NGF-Dependent Retrograde Signaling: Survival Versus Death

Total Page:16

File Type:pdf, Size:1020Kb

NGF-Dependent Retrograde Signaling: Survival Versus Death Cell Research (2009) 19:525-526. npg © 2009 IBCB, SIBS, CAS All rights reserved 1001-0602/09 $ 30.00 RESEARCH HIGHLIGHT www.nature.com/cr NGF-dependent retrograde signaling: survival versus death Yang Zhou1, Ting-Jia Lu1, Zhi-Qi Xiong1 1Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road Shanghai 200031, China Cell Research (2009) 19:525-526. doi: 10.1038/cr.2009.47; published online 4 May 2009 Nerve growth factor (NGF) was which could also provide as the ret- nisms underlying NGF-dependent first discovered more than 5 decades rograde signals [7]. These hypotheses retrograde signaling. Previous studies ago as a molecule that promotes the are not mutually exclusive, and mul- from Campenot’s laboratory demon- survival and maturation of develop- tiple retrograde signals may exist. strated that NGF applied to distal ax- ing neurons in the peripheral nervous In this issue, Mok and colleagues ons of sympathetic neurons supports system [1]. NGF released from target describe a fundamentally different neuronal survival without transport of cells activates tropomyosin-related retrograde mechanism in which NGF NGF towards the cell bodies or TrkA kinase A (TrkA) on axon terminals and suppresses an apoptotic signal in distal phosphorylation in the cell bodies, triggers activation of PI3K/Akt, MEK/ axons [8]. Campenot’s group devel- suggesting that NGF binding to TrkA ERK, and PLCg signaling pathways. oped compartmentalized cultures of in distal axons triggers its downstream The signal then travels retrogradely sympathetic neurons which could seg- signaling cascades locally; afterwards along axon to cell body to promote regate the distal axons from cell bod- the signals travel retrogradely to the neuronal survival [2]. However, the ies and proximal axons by a distance cell bodies and communicate with nature of the retrograde signal remains of about 1 mm. By employing this soma [9]. In the current study, the au- mysterious. system with advantages of segregating thors found that neutralizing NGF in Several distinct types of retrograde cellular compartments, researchers distal segment of axons but not in the signals could derive from axon ter- could dissect the molecular mecha- cell bodies led to activation of c-jun minals [3]. First, NGF itself could undergo retrograde transport from terminals to cell body thus activates NGF intracellular TrkA receptor. Indeed, A 125 I-labeled NGF applied to axon p-GSK3 p-CREB pro-survival axon terminals in vivo was found to be ret- p-Akt rogradely transported to the neuronal cell bodies [4]. Second, NGF triggers TrkA endocytosis through binding to B TrkA, and the endocytic TrkA might GSK3 serve as the retrograde signal [5]. In p-c-jun pro-apoptotic axon supporting of this notion, both NGF caspase-3 and phosphorylated TrkA are found in endosomes [6]. Finally, NGF activates Figure 1 Schematic model of NGF-dependent sympathetic neuron survival or TrkA downstream signal molecules, apoptosis. (A) In the presence of NGF in axon terminals, retrogradely transmit- ted pro-survival signal facilitates neuronal survival via p-GSK3, p-Akt and p- CREB signaling pathways. (B) In the absence of NGF in axon terminals, retro- grade pro-apoptotic signal leads to cleavage of caspase-3, dephosphorylation Correspondence: Zhi-Qi Xiong of GSK3, as well as phosphorylation of c-jun, thus promoting the apoptosis of E-mail: [email protected] sympathetic neuron. npg 526 and cleavage of caspase-3 in the cell Growing evidence suggests that notion be applied to situations such as bodies as illustrated in the Figure 1 of NGF supports neuronal survival by in nerve injury? Finding answers to schematic model. Interestingly, when activating TrkA and its downstream these questions is of high importance, NGF was applied to cell bodies while signals at the axon terminals which both for basic neurobiology and neu- deprived from the distal axons at the retrogradely transmit to the cell bod- rodegenerative diseases. same time, nuclear accumulation of ies. The current study demonstrates phosphorylated c-jun was still ob- that NGF deprivation at the distal References served, similar to cultures completely axons induces a transportable retro- deprived of NGF. These findings are grade pro-apoptotic signal traveling 1 Levi-Montalcini R, Angeletti PU. consistent with the notion that loss towards the cell bodies to initiate Nerve growth factor. Physiol Rev 1968; of NGF in the distal axons gener- apoptosis. Whether the inhibition of 48:534-569. 