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  1. Article ; Online: Interpretation of presynaptic phenotypes of synaptic plasticity in terms of a two-step priming process.

    Neher, Erwin

    The Journal of general physiology

    2023  Volume 156, Issue 1

    Abstract: Studies on synaptic proteins involved in neurotransmitter release often aim at distinguishing between their roles in vesicle priming (the docking of synaptic vesicles to the plasma membrane and the assembly of a release machinery) as opposed to the ... ...

    Abstract Studies on synaptic proteins involved in neurotransmitter release often aim at distinguishing between their roles in vesicle priming (the docking of synaptic vesicles to the plasma membrane and the assembly of a release machinery) as opposed to the process of vesicle fusion. This has traditionally been done by estimating two parameters, the size of the pool of fusion-competent vesicles (the readily releasable pool, RRP) and the probability that such vesicles are released by an action potential, with the aim of determining how these parameters are affected by molecular perturbations. Here, it is argued that the assumption of a homogeneous RRP may be too simplistic and may blur the distinction between vesicle priming and fusion. Rather, considering priming as a dynamic and reversible multistep process allows alternative interpretations of mutagenesis-induced changes in synaptic transmission and suggests mechanisms for variability in synaptic strength and short-term plasticity among synapses, as well as for interactions between short- and long-term plasticity. In many cases, assigned roles of proteins or causes for observed phenotypes are shifted from fusion- to priming-related when considering multistep priming. Activity-dependent enhancement of priming is an essential element in this alternative view and its variation among synapse types can explain why some synapses show depression and others show facilitation at low to intermediate stimulation frequencies. Multistep priming also suggests a mechanism for frequency invariance of steady-state release, which can be observed in some synapses involved in sensory processing.
    MeSH term(s) Synapses/metabolism ; Synaptic Vesicles/metabolism ; Synaptic Transmission/physiology ; Action Potentials ; Proteins/metabolism ; Neuronal Plasticity/physiology
    Chemical Substances Proteins
    Language English
    Publishing date 2023-12-19
    Publishing country United States
    Document type Journal Article
    ZDB-ID 3118-5
    ISSN 1540-7748 ; 0022-1295
    ISSN (online) 1540-7748
    ISSN 0022-1295
    DOI 10.1085/jgp.202313454
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Different states of synaptic vesicle priming explain target cell type-dependent differences in neurotransmitter release.

    Aldahabi, Mohammad / Neher, Erwin / Nusser, Zoltan

    Proceedings of the National Academy of Sciences of the United States of America

    2024  Volume 121, Issue 18, Page(s) e2322550121

    Abstract: Pronounced differences in neurotransmitter release from a given presynaptic neuron, depending on the synaptic target, are among the most intriguing features of cortical networks. Hippocampal pyramidal cells (PCs) release glutamate with low probability to ...

    Abstract Pronounced differences in neurotransmitter release from a given presynaptic neuron, depending on the synaptic target, are among the most intriguing features of cortical networks. Hippocampal pyramidal cells (PCs) release glutamate with low probability to somatostatin expressing oriens-lacunosum-moleculare (O-LM) interneurons (INs), and the postsynaptic responses show robust short-term facilitation, whereas the release from the same presynaptic axons onto fast-spiking INs (FSINs) is ~10-fold higher and the excitatory postsynaptic currents (EPSCs) display depression. The mechanisms underlying these vastly different synaptic behaviors have not been conclusively identified. Here, we applied a combined functional, pharmacological, and modeling approach to address whether the main difference lies in the action potential-evoked fusion or else in upstream priming processes of synaptic vesicles (SVs). A sequential two-step SV priming model was fitted to the peak amplitudes of unitary EPSCs recorded in response to complex trains of presynaptic stimuli in acute hippocampal slices of adult mice. At PC-FSIN connections, the fusion probability (P
    MeSH term(s) Animals ; Synaptic Vesicles/metabolism ; Synaptic Vesicles/physiology ; Mice ; Neurotransmitter Agents/metabolism ; Hippocampus/metabolism ; Hippocampus/physiology ; Excitatory Postsynaptic Potentials/physiology ; Synaptic Transmission/physiology ; Interneurons/metabolism ; Interneurons/physiology ; Pyramidal Cells/metabolism ; Pyramidal Cells/physiology ; Synapses/metabolism ; Synapses/physiology ; Models, Neurological
    Chemical Substances Neurotransmitter Agents
    Language English
    Publishing date 2024-04-24
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2322550121
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  3. Article ; Online: Neurosecretion: what can we learn from chromaffin cells.

