DOCSLIB.ORG

Chemical Transmission Between DRG Somata Via Intervening Satellite Cell

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Chemical Transmission Between DRG Somata Via Intervening Satellite Cell Sandwich Synapse: Chemical Transmission Between DRG Somata via Intervening Satellite cell by Hyunhee Kim A thesis submitted in conformity with the requirements for the degree of Master of Science Department of Physiology and Neuroscience University of Toronto © Copyright by Hyunhee Kim 2010 ii Sandwich Synapse: Chemical Transmission between Dorsal Root Ganglion Somata via Intervening Satellite Glial Cell Hyunhee Kim Master of Science Department of Physiology and Neuroscience University of Toronto 2010 ABSTRACT The structure of afferent neurons is pseudounipolar. Studies suggest that they relay action potentials (APs) to both directions of the T-junctions to reach the cell body and the spinal cord. Moreover, the somata are electrically excitable and shown to be able to transmit the signals to associated satellite cells. Our study demonstrates that this transmission can go further and pass onto passive neighbouring somata, if they are in direct contact with same satellite cells. The neurons activate the satellite cells by releasing ATP. This triggers the satellite cells to exocytose acetylcholine to the neighbouring neurons. In addition, the ATP inhibits the nicotinic receptors of the neurons by activating P2Y receptors and initiating the G-protein-mediated pathway, thus reducing the signals that return to the neurons that initiated the signals. This “sandwich synapse” represents a unique pathway by the ectopic release between the somata and the satellite cells. iii ACKNOWLEDGEMENT First and foremost, I would like to express my most sincere gratitude to Dr. Elise F. Stanley, my supervisor. All of the work was made possible by her continuous guidance and support. Throughout the course of my study, she has taught me of scientific knowledge, critical thinking skills, the integrity required as a researcher, and most importantly the passion for scientific research. I am also grateful for her hard work needed in order to teach a girl who did not have any experience outside of school. It has been such an honour to be one of her graduate students. I would like to thank my supervisory committee, Drs. Milton P. Charlton and Peter Backx. I am in debt of their valuable suggestions and insightful comments that significantly influenced this work. I am also thankful to my defense committee, Drs. Melanie Woodin, Diane M. Broussard, and Shuzo Sugita. A thousand thanks to all my lab members, past and present, Dr. Qi Li, Alex Webber, Fiona K. Wong and Sabiha Gardezi, Adele Tufford, and Maria Altshuler. It was a great learning experience for me to work with them. I appreciate all the knowledge and techniques that they taught me. I also would like to express my gratitude to my friends who cheered and supported me for the last two years. To my dearest friends, Wenjun, Jinnie, Melody and Youngjoo: you guys are the best. I am also thankful to Dr. Schlichter’s lab. I had such a wonderful time with them. I would like to express my special love and gratitude to Mother, Father and Namhee who have been always there for me and gave me strength to go further. I love you, Umma. I would like to dedicate this thesis to you. Lastly, Thank you, God, for always giving me more than I deserve. iv TABLE OF CONTENTS ABSTRACT ii ACKNOWLEDGEMENTS iii TABLE OF CONTENTS iv LIST OF FIGURES vi LIST OF ABBREVIATIONS vii INTRODUCTION 1 PART 1: OVERVIEW OF SOMATOSENSORY SYSTEM 1 Spinal somatosensory pathways 1 PART 2: DORSAL ROOT GANGLION NEURONS 4 Anatomy of DRG 4 The functional cell-types in DRG neurons 4 Morphology of the afferent sensory neurons 5 Ectopic release from DRG neurons 6 Receptor in DRG neurons 7 Nicotinic acetylcholine receptor 7 P2X receptor 8 P2Y receptor 9 Cross excitation between DRG neurons 10 PART 3: SATELLITE GLIAL CELLS 11 Anatomy and physiology 11 The satellite cell as a protective layer of DRG neurons 12 Receptors in satellite glial cells 13 Neuron-satellite cell interactions 