2 Zweifel LS, Kuruvilla R, Ginty DD. ates an apoptotic signal in the axon the retrograde apoptotic signal initi- Functions and mechanisms of retrograde terminals which travels to the cell ated at the axon terminals accounts for neurotrophin signalling. Nat Rev Neuro- bodies and activates c-jun. However, NGF-dependent neuronal survival or sci 2005; 6:615-625. local delivery of NGF at cell bodies this novel mechanism operates along 3 Howe CL, Mobley WC. Long-distance protected against cell death despite with other distinct pathways within retrograde neurotrophic signaling. Curr the activation of c-jun, suggesting that the same neurons remains unknown. It Opin Neurobiol 2005; 15:40-48. survival signals activated by NGF in is possible that sustained pro-survival 4 Campenot RB, MacInnis BL. Retro- the cell bodies do not simply override signal is activated in the presence of grade transport of neurotrophins: fact and function. J Neurobiol 2004; 58:217- the retrograde apoptotic signal but NGF in axon terminals to antagonize 229. promote neuronal survival probably endogenous pro-apoptotic signal. 5 Ginty DD, Segal RA. Retrograde by acting downstream of c-jun. The Taken together, this study provides neurotrophin signaling: Trk-ing along axon-specific pro-apoptotic signal evidence in cultured sympathetic neu- the axon. Curr Opin Neurobiol 2002; was blocked by treating cultures with rons that deprivation of NGF at axon 12:268-274. the protein kinase C (PKC) inhibitor terminal triggers the pro-apoptotic 6 Ye H, Kuruvilla R, Zweifel LS, et rottlerin, but not by down-regulating signal which in turn transmits to cell al. Evidence in support of signaling d endosome-based retrograde survival the proposed isoform of PKC. This body. Results of this study also shed of sympathetic neurons. Neuron 2003; inconsistency between pharmacologi- lights on neurodegenerative diseases 39:57-68. cal approach and molecular manipula- [10]. However, several important is- 7 Miller FD, Kaplan DR. On Trk for tion may be due to the inefficiency of sues remain to be solved: how does retrograde signaling. Neuron 2001; siRNA knockdown or non-specific the retrograde signal transport from 32:767-770. effects of pharmacological inhibitor. axon terminal to cell body? Is it in a 8 Mok SA, Lund K, Campenot RB. A Further efforts to understand how cargo-like transport manner or a flow retrograde apoptotic signal originating in NGF-deprived distal axons of rat rottlerin exerts its protective effect of continuously signaling activation sympathetic neurons in compartmented showed that NGF deprivation in along the axon segment from distal cultures. Cell Research 2009; 19:xx- axon terminals activated GSK3 in a part to soma? What is the minimal xx. rottlerin-sensitive manner in the distal amount of NGF required to antago- 9 MacInnis BL, Campenot RB. Retrograde axons. Furthermore, inhibiting GSK3 nize the apoptotic signal? What is the support of neuronal survival without ret- activity in distal axons or cell bodies/ molecular mechanism underlying the rograde transport of nerve growth factor. proximal axons was able to prevent cross-talk between pro-survival and Science 2002; 295:1536-1539. NGF deprivation-induced apoptosis. pro-apoptotic signals? Does neurotro- 10 Sofroniew MV, Howe CL, Mobley WC. Nerve growth factor signaling, neuro- However, how PKC and GSK3 were phin deprivation induce retrograde protection, and neural repair. Annu Rev activated at axon terminals were not pro-apoptotic signaling in sympa- Neurosci 2001; 24:1217-1281. clear. thetic neurons in vivo? Can the same Cell Research | Vol 19 No 5 | May 2009 .