    Neher, Erwin

    Pflugers Archiv : European journal of physiology

    2018  Volume 470, Issue 1, Page(s) 7–11

    Abstract: Many of the molecular players in the stimulus-secretion chain are similarly active in neurosecretion and catecholamine release. Therefore, studying chromaffin cells uncovered many details of the processes of docking, priming, and exocytosis of vesicles. ... ...

    Abstract Many of the molecular players in the stimulus-secretion chain are similarly active in neurosecretion and catecholamine release. Therefore, studying chromaffin cells uncovered many details of the processes of docking, priming, and exocytosis of vesicles. However, morphological specializations at synapses, called active zones (AZs), confer extra speed of response and another layer of control to the fast release of vesicles by action potentials. Work at the Calyx of Held, a glutamatergic nerve terminal, has shown that in addition to such rapidly released vesicles, there is a pool of "Slow Vesicles," which are held to be perfectly release-competent, but lack a final step of tight interaction with the AZ. It is argued here that such "Slow Vesicles" have many properties in common with chromaffin granules. The added complexity in the AZ-dependent regulation of "Fast Vesicles" can lead to misinterpretation of data on neurosecretion. Therefore, the study of Slow Vesicles and of chromaffin granules may provide a clearer picture of the early steps in the highly regulated process of neurosecretion.
    MeSH term(s) Animals ; Chromaffin Granules/metabolism ; Chromaffin Granules/physiology ; Humans ; Neurosecretion ; Synaptic Transmission
    Language English
    Publishing date 2018
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 6380-0
    ISSN 1432-2013 ; 0031-6768
    ISSN (online) 1432-2013
    ISSN 0031-6768
    DOI 10.1007/s00424-017-2051-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Physiology of intracellular calcium buffering.

    Eisner, David / Neher, Erwin / Taschenberger, Holger / Smith, Godfrey

    Physiological reviews

    2023  Volume 103, Issue 4, Page(s) 2767–2845

    Abstract: Calcium signaling underlies much of physiology. Almost all the ... ...

    Abstract Calcium signaling underlies much of physiology. Almost all the Ca
    MeSH term(s) Humans ; Calcium/metabolism ; Buffers ; Cytoplasm/metabolism ; Heart ; Synaptic Transmission ; Calcium Signaling/physiology
    Chemical Substances Calcium (SY7Q814VUP) ; Buffers
    Language English
    Publishing date 2023-06-16
    Publishing country United States
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 209902-0
    ISSN 1522-1210 ; 0031-9333
    ISSN (online) 1522-1210
    ISSN 0031-9333
    DOI 10.1152/physrev.00042.2022
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  5. Article ; Online: Some Subtle Lessons from the Calyx of Held Synapse.

    Neher, Erwin

    Biophysical journal

    2017  Volume 112, Issue 2, Page(s) 215–223

    Abstract: The calyx of Held is a giant nerve terminal that forms a glutamatergic synapse in the auditory pathway. Due to its large size, it offers a number of advantages for biophysical studies, including voltage-clamp of both pre- and postsynaptic compartments ... ...

