":"https://doi.org/10.3389/fnsyn.2022.826098","url":null,"abstract":"The endolysosomal system is present in all cell types. Within these cells, it performs a series of essential roles, such as trafficking and sorting of membrane cargo, intracellular signaling, control of metabolism and degradation. A specific compartment within central neurons, called the presynapse, mediates inter-neuronal communication via the fusion of neurotransmitter-containing synaptic vesicles (SVs). The localized recycling of SVs and their organization into functional pools is widely assumed to be a discrete mechanism, that only intersects with the endolysosomal system at specific points. However, evidence is emerging that molecules essential for endolysosomal function also have key roles within the SV life cycle, suggesting that they form a continuum rather than being isolated processes. In this review, we summarize the evidence for key endolysosomal molecules in SV recycling and propose an alternative model for membrane trafficking at the presynapse. This includes the hypotheses that endolysosomal intermediates represent specific functional SV pools, that sorting of cargo to SVs is mediated via the endolysosomal system and that manipulation of this process can result in both plastic changes to neurotransmitter release and pathophysiology via neurodegeneration.","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2022-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45104694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correlative Live-Cell and Super-Resolution Imaging to Link Presynaptic Molecular Organisation With Function.","authors":"Rachel E Jackson, Benjamin Compans, Juan Burrone","doi":"10.3389/fnsyn.2022.830583","DOIUrl":"10.3389/fnsyn.2022.830583","url":null,"abstract":"<p><p>Information transfer at synapses occurs when vesicles fuse with the plasma membrane to release neurotransmitters, which then bind to receptors at the postsynaptic membrane. The process of neurotransmitter release varies dramatically between different synapses, but little is known about how this heterogeneity emerges. The development of super-resolution microscopy has revealed that synaptic proteins are precisely organised within and between the two parts of the synapse and that this precise spatiotemporal organisation fine-tunes neurotransmission. However, it remains unclear if variability in release probability could be attributed to the nanoscale organisation of one or several proteins of the release machinery. To begin to address this question, we have developed a pipeline for correlative functional and super-resolution microscopy, taking advantage of recent technological advancements enabling multicolour imaging. Here we demonstrate the combination of live imaging of SypHy-RGECO, a unique dual reporter that simultaneously measures presynaptic calcium influx and neurotransmitter release, with <i>post hoc</i> immunolabelling and multicolour single molecule localisation microscopy, to investigate the structure-function relationship at individual presynaptic boutons.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2022-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8885727/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49187419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamics of Neuromuscular Transmission Reproduced by Calcium-Dependent and Reversible Serial Transitions in the Vesicle Fusion Complex","authors":"A. Martínez-Valencia, G. Ramírez‐Santiago, F. F. De-Miguel","doi":"10.3389/fnsyn.2021.785361","DOIUrl":"https://doi.org/10.3389/fnsyn.2021.785361","url":null,"abstract":"Neuromuscular transmission, from spontaneous release to facilitation and depression, was accurately reproduced by a mechanistic kinetic model of sequential maturation transitions in the molecular fusion complex. The model incorporates three predictions. First, calcium-dependent forward transitions take vesicles from docked to preprimed to primed states, followed by fusion. Second, prepriming and priming are reversible. Third, fusion and recycling are unidirectional. The model was fed with experimental data from previous studies, whereas the backward (β) and recycling (ρ) rate constant values were fitted. Classical experiments were successfully reproduced with four transition states in the model when every forward (α) rate constant had the same value, and both backward rate constants were 50–100 times larger. Such disproportion originated an abruptly decreasing gradient of resting vesicles from docked to primed states. By contrast, a three-state version of the model failed to reproduce the dynamics of transmission by using the same set of parameters. Simulations predict the following: (1) Spontaneous release reflects primed to fusion spontaneous transitions. (2) Calcium elevations synchronize