Recommended publications
  • Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System
    International Journal of Molecular Sciences Review Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System Shenglong Zou and Ujendra Kumar * Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC V6T 1Z4, Canada; [email protected] * Correspondence: [email protected]; Tel.: +1-604-827-3660; Fax: +1-604-822-3035 Received: 9 February 2018; Accepted: 11 March 2018; Published: 13 March 2018 Abstract: The biological effects of cannabinoids, the major constituents of the ancient medicinal plant Cannabis sativa (marijuana) are mediated by two members of the G-protein coupled receptor family, cannabinoid receptors 1 (CB1R) and 2. The CB1R is the prominent subtype in the central nervous system (CNS) and has drawn great attention as a potential therapeutic avenue in several pathological conditions, including neuropsychological disorders and neurodegenerative diseases. Furthermore, cannabinoids also modulate signal transduction pathways and exert profound effects at peripheral sites. Although cannabinoids have therapeutic potential, their psychoactive effects have largely limited their use in clinical practice. In this review, we briefly summarized our knowledge of cannabinoids and the endocannabinoid system, focusing on the CB1R and the CNS, with emphasis on recent breakthroughs in the field. We aim to define several potential roles of cannabinoid receptors in the modulation of signaling pathways and in association with several pathophysiological conditions. We believe that the therapeutic significance of cannabinoids is masked by the adverse effects and here alternative strategies are discussed to take therapeutic advantage of cannabinoids. Keywords: cannabinoid; endocannabinoid; receptor; signaling; central nervous system 1. Introduction The plant Cannabis sativa, better known as marijuana, has long been used for medical purpose throughout human history.
    [Show full text]
  • Endocannabinoid Biosynthesis and Inactivation, from Simple to Complex
    REVIEWS Drug Discovery Today Volume 15, Numbers 11/12 June 2010 Reviews POST SCREEN Endocannabinoid biosynthesis and inactivation, from simple to complex Giulio G. Muccioli Bioanalysis and Pharmacology of Bioactive Lipids Laboratory, CHAM7230, Louvain Drug Research Institute, Universite´ catholique de Louvain, Av. E. Mounier 72, B- 1200 Bruxelles, Belgium Cannabinoid receptors, the primary molecular targets of the endocannabinoid system, are activated by specific bioactive lipids termed ‘endocannabinoids’. These lipid transmitters are synthesized from cell membrane phospholipids through multiple pathways and are inactivated by enzymatic hydrolysis, and their levels are the major parameter driving the endocannabinoid system activity. An in-depth understanding of their metabolic pathways is essential to unravel the endocannabinoid system’s role in physiological and pathological situations and to devise new therapeutic strategies based on the endocannabinoid system. Major advances both in the characterization of anandamide’s and 2- arachidonoylglycerol’s biosynthesis and inactivation pathways and in the discovery of pharmacological tools used to interfere with their metabolism have been made and are discussed in this review. Endocannabinoids are endogenous lipid transmitters that act by persistent activation or blockade and by the lack of tissue speci- binding and activating specific G-protein-coupled-receptors ficity of the ligands developed so far. A novel, more subtle, termed ‘CB1 and CB2 cannabinoid receptors’. To date, N-arachi- approach is the use of allosteric modulators, thus potentially donoylethanolamine (anandamide) and 2-arachidonoylglycerol avoiding some of the aforementioned drawbacks. However, the are the most thoroughly studied endocannabinoids. Anandamide most promising alternative strategy, now supported by a growing is a member of the N-acylethanolamine (NAE) family, a large group number of studies, is to modulate endogenous ligand levels.
    [Show full text]
  • Metabotropic Glutamate Receptors: Intracellular Signaling Pathways Urs Gerber1, Christine E Gee1,2 and Pascal Benquet3
    Metabotropic glutamate receptors: intracellular signaling pathways Urs Gerber1, Christine E Gee1,2 and Pascal Benquet3 Metabotropic glutamate receptors are classified into three mGluRs, will not be discussed explicitly here as this groups, primarily on the basis of sequence similarity and topic is the subject of several comprehensive recent whether they positively couple to the phospholipase C cascade reviews (e.g. see [5]). or negatively couple to adenylyl cyclases. The past decade of research, drawing on sophisticated molecular approaches, has Transduction within the mGluR revealed a multitude of additional intracellular components that Upon binding of glutamate, a conformational change in assemble as protein scaffolds around neuronal metabotropic homodimeric mGluRs promotes the coupling of G pro- glutamate receptors, establishing functional links to teins to specific intracellular domains. Structural studies, postsynaptic density structures, to membrane-bound enzymes beginning with the crystallization and characterization of and ion channels, and to the nucleus. Characterization of these the agonist-bound and ‘unliganded’ forms of the gluta- novel transduction mechanisms is providing new insights into mate binding site of mGluR1, provided initial insights the roles of metabotropic glutamate receptors in the regulation into the underlying process [6]. Agonist binding stabilizes and modulation of diverse functions in the nervous system. the closed conformation of the extracellular domain and Addresses results in G protein activation that is dependent upon a 1 Brain Research Institute, University of Zurich, CH-8057 Zurich, disulfide bridge between conserved cysteine residues in Switzerland the extracellular agonist binding loop and the third trans- 2 Novartis Institutes for Biomedical Research, Novartis Pharma AG, membrane domain [6,7].