13 Role of the satellite cells in neuronal development and regeneration 14 Bi-directional communication between the satellite cells and the neurons 15 GOAL OF THE STUDY 19 HYPOTHESIS 20 METHODS 21 Dorsal root ganglia (DRG) dissection 21 Enzyme Treatment 21 Dissociating and plating of the DRG cells 22 v Electrophysiology 22 Single patch-clamp recordings 22 Pair patch-clamp recording 23 Drug experiment (electrophysiology) 24 Immunocytochemistry 24 Electron Microscopy 26 Statistical Analysis 26 RESULTS 28 Presynaptic markers are localized at the junction between DRG neuron 28 The current fluctuation in a DRG neuron often increases with adjacent neuron excitation 28 Satellite cells reside in between DRG neurons. 34 DRG neuron to satellite cell transmission is purinergic (P2X receptor mediation) 36 Satellite cell to DRG neuron transmission is cholinergic 41 P2Y receptors in DRG neuron inhibit satellite to DRG neuron transmission 45 Relief of G-protein inhibition in DRG neurons enhances neuronal cross-excitation 55 DISCUSSION 56 The chemical basis of the sandwich synapse 56 The sandwich synapse as the functional unit of DRG neuronal communication 61 REFERENCE LIST 65 vi LIST OF FIGURES Figure 1: Simplified diagram of somatosensory pathway 3 Figure 2: Chemical signalling between DRG neurons and satellite cells 17 Figure 3: Hypothesis 20 Figure 4. Synaptic proteins at the junction between the DRG pair 29 Figure 5. DRG neurons display spontaneous inward current transients 31 Figure 6. Inward current transient of DRG pairs become enhanced after stimulation in adjacent neurons 32 Figure 7. Satellite cell separating neighbouring DRG neuronal pair 35 Figure 8. Miniature excitatory postsynaptic currents (mEPCs) in satellite cells. 37 Figure 9. DRG neuron to satellite cell transmission is purinergic. 40 Figure 10. Response of DRG neurons to the purinergic and cholinergic agonists. 42 Figure 11. satellite cell to DRG neuron transmission is cholinergic. 43 Figure 12. mEPC-like activities appear in the neurons after the inhibition of G protein. 46 Figure 13. Neuronal mEPCs are cholinergic. 47 Figure 14. ATP applied to the satellite cells triggers mEPC activity in the neuron 49 Figure 15. G-protein mediated inhibition of the cholinergic transmission is induced by the activation of P2Y receptors. 51 Figure 16. Role of G protein activities in the neuronal-pair communication. 54 Figure 17. Schematic diagram of the Sandwich Synapse 62 vii LIST OF ABBREVIATIONS Abbreviation Full name ACh Acetylcholine ATP Adenosine triphosphate Cav2.2 N-type calcium channel ChAT Choline-O-acetyltrasferase CNQX 6-cyano-7-nitroquinoxaline-2,3-dione DRG Dorsal Root Ganglion D-TC d-tubocurarine EGTA ethylene glycol tetra-acetic acid GDPβS guanosine 5'-O-[gamma-thio] diphosphate HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid MEM Minimum essential medium nAChR Nicotinic acetylcholine receptor P2XR Purinergic receptor (ionotropic) P2YR Purinergic receptor (metabotropic) PCB Pancuronium bromide RIM Rab3-interacting molecule SGC Satellite glial cell SP Substance P SV2 Synaptic Vesicle Protein 2 TRP Transient receptor potential TTX Tetrodotoxin 1 INTRODUCTION PART 1: OVERVIEW OF THE SOMATOSENSORY NERVOUS SYSTEM The sensory system monitors the state of the organism and changes in its environment. It does so by using external detection via sense organs, such as touch, taste, smell, vision and sounds, and internal detection via mechanical receptors such as proprioception, pressure and temperature. The detected signal is transferred to the brain by different neuronal systems (e.g., visual or olfactory systems). Among these, the somatosensory system governs the recognition of mechanical stimulation, such as touch, temperature, nociception and proprioception (Arezzo et al., 1982). Spinal somatosensory system pathways Sensory information, coded as action potentials (APs), passes from the sensory endings to the somatosensory cortex in the brain via a series of neuronal relays through three orders of organization. First order neurons have their cell bodies in the dorsal root ganglion which project axons to