    Abstract The calyx of Held is a giant nerve terminal that forms a glutamatergic synapse in the auditory pathway. Due to its large size, it offers a number of advantages for biophysical studies, including voltage-clamp of both pre- and postsynaptic compartments and the loading with indicator dyes and caged compounds. Three aspects of recent findings on the calyx are reviewed here, each of which seems to have only subtle consequences for nerve-evoked excitatory postsynaptic currents: vesicle heterogeneity, refractoriness of release sites, and superpriming. Together, they determine short-term plasticity features that are superficially similar to those expected for a simple vesicle pool model. However, detailed consideration of these aspects may be required for the correct mechanistic interpretation of data from synapses with normal and perturbed function, as well as for modeling the dynamics of short-term plasticity.
    MeSH term(s) Auditory Pathways/physiology ; Kinetics ; Synapses/metabolism
    Language English
    Publishing date 2017-01-24
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 218078-9
    ISSN 1542-0086 ; 0006-3495
    ISSN (online) 1542-0086
    ISSN 0006-3495
    DOI 10.1016/j.bpj.2016.12.017
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  6. Article ; Online: Introduction: regulated exocytosis.

    Neher, E

    Cell calcium

    2012  Volume 52, Issue 3-4, Page(s) 196–198

    Abstract: Calcium ions regulate secretory processes in several ways. Most prominently they (i) trigger the release of vesicle contents rapidly and in a highly cooperative way and they (ii) control priming steps, which prepare vesicles for release. The importance ... ...

    Abstract Calcium ions regulate secretory processes in several ways. Most prominently they (i) trigger the release of vesicle contents rapidly and in a highly cooperative way and they (ii) control priming steps, which prepare vesicles for release. The importance of using assays with high time resolution for separating these distinct roles is pointed out here.
    MeSH term(s) Calcium/metabolism ; Exocytosis/physiology ; Kinetics ; Secretory Vesicles/metabolism
    Chemical Substances Calcium (SY7Q814VUP)
    Language English
    Publishing date 2012-09
    Publishing country Netherlands
    Document type Introductory Journal Article
    ZDB-ID 757687-0
    ISSN 1532-1991 ; 0143-4160
    ISSN (online) 1532-1991
    ISSN 0143-4160
    DOI 10.1016/j.ceca.2012.04.013
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Non-negative Matrix Factorization as a Tool to Distinguish Between Synaptic Vesicles in Different Functional States.

    Neher, Erwin / Taschenberger, Holger

    Neuroscience

    2021  Volume 458, Page(s) 182–202

    Abstract: Synaptic vesicles (SVs) undergo multiple steps of functional maturation (priming) before being fusion competent. We present an analysis technique, which decomposes the time course of quantal release during repetitive stimulation as a sum of contributions ...

    Abstract Synaptic vesicles (SVs) undergo multiple steps of functional maturation (priming) before being fusion competent. We present an analysis technique, which decomposes the time course of quantal release during repetitive stimulation as a sum of contributions of SVs, which existed in distinct functional states prior to stimulation. Such states may represent different degrees of maturation in priming or relate to different molecular composition of the release apparatus. We apply the method to rat calyx of Held synapses. These synapses display a high degree of variability, both with respect to synaptic strength and short-term plasticity during high-frequency stimulus trains. The method successfully describes time courses of quantal release at individual synapses as linear combinations of three components, representing contributions from functionally distinct SV subpools, with variability among synapses largely covered by differences in subpool sizes. Assuming that SVs transit in sequence through at least two priming steps before being released by an action potential (AP) we interpret the components as representing SVs which had been 'fully primed', 'incompletely primed' or undocked prior to stimulation. Given these assumptions, the analysis reports an initial release probability of 0.43 for SVs that were fully primed prior to stimulation. Release probability of that component was found to increase during high-frequency stimulation, leading to rapid depletion of that subpool. SVs that were incompletely primed at rest rapidly obtain fusion-competence during repetitive stimulation and contribute the majority of release after 3-5 stimuli.
    MeSH term(s) Action Potentials ; Animals ; Rats ; Synapses ; Synaptic Transmission ; Synaptic Vesicles
    Language English
    Publishing date 2021-01-13
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 196739-3
    ISSN 1873-7544 ; 0306-4522
    ISSN (online) 1873-7544
    ISSN 0306-4522
    DOI 10.1016/j.neuroscience.2020.10.012
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  8. Article ; Online: A sequential two-step priming scheme reproduces diversity in synaptic strength and short-term plasticity.