    [Show full text]
  • Neurotransmission: Emerging Roles of Endocannabinoids
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Dispatch R549 and Keller, L. (2005). Clonal reproduction (2001). Genetic variation in a host- sexes reveals ontogenetic conflict in by males and females in the little fire ant. parasite association: potential for Drosophila. Evolution Int. J. Org. Nature 435, 1230-1234. coevolution and frequency-dependent Evolution 98, 1671–1675. 5. Hamilton, W.D., Axelrod, R., and Tanese, selection. Evolution Int. J. Org. Evolution R. (1990). Sexual reproduction as an 55, 1136–1145. adaptation to resist parasites (A Review). 8. Liersch, S., and Schmid-Hempel, P. Institute of Evolutionary Biology, Proc. Natl. Acad. Sci. USA 87, (1998). Genetic variation within social University of Edinburgh, West Mains 3566–3573. insect colonies reduces parasite load. Road, Edinburgh EH9 3JT, UK. 6. Kondrashov, A.S. (1982). Selection Proc. R. Soc. Lond. B. Biol. Sci. 265, against harmful mutations in large sexual 221–225. E-mail: [email protected] and asexual populations. Genet. Res. 40, 9. Chippendale, A.K., Gibson, J.R., and 325–332. Rice, W.R. (2001). Negative genetic 7. Carius, H.J., Little, T.J., and Ebert, D. correlation for adult fitness between DOI: 10.1016/j.cub.2005.07.001 Neurotransmission: Emerging requires a sustained (5–10 minute) activation of presynaptic CB1 Roles of Endocannabinoids receptors [12,13]. Modulation of synaptic transmission by endocannabinoids Postsynaptic release of endocannabinoids can inhibit presynaptic was initially studied using non- neurotransmitter release on short and long timescales. This retrograde physiological methods, such as inhibition occurs at both excitatory and inhibitory synapses and may seconds-long depolarization or provide a mechanism for synaptic gain control, short-term associative application of high-affinity plasticity, reduction of synaptic crosstalk, and metaplasticity.
    [Show full text]
  • Depletion of Calcium in the Synaptic Cleft of a Calyx-Type Synapse in the Rat Brainstem
    9501 Journal of Physiology (1999), 521.1, pp.123—133 123 Depletion of calcium in the synaptic cleft of a calyx-type synapse in the rat brainstem J. G. G. Borst and B. Sakmann Max-Planck-Institut fur medizinische Forschung, Abteilung Zellphysiologie, Jahnstrasse 29, D_69120 Heidelberg, Germany Appendix by Eberhard von Kitzing (Received 12 April 1999; accepted after revision 23 August 1999) 1. A new form of synaptic depression of excitatory synaptic transmission was observed when making voltage-clamp recordings from large presynaptic terminals, the calyces of Held and postsynaptic cells, the principal cells of the medial nucleus of the trapezoid body (MNTB), in slices of the rat auditory brainstem. 2. A short (100 ms) depolarization of the postsynaptic cell to 0 mV reduced the amplitude of the EPSCs by 35 ± 5 % (n = 7), measured at 10 ms following the depolarization. Recovery occurred within 0·5 s. 3. The reduction of the EPSCs was most probably due to reduced presynaptic calcium influx, since postsynaptic depolarization reduced presynaptic calcium or barium currents. Conversely, presynaptic depolarization also reduced postsynaptic calcium or barium influx, under conditions where transmitter release was minimal. 4. The calcium currents and the postsynaptic depolarization-induced suppression of synaptic transmission recovered with a similar time course, suggesting that this form of synaptic depression was, most probably, due to depletion of Ca¥ in the synaptic cleft. 5. We conclude that when the Ca¥ influx into the pre- or postsynaptic cell is large, extra- cellular Ca¥ is depleted. Under these conditions, the Ca¥ concentration in the synaptic cleft is a sensitive indicator of the level of synaptic activity.