the sense organ or ending and to the dorsal horn of the spinal cord where they synapse onto dendrites of the second order neurons. These axons ascend within the spinothalamic tract or dorsal column-medial lemniscus to the thalamus. The third order is composed of a neuronal network that connects the thalamus to an area of the cerebral cortex layer IV (Greenstein and Greenstein, 2000; Kandel et al., 2000; Martini et al., 2004; Randall et al., 2002). The first order neurons, whose endings express sensory receptors that extend across the periphery, relay the information to the central nervous system as AP trains. The nerve endings are equipped with mechanoreceptors that transform the physical 2 stimulus to electrical impulses (Greenstein and Greenstein, 2000). Two of the most common mechanoreceptors are Meissner’s corpuscles and Pacinian corpuscles (Smith, 2008). Deformation of the corpuscle opens Na + channels in the nerve terminal, bringing up membrane potential to threshold and generating APs (Greenstein and Greenstein, 2000). The APs travel along the afferent axons within the peripheral nerve, through the dorsal roots to the nerve terminals within the spinal cord. The nerve fibers that carry the APs to the spinal cord differ in diameter and morphology, with size classes that are related to sense organ functions. There are two main types of sensory axon: myelinated “A” type, and the slowly conducting, unmyelinated “C” type. The A type can be further subdivided into three subtypes: Aα, Aβ, Aγ in order of diameter and conduction velocity, where the Aα fibers are the largest and fastest (Greenstein and Greenstein, 2000; Lawson et al., 1993; Lawson, 2002). The nerve terminals of the afferent neurons eventually transmit the signals to the laminae I to IV of the gray matter. The different fibers innervate different regions (Smith, 2008). After reaching the spinal cord the signal generally ascends to the ventral posterolateral (VPL) nucleus in the thalamus. However, some fibers project into the ventral root that induce muscle reflexes (Fig. 1; Martini et al., 2004). The APs from the VPL nucleus eventually pass the posterior limb of the internal capsule and reach the postcentral gyrus.
Load more

Recommended publications
  • Plp-Positive Progenitor Cells Give Rise to Bergmann Glia in the Cerebellum
    Citation: Cell Death and Disease (2013) 4, e546; doi:10.1038/cddis.2013.74 OPEN & 2013 Macmillan Publishers Limited All rights reserved 2041-4889/13 www.nature.com/cddis Olig2/Plp-positive progenitor cells give rise to Bergmann glia in the cerebellum S-H Chung1, F Guo2, P Jiang1, DE Pleasure2,3 and W Deng*,1,3,4 NG2 (nerve/glial antigen2)-expressing cells represent the largest population of postnatal progenitors in the central nervous system and have been classified as oligodendroglial progenitor cells, but the fate and function of these cells remain incompletely characterized. Previous studies have focused on characterizing these progenitors in the postnatal and adult subventricular zone and on analyzing the cellular and physiological properties of these cells in white and gray matter regions in the forebrain. In the present study, we examine the types of neural progeny generated by NG2 progenitors in the cerebellum by employing genetic fate mapping techniques using inducible Cre–Lox systems in vivo with two different mouse lines, the Plp-Cre-ERT2/Rosa26-EYFP and Olig2-Cre-ERT2/Rosa26-EYFP double-transgenic mice. Our data indicate that Olig2/Plp-positive NG2 cells display multipotential properties, primarily give rise to oligodendroglia but, surprisingly, also generate Bergmann glia, which are specialized glial cells in the cerebellum. The NG2 þ cells also give rise to astrocytes, but not neurons. In addition, we show that glutamate signaling is involved in distinct NG2 þ cell-fate/differentiation pathways and plays a role in the normal development of Bergmann glia. We also show an increase of cerebellar oligodendroglial lineage cells in response to hypoxic–ischemic injury, but the ability of NG2 þ cells to give rise to Bergmann glia and astrocytes remains unchanged.