the series of forward transitions that lead to fusion. (3) Facilitation reflects a transient increase of priming following the calcium-dependent maturation transitions. (4) The calcium sensors that produce facilitation are those that evoke the transitions form docked to primed states. (5) Backward transitions and recycling restore the resting state. (6) Depression reflects backward transitions and slow recycling after intense release. Altogether, our results predict that fusion is produced by one calcium sensor, whereas the modulation of the number of vesicles that fuse depends on the calcium sensors that promote the early transition states. Such finely tuned kinetics offers a mechanism for collective non-linear transitional adaptations of a homogeneous vesicle pool to the ever-changing pattern of electrical activity in the neuromuscular junction.","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2022-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44710794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selective Enrichment of Munc13-2 in Presynaptic Active Zones of Hippocampal Pyramidal Cells That Innervate mGluR1α Expressing Interneurons","authors":"Noémi Holderith, Mohammad Aldahabi, Z. Nusser","doi":"10.3389/fnsyn.2021.773209","DOIUrl":"https://doi.org/10.3389/fnsyn.2021.773209","url":null,"abstract":"Selective distribution of proteins in presynaptic active zones (AZs) is a prerequisite for generating postsynaptic target cell type-specific differences in presynaptic vesicle release probability (Pv) and short-term plasticity, a characteristic feature of cortical pyramidal cells (PCs). In the hippocampus of rodents, somatostatin and mGluR1α expressing interneurons (mGluR1α+ INs) receive small, facilitating excitatory postsynaptic currents (EPSCs) from PCs and express Elfn1 that trans-synaptically recruits mGluR7 into the presynaptic AZ of PC axons. Here we show that Elfn1 also has a role in the selective recruitment of Munc13-2, a synaptic vesicle priming and docking protein, to PC AZs that innervate mGluR1α+ INs. In Elfn1 knock-out mice, unitary EPSCs (uEPSCs) in mGluR1α+ INs have threefold larger amplitudes with less pronounced short-term facilitation, which might be the consequence of the loss of either mGluR7 or Munc13-2 or both. Conditional genetic deletion of Munc13-2 from CA1 PCs results in the loss of Munc13-2, but not mGluR7 from the AZs, and has no effect on the amplitude of uEPSCs and leaves the characteristic short-term facilitation intact at PC to mGluR1α+ IN connection. Our results demonstrate that Munc13-1 alone is capable of imposing low Pv at PC to mGluR1α+ IN synapses and Munc13-2 has yet an unknown role in this synapse.","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2022-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48301895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative Imaging With DNA-PAINT for Applications in Synaptic Neuroscience.","authors":"Eduard M Unterauer, Ralf Jungmann","doi":"10.3389/fnsyn.2021.798267","DOIUrl":"10.3389/fnsyn.2021.798267","url":null,"abstract":"<p><p>Super-resolution (SR) microscopy techniques have been advancing the understanding of neuronal protein networks and interactions. Unraveling the arrangement of proteins with molecular resolution provided novel insights into neuron cytoskeleton structure and actin polymerization dynamics in synaptic spines. Recent improvements in quantitative SR imaging have been applied to synaptic protein clusters and with improved multiplexing technology, the interplay of multiple protein partners in synaptic active zones has been elucidated. While all SR techniques come with benefits and drawbacks, true molecular quantification is a major challenge with the most complex requirements for labeling reagents and careful experimental design. In this perspective, we provide an overview of quantitative SR multiplexing and discuss in greater detail the quantification and multiplexing capabilities of the SR technique DNA-PAINT. Using predictable binding kinetics of short oligonucleotides, DNA-PAINT provides two unique approaches to address multiplexed molecular quantification: qPAINT and Exchange-PAINT. With precise and accurate quantification and spectrally unlimited multiplexing, DNA-PAINT offers an attractive route to unravel complex protein interaction networks in neurons. Finally, while the SR community has been pushing technological advances from an imaging technique perspective, the development of universally available, small, efficient, and quantitative labels remains a major challenge in the field.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2022-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8860300/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39947082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}