Synaptic Vesicles Undock and Then Transiently Dock After an Action Potential
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Variable Priming of a Docked Synaptic Vesicle PNAS PLUS
Variable priming of a docked synaptic vesicle PNAS PLUS Jae Hoon Junga,b,c, Joseph A. Szulea,c, Robert M. Marshalla,c, and Uel J. McMahana,c,1 aDepartment of Neurobiology, Stanford University School of Medicine, Stanford, CA 94305; bDepartment of Physics, Stanford University School of Humanities and Sciences, Stanford, CA 94305; and cDepartment of Biology, Texas A&M University, College Station, TX 77845 Edited by Thomas S. Reese, National Institutes of Health, Bethesda, MD, and approved January 12, 2016 (received for review November 30, 2015) The priming of a docked synaptic vesicle determines the proba- transition. Biochemical and electrophysiological approaches have bility of its membrane (VM) fusing with the presynaptic membrane provided evidence that priming is mediated by interactions be- (PM) when a nerve impulse arrives. To gain insight into the nature tween the SNARE proteins and their regulators (7, 12–14, 24) and of priming, we searched by electron tomography for structural can involve differences in positioning of docked SVs relative to + relationships correlated with fusion probability at active zones of Ca2 channels (25). Biochemistry has also led to the suggestion axon terminals at frog neuromuscular junctions. For terminals that primed SVs may become deprimed (26). fixed at rest, the contact area between the VM of docked vesicles We have previously shown by electron tomography on frog and PM varied >10-fold with a normal distribution. There was no neuromuscular junctions (NMJs) fixed at rest that there are, for merging of the membranes. For terminals fixed during repetitive docked SVs, variations in the extent of the VM–PM contact area evoked synaptic transmission, the normal distribution of contact and in the length of the several AZM macromolecules linking areas was shifted to the left, due in part to a decreased number of the VM to the PM, the so-called ribs, pegs, and pins (2, 27). -
Mechanisms of Synaptic Plasticity Mediated by Clathrin Adaptor-Protein Complexes 1 and 2 in Mice
Mechanisms of synaptic plasticity mediated by Clathrin Adaptor-protein complexes 1 and 2 in mice Dissertation for the award of the degree “Doctor rerum naturalium” at the Georg-August-University Göttingen within the doctoral program “Molecular Biology of Cells” of the Georg-August University School of Science (GAUSS) Submitted by Ratnakar Mishra Born in Birpur, Bihar, India Göttingen, Germany 2019 1 Members of the Thesis Committee Prof. Dr. Peter Schu Institute for Cellular Biochemistry, (Supervisor and first referee) University Medical Center Göttingen, Germany Dr. Hans Dieter Schmitt Neurobiology, Max Planck Institute (Second referee) for Biophysical Chemistry, Göttingen, Germany Prof. Dr. med. Thomas A. Bayer Division of Molecular Psychiatry, University Medical Center, Göttingen, Germany Additional Members of the Examination Board Prof. Dr. Silvio O. Rizzoli Department of Neuro-and Sensory Physiology, University Medical Center Göttingen, Germany Dr. Roland Dosch Institute of Developmental Biochemistry, University Medical Center Göttingen, Germany Prof. Dr. med. Martin Oppermann Institute of Cellular and Molecular Immunology, University Medical Center, Göttingen, Germany Date of oral examination: 14th may 2019 2 Table of Contents List of abbreviations ................................................................................. 5 Abstract ................................................................................................... 7 Chapter 1: Introduction ............................................................................ -
Multivesicular Release Differentiates the Reliability of Synaptic Transmission Between the Visual Cortex and the Somatosensory Cortex