    [Show full text]
  • Alumni Director Cover Page.Pub
    Harvard University Program in Neuroscience History of Enrollment in The Program in Neuroscience July 2018 Updated each July Nicholas Spitzer, M.D./Ph.D. B.A., Harvard College Entered 1966 * Defended May 14, 1969 Advisor: David Poer A Physiological and Histological Invesgaon of the Intercellular Transfer of Small Molecules _____________ Professor of Neurobiology University of California at San Diego Eric Frank, Ph.D. B.A., Reed College Entered 1967 * Defended January 17, 1972 Advisor: Edwin J. Furshpan The Control of Facilitaon at the Neuromuscular Juncon of the Lobster _______________ Professor Emeritus of Physiology Tus University School of Medicine Albert Hudspeth, M.D./Ph.D. B.A., Harvard College Entered 1967 * Defended April 30, 1973 Advisor: David Poer Intercellular Juncons in Epithelia _______________ Professor of Neuroscience The Rockefeller University David Van Essen, Ph.D. B.S., California Instute of Technology Entered 1967 * Defended October 22, 1971 Advisor: John Nicholls Effects of an Electronic Pump on Signaling by Leech Sensory Neurons ______________ Professor of Anatomy and Neurobiology Washington University David Van Essen, Eric Frank, and Albert Hudspeth At the 50th Anniversary celebraon for the creaon of the Harvard Department of Neurobiology October 7, 2016 Richard Mains, Ph.D. Sc.B., M.S., Brown University Entered 1968 * Defended April 24, 1973 Advisor: David Poer Tissue Culture of Dissociated Primary Rat Sympathec Neurons: Studies of Growth, Neurotransmier Metabolism, and Maturaon _______________ Professor of Neuroscience University of Conneccut Health Center Peter MacLeish, Ph.D. B.E.Sc., University of Western Ontario Entered 1969 * Defended December 29, 1976 Advisor: David Poer Synapse Formaon in Cultures of Dissociated Rat Sympathec Neurons Grown on Dissociated Rat Heart Cells _______________ Professor and Director of the Neuroscience Instute Morehouse School of Medicine Peter Sargent, Ph.D.
    [Show full text]
  • A Dissertation Entitled Pituitary Adenylate Cyclase Activating
    A Dissertation entitled Pituitary Adenylate Cyclase Activating Polypeptide and Synaptic Plasticity at Autonomic Cholinergic Synapses By Eric R. Starr Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Doctor of Philosophy Degree in Biomedical Sciences __________________________________________ Joseph F. Margiotta, PhD, Committee Chair __________________________________________ David R. Giovanucci, PhD, Committee Member __________________________________________ Scott Molitor, PhD, Committee Member __________________________________________ Joshua Park, PhD, Committee Member __________________________________________ Ruili Xie, PhD, Committee Member __________________________________________ Amanda Byrant-Friedrich, Dr. rer. Nat., Dean College of Graduate Studies The University of Toledo August 2017 i Copyright 2017, Eric R. Starr This document is copyright material. Under copyright law, no parts of this document may be reproduced without the expressed permission of the author. ii An Abstract of Pituitary Adenylate Cyclase Activating Polypeptide and Synaptic Plasticity at Autonomic Cholinergic Synapses By Eric R. Starr Submitted to the Graduate Faculty as partial fulfillment of the requirements of the Doctor of Philosophy Degree in Biomedical Sciences The University of Toledo July 2017 Pituitary adenylate cyclase activating polypeptide (PACAP) is a secretin family neuropeptide, localized to presynaptic terminals throughout the nervous system. In autonomic ciliary ganglion (CG) neurons, PACAP exposure engages
    [Show full text]
  • Role of Endogenous Cannabinoids in Synaptic Signaling