    [Show full text]
  • Control of Synapse Number by Glia Erik M
    R EPORTS RGCs (8). Similar results were obtained un- der both conditions. After 2 weeks in culture, Control of Synapse Number we used whole-cell patch-clamp recording to measure the significant enhancement of spon- by Glia taneous synaptic activity by astrocytes (Fig. 1, A and B) (9). In the absence of astroglia, Erik M. Ullian,* Stephanie K. Sapperstein, Karen S. Christopherson, little synaptic activity occurred even when Ben A. Barres RGCs were cultured with their tectal target cells (6). This difference in synaptic activity Although astrocytes constitute nearly half of the cells in our brain, their persisted even after a month in culture, indi- function is a long-standing neurobiological mystery. Here we show by quantal cating that it is not accounted for by a matu- analyses, FM1-43 imaging, immunostaining, and electron microscopy that few rational delay. To examine whether glia reg- synapses form in the absence of glial cells and that the few synapses that do ulate synaptic activity by enhancing postsyn- form are functionally immature. Astrocytes increase the number of mature, aptic responsiveness, we measured the re- functional synapses on central nervous system (CNS) neurons by sevenfold and sponse of RGCs to pulses of L-glutamate are required for synaptic maintenance in vitro. We also show that most syn- applied to the cell somas. Regardless of the apses are generated concurrently with the development of glia in vivo. These presence of glia, RGCs responded with in- data demonstrate a previously unknown function for glia in inducing and ward currents (Fig. 1C) that were blocked by stabilizing CNS synapses, show that CNS synapse number can be profoundly glutamate receptor antagonists (10).
    [Show full text]
  • Area-Specific Synapse Structure in Branched Posterior Nucleus Axons Reveals a New Level of Complexity in Thalamocortical Networks
    The Journal of Neuroscience, March 25, 2020 • 40(13):2663–2679 • 2663 Systems/Circuits Area-Specific Synapse Structure in Branched Posterior Nucleus Axons Reveals a New Level of Complexity in Thalamocortical Networks Javier Rodriguez-Moreno,1 Cesar Porrero,1 Astrid Rollenhagen,2 Mario Rubio-Teves,1 Diana Casas-Torremocha,1 X Lidia Alonso-Nanclares,3 Rachida Yakoubi,2 XAndrea Santuy,3 XAngel Merchan-Pe´rez,3,5,6 XJavier DeFelipe,3,4,5 Joachim H.R. Lu¨bke,2,7,8* and XFrancisco Clasca1* 1Department of Anatomy and Neuroscience, School of Medicine, Auto´noma de Madrid University, 28029 Madrid, Spain, 2Institute of Neuroscience and Medicine INM-10, Research Centre Ju¨lich GmbH, 52425 Ju¨lich, Germany, 3Laboratorio Cajal de Circuitos Corticales, Centro de Tecnología Biome´dica, Universidad Polite´cnica de Madrid, Pozuelo de Alarco´n, 28223 Madrid, Spain, 4Instituto Cajal, Consejo Superior de Investigaciones Científicas, Arce 37 28002, Madrid, Spain, 5CIBERNED, Centro de Investigacio´n Biome´dica en Red de Enfermedades Neurodegenerativas, 28031 Madrid, Spain, 6Departamento de Arquitectura y Tecnología de Sistemas Informa´ticos, Universidad Polite´cnica de Madrid. Boadilla del Monte, 28660 Madrid, Spain, 7Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty RWTH University Hospital Aachen, 52074 Aachen, Germany, and 8JARA-Translational Brain Medicine, 52425 Ju¨lich-Aachen, Germany Thalamocortical posterior nucleus (Po) axons innervating the vibrissal somatosensory (S1) and motor (MC) cortices are key links in the brain neuronal network that allows rodents to explore the environment whisking with their motile snout vibrissae. Here, using fine-scale high-end 3D electron microscopy, we demonstrate in adult male C57BL/6 wild-type mice marked differences between MC versus S1 Po synapses in (1) bouton and active zone size, (2) neurotransmitter vesicle pool size, (3) distribution of mitochondria around synapses, and (4) proportion of synapses established on dendritic spines and dendritic shafts.