11994 • The Journal of Neuroscience, September 8, 2010 • 30(36):11994–12004 Cellular/Molecular Multivesicular Release Differentiates the Reliability of Synaptic Transmission between the Visual Cortex and the Somatosensory Cortex Chao-Hua Huang, Jin Bao, and Takeshi Sakaba Independent Junior Research Group Biophysics of Synaptic Transmission, Max Planck Institute for Biophysical Chemistry, 37077, Goettingen, Germany Neurons in layer 4 (L4) of the cortex play an important role in transferring signals from thalamus to other layers of the cortex. Under- standing the fundamental properties of synaptic transmission between L4 neurons helps us gain a clear picture of how the neuronal network in L4 cooperates to process sensory information. In the present study, we have determined the underlying parameters that govern synaptic strength, such as quantal size, size of readily releasable vesicle pool, and release probability (Pr) of excitatory synaptic connections within L4 of the visual cortex (V1) and the somatosensory cortex (S1) in mice. Although only a single vesicle is released per release site under physiological conditions at V1 synapses, multivesicular release (MVR) is observed at S1 synapses. In addition, we observed a saturation of postsynaptic receptors at S1 synapses. Other synaptic properties are similar in both cortices. Dynamic clamp experiments suggest that higher Pr and MVR at S1 synapses lower the requirement of the number of synaptic inputs to generate postsynaptic action potentials. In addition, the slower decay of synaptic current and the intrinsic membrane properties of the postsyn- aptic neuron also contribute to the reliable transmission between S1 neurons. Introduction synapses, remains controversial. Variability of synaptic responses Synaptic strength is determined by both presynaptic and postsyn- is further determined by postsynaptic receptor properties such as aptic factors. -
Part III: Modeling Neurotransmission – a Cholinergic Synapse
Part III: Modeling Neurotransmission – A Cholinergic Synapse Operation of the nervous system is dependent on the flow of information through chains of neurons functionally connected by synapses. The neuron conducting impulses toward the synapse is the presynaptic neuron, and the neuron transmitting the signal away from the synapse is the postsynaptic neuron. Chemical synapses are specialized for release and reception of chemical neurotransmitters. For the most part, neurotransmitter receptors in the membrane of the postsynaptic cell are either 1.) channel-linked receptors, which mediate fast synaptic transmission, or 2.) G protein-linked receptors, which oversee slow synaptic responses. Channel-linked receptors are ligand-gated ion channels that interact directly with a neurotransmitter and are called ionotropic receptors. Alternatively, metabotropic receptors do not have a channel that opens or closes but rather, are linked to a G-protein. Once the neurotransmitter binds to the metabotropic receptor, the receptor activates the G-protein which, in turn, goes on to activate another molecule. 3a. Model the ionotropic cholinergic synapse shown below. Be sure to label all of the following: voltage-gated sodium channel, voltage-gated potassium channel, neurotransmitter, synaptic vesicle, presynaptic cell, postsynaptic cell, potassium leak channel, sodium-potassium pump, synaptic cleft, acetylcholine receptor, acetylcholinesterase, calcium channel. When a nerve impulse (action potential) reaches the axon terminal, it sets into motion a chain of events that triggers the release of neurotransmitter. You will next model the events of neurotransmission at a cholinergic synapse. Cholinergic synapses utilize acetylcholine as the chemical of neurotransmission. MSOE Center for BioMolecular Modeling Synapse Kit: Section 3-6 | 1 Step 1 - Action potential arrives at the Step 2 - Calcium channels open in the terminal end of the presynaptic cell. -
Synaptics and the Auditory Nerve;.Pdf
Salamanca Study Abroad Program: Neurobiology of Hearing Synaptics and the auditory nerve R. Keith Duncan University of Michigan [email protected] Review Resources Reviews: Safieddine et al., 2012, The auditory hair cell ribbon synapse: From assembly to function, Ann Rev Neurosci, 35:509-528 Kim et al., 2013, Single Ca2+ channels and exocytosis at sensory synapses, J Physiol, epub Note: this is an excellent review describing the differences between cochlear and retinal ribbon synapses. Rabbitt and Brownell, 2011 Efferent modulation of hair cell function, Curr Opinion Otolaryngol Head Neck Surg,19:376-381 Outline Exocytosis and synaptics Afferent physiology Efferent physiology Afferent cochlear innervation Type 1 afferents: • 95% of cochlear afferents • account for hearing • each innervates only 1 IHC • ~20 innervate one IHC Type 2 afferents: • less well-described • en passant innervation of OHCs; 4 Hair cells form ribbon synapses with afferent neurons 5 Distinct pools of vesicles • Electron tomography reconstruction shows 4 pools Ribbon docked vesicles (readily releasable pool, ~10) Tethered vesicles (releasable pool, ~200) Extrasynaptic docked vesicles Cytoplasmic vesicles (recruitable pool?) • These pools likely contribute to distinct kinetics of exocytosis as Lenzi & von Gersdorff, 2001 stimulus duration increases. Distinct phases of exocytosis Capacitance is a proxy for exocytosis. Vesicle fusion increases surface area which increases capacitance. (see supplemental slides) Exocytosis occurs in calcium nanodomains Hair cells The synaptic vesicle cycle NT uptake, translocation, docking Molecular Components of Ribbon Synapses Differ from Conventional Synapses Vesicle related: • Synaptotagmins are the Ca2+ sensors in most synapses. Mature hair cells lack SYT I and II but have IV, VI-IX (rare types). -