    Physiol Rev 83: 1017–1066, 2003; 10.1152/physrev.00004.2003. Role of Endogenous Cannabinoids in Synaptic Signaling TAMAS´ F. FREUND, ISTVAN´ KATONA, AND DANIELE PIOMELLI Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary; Department of Clinical Neurobiology, University Hospital of Neurology, Heidelberg, Germany; and Department of Pharmacology, University of California Irvine, Irvine, California I. Introduction 1018 II. The Life Cycle of Endocannabinoids 1020 A. Introduction 1020 B. Biosynthetic pathways 1020 C. Termination of endocannabinoid effects: transport and degradation 1023 III. Regional and Cellular Distribution of Neuronal CB1 Cannabinoid Receptors 1028 A. Characteristic differences in CB1 receptor distribution in the brain 1028 B. Selective expression of CB1 cannabinoid receptors by identified cell types of complex networks 1030 IV. Anatomical, Physiological, and Pharmacological Evidence for the Presynaptic Localization of CB1 Cannabinoid Receptors in the Brain 1035 A. Anatomical evidence for presynaptic cannabinoid receptors 1036 B. Physiological and pharmacological evidence for presynaptic cannabinoid receptors 1039 C. Are there postsynaptic CB1 receptors? 1044 V. Physiological Roles of Endocannabinoids 1045 A. The cannabinoid root 1045 B. The DSI (DSE) root: control of GABAergic and glutamatergic synaptic transmission via retrograde synaptic signaling 1048 C. Marriage of the two lines of research explains the mechanism of DSI (and DSE) while endowing endocannabinoids with function 1049 D. Electrical activity patterns required for the release of endocannabinoids 1054 VI. Conclusions 1056 Freund, Tama´s F., Istva´n Katona, and Daniele Piomelli. Role of Endogenous Cannabinoids in Synaptic Signaling. Physiol Rev 83: 1017–1066, 2003; 10.1152/physrev.00004.2003.—Research of cannabinoid actions was boosted in the 1990s by remarkable discoveries including identification of endogenous compounds with cannabimi- metic activity (endocannabinoids) and the cloning of their molecular targets, the CB1 and CB2 receptors.
    [Show full text]
  • Drug-Induced Alterations of Endocannabinoid-Mediated Plasticity in Brain Reward Regions
    10230 • The Journal of Neuroscience, October 5, 2016 • 36(40):10230–10238 Viewpoints Drug-Induced Alterations of Endocannabinoid-Mediated Plasticity in Brain Reward Regions X Natalie E. Zlebnik1 and XJoseph F. Cheer1,2 Departments of 1Anatomy and Neurobiology and 2Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland 21201 The endocannabinoid (eCB) system has emerged as one of the most important mediators of physiological and pathological reward- related synaptic plasticity. eCBs are retrograde messengers that provide feedback inhibition, resulting in the suppression of neurotrans- mitter release at both excitatory and inhibitory synapses, and they serve a critical role in the spatiotemporal regulation of both short- and long-term synaptic plasticity that supports adaptive learning of reward-motivated behaviors. However, mechanisms of eCB-mediated synaptic plasticity in reward areas of the brain are impaired following exposure to drugs of abuse. Because of this, it is theorized that maladaptive eCB signaling may contribute to the development and maintenance of addiction-related behavior. Here we review various forms of eCB-mediated synaptic plasticity present in regions of the brain involved in reward and reinforcement and explore the potential physiological relevance of maladaptive eCB signaling to addiction vulnerability. Key words: addiction; cocaine; drugs of abuse; endocannabinoid; nucleus accumbens; plasticity; reward; THC; ventral tegmental nucleus Introduction Overview of the eCB system Emerging work has identified endocannabinoid (eCB) signaling The eCB system encompasses several G-protein-coupled recep- as an important mediator of synaptic plasticity in mesocortico- tors (GPCRs) and lipid signaling molecules as well as their limbic and corticostriatal pathways involved in the control of biosynthetic and metabolic machinery.