    [Show full text]
  • The Interplay Between Neurons and Glia in Synapse Development And
    Available online at www.sciencedirect.com ScienceDirect The interplay between neurons and glia in synapse development and plasticity Jeff A Stogsdill and Cagla Eroglu In the brain, the formation of complex neuronal networks and regulate distinct aspects of synaptic development and amenable to experience-dependent remodeling is complicated circuit connectivity. by the diversity of neurons and synapse types. The establishment of a functional brain depends not only on The intricate communication between neurons and glia neurons, but also non-neuronal glial cells. Glia are in and their cooperative roles in synapse formation are now continuous bi-directional communication with neurons to direct coming to light due in large part to advances in genetic the formation and refinement of synaptic connectivity. This and imaging tools. This article will examine the progress article reviews important findings, which uncovered cellular made in our understanding of the role of mammalian and molecular aspects of the neuron–glia cross-talk that perisynaptic glia (astrocytes and microglia) in synapse govern the formation and remodeling of synapses and circuits. development, maturation, and plasticity since the previ- In vivo evidence demonstrating the critical interplay between ous Current Opinion article [1]. An integration of past and neurons and glia will be the major focus. Additional attention new findings of glial control of synapse development and will be given to how aberrant communication between neurons plasticity is tabulated in Box 1. and glia may contribute to neural pathologies. Address Glia control the formation of synaptic circuits Department of Cell Biology, Duke University Medical Center, Durham, In the CNS, glial cells are in tight association with NC 27710, USA synapses in all brain regions [2].
    [Show full text]
  • Electrical Synapses and Their Functional Interactions with Chemical Synapses
    REVIEWS Electrical synapses and their functional interactions with chemical synapses Alberto E. Pereda Abstract | Brain function relies on the ability of neurons to communicate with each other. Interneuronal communication primarily takes place at synapses, where information from one neuron is rapidly conveyed to a second neuron. There are two main modalities of synaptic transmission: chemical and electrical. Far from functioning independently and serving unrelated functions, mounting evidence indicates that these two modalities of synaptic transmission closely interact, both during development and in the adult brain. Rather than conceiving synaptic transmission as either chemical or electrical, this article emphasizes the notion that synaptic transmission is both chemical and electrical, and that interactions between these two forms of interneuronal communication might be required for normal brain development and function. Communication between neurons is required for Electrical and chemical synapses are now known to brain function, and the quality of such communica- coexist in most organisms and brain structures, but details tion enables hardwired neural networks to act in a of the properties and distribution of these two modalities of dynamic fashion. Functional interactions between transmission are still emerging. Most research efforts neurons occur at anatomically identifiable cellular have focused on exploring the mechanisms of chemi- regions called synapses. Although the nature of synaptic cal transmission, and considerably less is known transmission has been an area of enormous controversy about those underlying electrical transmission. It was (BOX 1), two main modalities of synaptic transmission — thought that electrical synapses were more abundant namely, chemical and electrical — are now recognized. At in invertebrates and cold-blooded vertebrates than chemical synapses, information is transferred through in mammals.