The Diverse Roles of Ribbon Synapses in Sensory Neurotransmission
Nature Reviews Neuroscience | AOP, published online 3 November 2010; doi:10.1038/nrn2924 REVIEWS The diverse roles of ribbon synapses in sensory neurotransmission Gary Matthews* and Paul Fuchs‡ Abstract | Sensory synapses of the visual and auditory systems must faithfully encode a wide dynamic range of graded signals, and must be capable of sustained transmitter release over long periods of time. Functionally and morphologically, these sensory synapses are unique: their active zones are specialized in several ways for sustained, rapid vesicle exocytosis, but their most striking feature is an organelle called the synaptic ribbon, which is a proteinaceous structure that extends into the cytoplasm at the active zone and tethers a large pool of releasable vesicles. But precisely how does the ribbon function to support tonic release at these synapses? Recent genetic and biophysical advances have begun to open the ‘black box’ of the synaptic ribbon with some surprising findings and promise to resolve its function in vision and hearing. Changes in our external environment are detected by photoreceptors, electroreceptors, and hair cells of sensory receptor cells, which transduce sensory stim- vesti bular organs and the lateral line system. In the uli into an electrical signal that is graded depending visual system, ribbons are also found at the output on the stimulus intensity. In vision, balance and hear- synapses of the second-order retinal b ipolar neurons, ing, synapses of the receptor cells are unusual because which signal by means of graded changes in mem- they function tonically — that is, they transmit graded brane potential, similar to photoreceptors and hair information with high fidelity across a broad range of cells. -
Molecular Assembly and Structural Plasticity of Sensory Ribbon Synapses—A Presynaptic Perspective
International Journal of Molecular Sciences Review Molecular Assembly and Structural Plasticity of Sensory Ribbon Synapses—A Presynaptic Perspective Roos Anouk Voorn 1,2,3 and Christian Vogl 1,3,* 1 Presynaptogenesis and Intracellular Transport in Hair Cells Junior Research Group, Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Goettingen, 37075 Goettingen, Germany; [email protected] 2 Göttingen Graduate Center for Neurosciences, Biophysics and Molecular Biosciences, 37075 Goettingen, Germany 3 Collaborative Research Center 889 “Cellular Mechanisms of Sensory Processing”, 37075 Goettingen, Germany * Correspondence: [email protected] Received: 21 October 2020; Accepted: 17 November 2020; Published: 19 November 2020 Abstract: In the mammalian cochlea, specialized ribbon-type synapses between sensory inner hair cells (IHCs) and postsynaptic spiral ganglion neurons ensure the temporal precision and indefatigability of synaptic sound encoding. These high-through-put synapses are presynaptically characterized by an electron-dense projection—the synaptic ribbon—which provides structural scaffolding and tethers a large pool of synaptic vesicles. While advances have been made in recent years in deciphering the molecular anatomy and function of these specialized active zones, the developmental assembly of this presynaptic interaction hub remains largely elusive. In this review, we discuss the dynamic nature of IHC (pre-) synaptogenesis and highlight molecular key players as well as the transport pathways underlying this process. Since developmental assembly appears to be a highly dynamic process, we further ask if this structural plasticity might be maintained into adulthood, how this may influence the functional properties of a given IHC synapse and how such plasticity could be regulated on the molecular level. -
The Ubiquitous Nature of Multivesicular Release