    [Show full text]
  • Communication Networks in the Brain
    Communication Networks in the Brain Neurons, Receptors, Neurotransmitters, and Alcohol David M. Lovinger, Ph.D. Nerve cells (i.e., neurons) communicate via a combination of electrical and chemical signals. Within the neuron, electrical signals driven by charged particles allow rapid conduction from one end of the cell to the other. Communication between neurons occurs at tiny gaps called synapses, where specialized parts of the two cells (i.e., the presynaptic and postsynaptic neurons) come within nanometers of one another to allow for chemical transmission. The presynaptic neuron releases a chemical (i.e., a neurotransmitter) that is received by the postsynaptic neuron’s specialized proteins called neurotransmitter receptors. The neurotransmitter molecules bind to the receptor proteins and alter postsynaptic neuronal function. Two types of neurotransmitter receptors exist—ligand-gated ion channels, which permit rapid ion flow directly across the outer cell membrane, and G-protein–coupled receptors, which set into motion chemical signaling events within the cell. Hundreds of molecules are known to act as neurotransmitters in the brain. Neuronal development and function also are affected by peptides known as neurotrophins and by steroid hormones. This article reviews the chemical nature, neuronal actions, receptor subtypes, and therapeutic roles of several transmitters, neurotrophins, and hormones. It focuses on neurotransmitters with important roles in acute and chronic alcohol effects on the brain, such as those that contribute to intoxication,
    [Show full text]
  • Retrograde Signaling at Central Synapses
    Colloquium Retrograde signaling at central synapses Huizhong W. Tao and Mu-ming Poo* Department of Molecular and Cellular Biology, University of California, Berkeley, CA 97420 Transcellular retrograde signaling from the postsynaptic target cell mation processing and storage in the brain, the central synapse to the presynaptic neuron plays critical roles in the formation, must be formed and regulated under appropriate control. Syn- maturation, and plasticity of synaptic connections. We here review apses are formed only between specific pre- and postsynaptic recent progress in our understanding of the retrograde signaling at partners and stabilized at specific locations on the dendrite. developing central synapses. Three forms of potential retrograde Synapse formation is accompanied by a coordinated develop- signals—membrane-permeant factors, membrane-bound factors, ment of pre- and postsynaptic molecular and structural special- and secreted factors—have been implicated at both developing izations, which requires exchanges of information between pre- and mature synapses. Although many of these signals may be and postsynaptic cells at all stages of synapse development, via active constitutively, retrograde factors produced in association anterograde as well as retrograde signaling. with activity-dependent synaptic plasticity, e.g., long-term poten- tiation and long-term depression, are of particular interest, be- (i) Signaling Before Synaptic Contact. After long-range axon path- cause they may induce modification of neuronal excitability and finding, growth cones approach their target cell, and the process synaptic transmission, functions directly related to the processing of synapse formation begins. It is likely that navigation of the and storage of information in the nervous system. growth cone is stalled and axon differentiation begins in re- sponse to factors secreted from the target cell.
    [Show full text]
  • Editorial: Homeostatic and Retrograde Signaling Mechanisms Modulating Presynaptic Function and Plasticity
    Editorial: Homeostatic and retrograde signaling mechanisms modulating presynaptic function and plasticity The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Subramanian, Jaichandar, and Dion Dickman. “Editorial: Homeostatic and Retrograde Signaling Mechanisms Modulating Presynaptic Function and Plasticity.” Front. Cell. Neurosci. 9 (September 30, 2015). As Published http://dx.doi.org/10.3389/fncel.2015.00380 Publisher Frontiers Research Foundation Version Final published version Citable link http://hdl.handle.net/1721.1/99678 Terms of Use Creative Commons Attribution Detailed Terms http://creativecommons.org/licenses/by/4.0/ EDITORIAL published: 30 September 2015 doi: 10.3389/fncel.2015.00380 Editorial: Homeostatic and retrograde signaling mechanisms modulating presynaptic function and plasticity Jaichandar Subramanian 1* and Dion Dickman 2 1 Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA, 2 Department of Neurobiology, University of Southern California, Los Angeles, CA, USA Keywords: homeostatic plasticity, presynaptic adaptation, retrograde signaling, neurotransmitter release, neurological disease Dynamic reorganization of neural circuits can occur through the selective strengthening of synapses between neurons that are coactive in response to the encoded information (Shatz, 1990). However, the positive feedback resulting from synaptic strengthening and neuronal coactivity can lead to the destabilization of neuronal networks. Thus, synapses must maintain the capacity for change necessary for learning and memory, yet constrain this inherently destabilizing flexibility to enable stable neural function throughout life. Evidence has emerged in recent years that activity within neural circuits can shape the synaptic properties of component neurons in a manner that maintains stable excitatory drive, a process referred to as homeostatic synaptic plasticity (Turrigiano and Nelson, 2000; Pozo and Goda, 2010; Davis, 2013).
    [Show full text]