    [Show full text]
  • 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.
    [Show full text]
  • Synaptophysin Regulates Activity-Dependent Synapse Formation in Cultured Hippocampal Neurons
    Synaptophysin regulates activity-dependent synapse formation in cultured hippocampal neurons Leila Tarsa and Yukiko Goda* Division of Biology, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0366 Edited by Charles F. Stevens, The Salk Institute for Biological Studies, La Jolla, CA, and approved November 20, 2001 (received for review October 29, 2001) Synaptophysin is an abundant synaptic vesicle protein without a homogenotypic syp-mutant cultures, however, synapse forma- definite synaptic function. Here, we examined a role for synapto- tion is similar to that observed for wild-type cultures. Interest- physin in synapse formation in mixed genotype micro-island cul- ingly, the decrease in syp-mutant synapse formation is prevented tures of wild-type and synaptophysin-mutant hippocampal neu- when heterogenotypic cultures are grown in the presence of rons. We show that synaptophysin-mutant synapses are poor tetrodotoxin (TTX) or postsynaptic receptor blockers. Our donors of presynaptic terminals in the presence of competing results demonstrate a role for syp in activity-dependent com- wild-type inputs. In homogenotypic cultures, however, mutant petitive synapse formation. neurons display no apparent deficits in synapse formation com- pared with wild-type neurons. The reduced extent of synaptophy- Materials and Methods sin-mutant synapse formation relative to wild-type synapses in Hippocampal Cultures. Primary cultures of dissociated hippocam- mixed genotype cultures is attenuated by blockers of synaptic pal neurons were prepared from late embryonic (E18–19) or transmission. Our findings indicate that synaptophysin plays a newborn (P1) wild-type and syp-mutant mice as described (10). previously unsuspected role in regulating activity-dependent syn- Briefly, dissected hippocampi were incubated for 30 min in 20 apse formation.
    [Show full text]
  • NEURAL CONNECTIONS: Some You Use, Some You Lose
    NEURAL CONNECTIONS: Some You Use, Some You Lose by JOHN T. BRUER SOURCE: Phi Delta Kappan 81 no4 264-77 D 1999 . The magazine publisher is the copyright holder of this article and it is reproduced with permission. Further reproduction of this article in violation of the copyright is prohibited JOHN T. BRUER is president of the James S. McDonnell Foundation, St. Louis. This article is adapted from his new book, The Myth of the First Three Years (Free Press, 1999), and is reprinted by arrangement with The Free Press, a division of Simon Schuster Inc. ©1999, John T. Bruer . OVER 20 YEARS AGO, neuroscientists discovered that humans and other animals experience a rapid increase in brain connectivity -- an exuberant burst of synapse formation -- early in development. They have studied this process most carefully in the brain's outer layer, or cortex, which is essentially our gray matter. In these studies, neuroscientists have documented that over our life spans the number of synapses per unit area or unit volume of cortical tissue changes, as does the number of synapses per neuron. Neuroscientists refer to the number of synapses per unit of cortical tissue as the brain's synaptic density. Over our lifetimes, our brain's synaptic density changes in an interesting, patterned way. This pattern of synaptic change and what it might mean is the first neurobiological strand of the Myth of the First Three Years. (The second strand of the Myth deals with the notion of critical periods, and the third takes up the matter of enriched, or complex, environments.) Popular discussions of the new brain science trade heavily on what happens to synapses during infancy and childhood.