Feature Review The ubiquitous nature of multivesicular release 1 1 2 Stephanie Rudolph , Ming-Chi Tsai , Henrique von Gersdorff , and 1 Jacques I. Wadiche 1 Department of Neurobiology and Evelyn McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA 2 The Vollum Institute, Oregon Health and Science University, Portland, OR 97239, USA ‘Simplicity is prerequisite for reliability’ (E.W. Dijkstra [1]) fluctuations of evoked synaptic responses [11] and high Presynaptic action potentials trigger the fusion of vesicles transmitter concentration in the synaptic cleft [12]. To to release neurotransmitter onto postsynaptic neurons. reconcile these findings, a more flexible hypothesis pro- Each release site was originally thought to liberate at poses that multiple vesicles can be released per active zone most one vesicle per action potential in a probabilistic with each action potential, defined as MVR. Indeed, stud- fashion, rendering synaptic transmission unreliable. How- ies have established that MVR occurs at many inhibitory ever, the simultaneous release of several vesicles, or and excitatory synapses throughout the brain, including multivesicular release (MVR), represents a simple mecha- nism to overcome the intrinsic unreliability of synaptic transmission. MVR was initially identified at specialized synapses but is now known to be common throughout Glossary the brain. MVR determines the temporal and spatial dis- Active zone: ultrastructurally and functionally specialized area at the pre- persion of transmitter, controls the extent of receptor synaptic terminal where readily-releasable vesicles fuse (see also Release site). Coefficient of variation (CV): standard deviation s divided by the mean (e.g., s activation, and contributes to adapting synaptic strength of current amplitude fluctuations and mean current). -
Molecular Mechanism of Fusion Pore Formation Driven by the Neuronal SNARE Complex
Molecular mechanism of fusion pore formation driven by the neuronal SNARE complex Satyan Sharmaa,1 and Manfred Lindaua,b aLaboratory for Nanoscale Cell Biology, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany and bSchool of Applied and Engineering Physics, Cornell University, Ithaca, NY 14850 Edited by Axel T. Brunger, Stanford University, Stanford, CA, and approved November 1, 2018 (received for review October 2, 2018) Release of neurotransmitters from synaptic vesicles begins with a systems in which various copy numbers of syb2 were incorporated narrow fusion pore, the structure of which remains unresolved. To in an ND while the t-SNAREs were present on a liposome have obtain a structural model of the fusion pore, we performed coarse- been used experimentally to study SNARE-mediated mem- grained molecular dynamics simulations of fusion between a brane fusion (13, 17). The small dimensions of the ND compared nanodisc and a planar bilayer bridged by four partially unzipped with a spherical vesicle makes such systems ideally suited for MD SNARE complexes. The simulations revealed that zipping of SNARE simulations without introducing extreme curvature, which is well complexes pulls the polar C-terminal residues of the synaptobrevin known to strongly influence the propensity of fusion (18–20). 2 and syntaxin 1A transmembrane domains to form a hydrophilic MARTINI-based CGMD simulations have been used in several – core between the two distal leaflets, inducing fusion pore forma- studies of membrane fusion (16, 21 23). To elucidate the fusion tion. The estimated conductances of these fusion pores are in good pore structure and the mechanism of its formation, we performed agreement with experimental values. -
Living Synaptic Vesicle Marker: Synaptotagmin-GFP
©2002Wiley-Liss,Inc. genesis34:142–145(2002) LivingSynapticVesicleMarker: Synaptotagmin-GFP YongQ.Zhang,ChristopherK.Rodesch,andKendalBroadie* DepartmentofBiologicalSciences,VanderbiltUniversity,Nashville,TN37235-1634 Received4June2002;Accepted17July2002 Synapsesarethesiteofchemicalcommunicationbe- tweenneuronsandbetweenneuronsandmuscles.The synapticvesicle(SV)isaprominentpresynapticor- ganellewhichcontainschemicalneurotransmittersand fuseswiththeplasmamembranetomediateneurotrans- mission.Thereareabout50orsosynapticproteins whichareeitherintegralvesiclemembraneproteins FIG.1.Mapofsyt-eGFPandsyb-eGFPfusionconstructs.Syt (e.g.,synaptotagmin,syt;andsynaptobrevin,syb)or (accessionnumberM55048)orsyb(neuronalsynaptobrevin,acces- vesicle-associatedproteins(e.g.,cysteinestringprotein, sionnumberS66686)codingregionwasfusedtotheN-terminalof CSP;Fernandez-ChaconandSudhof,1999).Wehave eGFP(enhancedGFP,catalognumber6084-1fromClonTech,Palo transformedDrosophilawithanovelsyt-eGFP(en- Alto,CA;sequenceaccessionnumberU55763)withEcoRIand XhoI.SytcDNA(encodingaproteinof475aminoacids)wasPCR- hancedGFP)fusionprotein,thefluorescencepatternof amplifiedandsequence-confirmedwithapairofprimerssyt.1: whichcolocalizeswithnativeSVproteinsatsynapses, gggaattcattaggggcaacaacacagc(EcoRI)andsyt.3:ccctcgagc suggestingthatthesyt-eGFPfusionproteiniscorrectly cttcatgttcttcaggatctc(XhoI).n-Syb(encoding180aminoacids) localizedasanintegralSVproteinandthereforeagood wasPCR-amplifiedandsequence-confirmedwithapairofprimers syb1:acagccgaattcgctgaggc(EcoRI)andprimersyb2:tcctc SVmarkerinlivingsynapses.Wedemonstratethatthe -