    Lin, Kun-Han / Taschenberger, Holger / Neher, Erwin

    Proceedings of the National Academy of Sciences of the United States of America

    2022  Volume 119, Issue 34, Page(s) e2207987119

    Abstract: Glutamatergic synapses display variable strength and diverse short-term plasticity (STP), even for a given type of connection. Using nonnegative tensor factorization and conventional state modeling, we demonstrate that a kinetic scheme consisting of two ... ...

    Abstract Glutamatergic synapses display variable strength and diverse short-term plasticity (STP), even for a given type of connection. Using nonnegative tensor factorization and conventional state modeling, we demonstrate that a kinetic scheme consisting of two sequential and reversible steps of release-machinery assembly and a final step of synaptic vesicle (SV) fusion reproduces STP and its diversity among synapses. Analyzing transmission at the calyx of Held synapses reveals that differences in synaptic strength and STP are not primarily caused by variable fusion probability (
    MeSH term(s) Exocytosis ; Membrane Fusion ; Neuronal Plasticity ; Synapses/physiology ; Synaptic Transmission ; Synaptic Vesicles/physiology
    Language English
    Publishing date 2022-08-15
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2207987119
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  9. Article ; Online: Merits and Limitations of Vesicle Pool Models in View of Heterogeneous Populations of Synaptic Vesicles.

    Neher, Erwin

    Neuron

    2015  Volume 87, Issue 6, Page(s) 1131–1142

    Abstract: The concept of a readily releasable pool (RRP) of synaptic vesicles has been used extensively for the analysis of neurotransmitter release. Traditionally the properties of vesicles in such a pool have been assumed to be homogeneous, and techniques have ... ...

    Abstract The concept of a readily releasable pool (RRP) of synaptic vesicles has been used extensively for the analysis of neurotransmitter release. Traditionally the properties of vesicles in such a pool have been assumed to be homogeneous, and techniques have been developed to determine pool parameters, such as the size of the pool and the probability with which a vesicle is released during an action potential. Increasing evidence, however, indicates that vesicles may be quite heterogeneous with respect to their release probability. The question, therefore, arises: what do the estimates of pool parameters mean in view of such heterogeneity? Here, four methods for obtaining pool estimates are reviewed, together with their underlying assumptions. The consequences of violation of these assumptions are discussed, and how apparent pool sizes are influenced by stimulation strength is explored by simulations.
    MeSH term(s) Action Potentials/physiology ; Animals ; Humans ; Models, Biological ; Synapses/metabolism ; Synapses/secretion ; Synaptic Transmission/physiology ; Synaptic Vesicles/metabolism ; Synaptic Vesicles/secretion
    Language English
    Publishing date 2015-09-23
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 808167-0
    ISSN 1097-4199 ; 0896-6273
    ISSN (online) 1097-4199
    ISSN 0896-6273
    DOI 10.1016/j.neuron.2015.08.038
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  10. Article: Introduction: Regulated exocytosis

    Neher, E

    Cell calcium. 2012 , v. 52, no. 3-4

    2012  

    Abstract: Calcium ions regulate secretory processes in several ways. Most prominently they (i) trigger the release of vesicle contents rapidly and in a highly cooperative way and they (ii) control priming steps, which prepare vesicles for release. The importance ... ...

    Abstract Calcium ions regulate secretory processes in several ways. Most prominently they (i) trigger the release of vesicle contents rapidly and in a highly cooperative way and they (ii) control priming steps, which prepare vesicles for release. The importance of using assays with high time resolution for separating these distinct roles is pointed out here.
    Keywords calcium ; exocytosis ; ions
    Language English
    Dates of publication 2012-09
    Size p. 196-198.
    Publishing place Elsevier India Pvt Ltd.
    Document type Article
    ZDB-ID 757687-0
    ISSN 1532-1991 ; 0143-4160
    ISSN (online) 1532-1991
    ISSN 0143-4160
    DOI 10.1016/j.ceca.2012.04.013
    Database NAL-Catalogue (AGRICOLA)

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