    [Show full text]
  • RIM-BP2 Primes Synaptic Vesicles Via Recruitment of Munc13-1 At
    RESEARCH ARTICLE RIM-BP2 primes synaptic vesicles via recruitment of Munc13-1 at hippocampal mossy fiber synapses Marisa M Brockmann1†, Marta Maglione2,3,4†, Claudia G Willmes5†, Alexander Stumpf6, Boris A Bouazza1, Laura M Velasquez6, M Katharina Grauel1, Prateep Beed6, Martin Lehmann3, Niclas Gimber6, Jan Schmoranzer4, Stephan J Sigrist2,4,5*, Christian Rosenmund1,4*, Dietmar Schmitz4,5,6* 1Institut fu¨ r Neurophysiologie, Charite´ – Universita¨ tsmedizin Berlin, corporate member of Freie Universita¨ t Berlin, Humboldt-Universita¨ t zu Berlin, and Berlin Institute of Health, Berlin, Germany; 2Freie Universita¨ t Berlin, Institut fu¨ r Biologie, Berlin, Germany; 3Leibniz-Forschungsinstitut fu¨ r Molekulare Pharmakologie (FMP), Berlin, Germany; 4NeuroCure Cluster of Excellence, Berlin, Germany; 5DZNE, German Center for Neurodegenerative Diseases, Berlin, Germany; 6Neuroscience Research Center, Charite´ – Universita¨ tsmedizin Berlin, corporate member of Freie Universita¨ t Berlin, Humboldt-Universita¨ t zu Berlin, and Berlin Institute of Health, Berlin, Germany Abstract All synapses require fusion-competent vesicles and coordinated Ca2+-secretion coupling for neurotransmission, yet functional and anatomical properties are diverse across *For correspondence: different synapse types. We show that the presynaptic protein RIM-BP2 has diversified functions in [email protected] (SJS); neurotransmitter release at different central murine synapses and thus contributes to synaptic [email protected] diversity. At hippocampal pyramidal CA3-CA1 synapses, RIM-BP2 loss has a mild effect on (CR); neurotransmitter release, by only regulating Ca2+-secretion coupling. However, at hippocampal [email protected] (DS) mossy fiber synapses, RIM-BP2 has a substantial impact on neurotransmitter release by promoting †These authors contributed vesicle docking/priming and vesicular release probability via stabilization of Munc13-1 at the active equally to this work zone.
    [Show full text]
  • Functional Consequences of Synapse Remodeling Following Astrocyte-Specific Regulation of Ephrin-B1 in the Adult Hippocampus
    5710 • The Journal of Neuroscience, June 20, 2018 • 38(25):5710–5726 Cellular/Molecular Functional Consequences of Synapse Remodeling Following Astrocyte-Specific Regulation of Ephrin-B1 in the Adult Hippocampus Jordan Koeppen,1,2* XAmanda Q. Nguyen,1,3* Angeliki M. Nikolakopoulou,1 XMichael Garcia,1 XSandy Hanna,1 Simone Woodruff,1 Zoe Figueroa,1 XAndre Obenaus,4 and XIryna M. Ethell1,2,3 1Division of Biomedical Sciences, University of California Riverside School of Medicine, Riverside, California 92521, 2Cell, Molecular, and Developmental Biology Graduate program, University of California Riverside, California, 92521, 3Neuroscience Graduate Program, University of California Riverside, Riverside, California 92521, and 4Department of Pediatrics, University of California Irvine, Irvine, California 92350 Astrocyte-derived factors can control synapse formation and functions, making astrocytes an attractive target for regulating neuronal circuits and associated behaviors. Abnormal astrocyte-neuronal interactions are also implicated in neurodevelopmental disorders and neurodegenera- tive diseases associated with impaired learning and memory. However, little is known about astrocyte-mediated mechanisms that regulate learning and memory. Here, we propose astrocytic ephrin-B1 as a regulator of synaptogenesis in adult hippocampus and mouse learning behaviors. We found that astrocyte-specific ablation of ephrin-B1 in male mice triggers an increase in the density of immature dendritic spines and excitatory synaptic sites in the adult CA1 hippocampus. However, the prevalence of immature dendritic spines is associated with decreased evoked postsynaptic firing responses in CA1 pyramidal neurons, suggesting impaired maturation of these newly formed and potentially silent synapses or increased excitatory drive on the inhibitory neurons resulting in the overall decreased postsynaptic firing.