The Molecular Machinery of Neurotransmitter Release Nobel Lecture, 7 December 2013
The Molecular Machinery of Neurotransmitter Release Nobel Lecture, 7 December 2013 by Thomas C. Südhof Dept. of Molecular and Cellular Physiology, and Howard Hughes Medical Institute, Stanford University, USA. 1. THE NEUROTRANSMITTER RELEASE ENIGMA Synapses have a long history in science. Synapses were frst functionally demon- strated by Emil duBois-Reymond (1818–1896), were morphologically identifed by classical neuroanatomists such as Rudolf von Kölliker (1817–1905) and San- tiago Ramon y Cajal (1852–1934), and named in 1897 by Michael Foster (1836– 1907). Although the chemical nature of synaptic transmission was already sug- gested by duBois-Reymond, it was long disputed because of its incredible speed. Over time, however, overwhelming evidence established that most synapses use chemical messengers called neurotransmitters, most notably with the pioneer- ing contributions by Otto Loewi (1873–1961), Henry Dale (1875–1968), Ulf von Euler (1905–1983), and Julius Axelrod (1912–2004). In parallel, arguably the most important advance to understanding how synapses work was provided by Bernard Katz (1911–2003), who elucidated the principal mechanism of syn- aptic transmission (Katz, 1969). Most initial studies on synapses were carried out on the neuromuscular junction, and central synapses have only come to the fore in recent decades. Here, major contributions by many scientists, including George Palade, Rodolfo Llinas, Chuck Stevens, Bert Sakmann, Eric Kandel, and Victor Whittaker, to name just a few, not only confrmed the principal results obtained in the neuromuscular junction by Katz, but also revealed that synapses 259 6490_Book.indb 259 11/4/14 2:29 PM 260 The Nobel Prizes exhibit an enormous diversity of properties as well as an unexpected capacity for plasticity. -
Synaptic Vesicle Dynamics in Living Cultured Hippocampal Neurons Visualized with CY3-Conjugated Antibodies Directed Against the Lumenal Domain of Synaptotagmin
The Journal of Neuroscience, June 1995, 1~76): 4328-4342 Synaptic Vesicle Dynamics in Living Cultured Hippocampal Neurons Visualized with CY3-Conjugated Antibodies Directed against the Lumenal Domain of Synaptotagmin Kajetan Kraszewski,’ Olaf Mundigl,’ Laurie DanielI,’ Claudia Verclerio,* Michela Matteoli,2 and Pietro De Camilli’ ‘Department of Cell Biology and Howard Hughes Medical Institute, Yale University School Medicine, New Haven, Connecticut 06510 and XNR Center of Cytopharmacology and Department of Medical Pharmacology, University of Milano, Milano, Italy Antibodies directed against the lumenal domain of synap- which representthe presynaptic elementsof synapses.They un- totagmin I conjugated to CY3 (CYB-Syt,-Abs) and video mi- dergo exocytosis selectively at specialized regions of the pre- croscopy were used to study the dynamics of synaptic ves- synaptic plasmalemmacalled active zones and their rate of exo- icles in cultured hippocampal neurons. When applied to cytosis is dramatically stimulated by depolarization-induced cultures after synapse formation, CY3-Syt,-Abs produced a Ca2+ influx (De Camilli and Jahn, 1990; Jesse1and Kandel, strong labeling of presynaptic vesicle clusters which was 1992; Stidhof et al., 1993; Bennett and Scheller, 1994). markedly increased by membrane depolarization. The in- Until recently, the properties of SVs in situ could only be crease of the rate of CYSSyt,-Ab uptake in a high K+ me- studied by conventional morphological approacheswhich in- dium was maximal during the first few minutes but per- volve cell fixation, or by using electrophysiological techniques sisted for as long as 60 min. In axons developing in iso- which detect effects produced by neurotransmitterrelease. New lation, CYSSyt,-Abs, in combination with electron micros- probes have now been developed which make possibleto mon- copy immunocytochemistry, revealed the presence of itor morphologically, at the light microscopic level, SV dynam- synaptic vesicle clusters which move in bulk in antero- ics in the living cell.