    [Show full text]
  • Microglia-Mediated Synapse Loss in Alzheimer's Disease
    The Journal of Neuroscience, March 21, 2018 • 38(12):2911–2919 • 2911 Dual Perspectives Dual Perspectives Companion Paper: Alzheimer’s Disease and Sleep-Wake Disturbances: Amyloid, Astrocytes, and Animal Models by William M. Vanderheyden, Miranda M. Lim, Erik S. Musiek, and Jason R. Gerstner Microglia-Mediated Synapse Loss in Alzheimer’s Disease Lawrence Rajendran and Rosa C. Paolicelli Systems and Cell Biology of Neurodegeneration, IREM, University of Zurich, Schlieren 8952, Switzerland Microglia are emerging as key players in neurodegenerative diseases, such as Alzheimer’s disease (AD). Thus far, microglia have rather been known as modulator of neurodegeneration with functions limited to neuroinflammation and release of neurotoxic molecules. However, several recent studies have demonstrated a direct role of microglia in “neuro” degeneration observed in AD by promoting phagocytosisofneuronal,inparticular,synapticstructures.Whilesomeofthestudiesaddresstheinvolvementofthe ␤-amyloidpeptides in the process, studies also indicate that this could occur independent of amyloid, further elevating the importance of microglia in AD. Here we review these recent studies and also speculate about the possible cellular mechanisms, and how they could be regulated by risk genes and sleep. Finally, we deliberate on possible avenues for targeting microglia-mediated synapse loss for therapy and prevention. Key words: microglia; synaptic pruning; amyloid; Alzheimer’s disease; clearance; phagocytosis Introduction tional genetic risk factor associated with sporadic AD (Roses, Alzheimer’s disease (AD) is the most common neurodegenera- 1996). In the case of late-onset AD, genome-wide association tive disorder; and because of its high costs toward patient care studies have identified several genetic polymorphisms in various and management, it is among the top devastating diseases gene loci that are associated with increased AD risk (Guerreiro (Scheltens et al., 2016).
    [Show full text]
  • Neuron-Satellite Glial Cell Interactions in Sympathetic Nervous System Development
    NEURON-SATELLITE GLIAL CELL INTERACTIONS IN SYMPATHETIC NERVOUS SYSTEM DEVELOPMENT by Erica D. Boehm A dissertation submitted to the Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland July 2020 © 2020 Erica Boehm All rights reserved. ABSTRACT Glial cells play crucial roles in maintaining the stability and structure of the nervous system. Satellite glial cells are a loosely defined population of glial cells that ensheathe neuronal cell bodies, dendrites, and synapses of the peripheral nervous system (Elfvin and Forsman 1978; Pannese 1981). Satellite glial cells are closely juxtaposed to peripheral neurons with only 20nm of space between their membranes (Dixon 1969). This close association suggests a tight coupling between the cells to allow for possible exchange of important nutrients, yet very little is known about satellite glial cell function and development. How neurons and glial cells co-develop to create this tightly knit unit remains undefined, as well as the functional consequences of disrupting these contacts. Satellite glial cells are derived from the same population of cells that give rise to peripheral neurons, but do not begin differentiation and proliferation until neurogenesis has been completed (Hall and Landis 1992). A key signaling pathway involved in glial specification is the Delta/Notch signaling pathway (Tsarovina et al. 2008). However, recent studies also implicate Notch signaling in the maturation of glia through non- canonical Notch ligands such as Delta/Notch-like EGF-related Receptor (DNER) (Eiraku et al. 2005). Interestingly, it has been reported that levels of DNER in sympathetic neurons may be dependent on the target-derived growth factor, nerve growth factor (NGF), and this signal is prominent in sympathetic neurons at the time in which satellite glial cells are developing (Deppmann et al.
    [Show full text]