DOCSLIB.ORG

Protection of Cochlear Synapses from Noise-Induced Excitotoxic Trauma by Blockade of Ca2+-Permeable AMPA Receptors

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Protection of Cochlear Synapses from Noise-Induced Excitotoxic Trauma by Blockade of Ca2+-Permeable AMPA Receptors Protection of cochlear synapses from noise-induced excitotoxic trauma by blockade of Ca2+-permeable AMPA receptors Ning Hua, Mark A. Rutherfordb, and Steven H. Greena,1 aDepartment of Biology, University of Iowa, Iowa City, IA 52242; and bDepartment of Otolaryngology, Washington University in St. Louis, St. Louis, MO 63110 Edited by David P. Corey, Harvard Medical School, Boston, MA, and accepted by Editorial Board Member David E. Clapham January 7, 2020 (received for review August 16, 2019) Exposure to loud sound damages the postsynaptic terminals the ribbon synapses between IHCs and SGNs (3, 4). This noise- of spiral ganglion neurons (SGNs) on cochlear inner hair cells induced cochlear synaptopathy (NICS) is detectable by counting (IHCs), resulting in loss of synapses, a process termed synaptopathy. synapses histologically or, noninvasively, by a persistent reduction Glutamatergic neurotransmission via α-amino-3-hydroxy-5- of auditory brainstem response (ABR) wave-I amplitude even methylisoxazole-4-propionic acid (AMPA)-type receptors is required after complete recovery of ABR thresholds. for synaptopathy, and here we identify a possible involvement of Available evidence strongly supports the presumption that NICS + GluA2-lacking Ca2 -permeable AMPA receptors (CP-AMPARs) using is excitotoxic damage caused by excessive release of glutamate IEM-1460, which has been shown to block GluA2-lacking AMPARs. from overstimulated IHCs. Direct application of glutamatergic In CBA/CaJ mice, a 2-h exposure to 100-dB sound pressure level agonists causes vacuolization of postsynaptic bouton terminals, octave band (8 to 16 kHz) noise results in no permanent threshold similar to the morphological changes seen after sound over- shift but does cause significant synaptopathy and a reduction in exposure (5, 6). Deficiency of the glutamate aspartate transporter auditory brainstem response (ABR) wave-I amplitude. Chronic intra- increases synaptic glutamate and exacerbates noise damage (7). cochlear perfusion of IEM-1460 in artificial perilymph (AP) into adult Conversely, blockade of glutamate receptors reduces noise dam- CBA/CaJ mice prevented the decrease in ABR wave-I amplitude and age to synapses (6), and genetic removal of vesicular glutamate NEUROSCIENCE the synaptopathy relative to intracochlear perfusion of AP alone. release from IHCs prevents synapse loss after noise exposure (8). Interestingly, IEM-1460 itself did not affect the ABR threshold, pre- Although NICS requires activation of glutamate receptors, the sumably because GluA2-containing AMPARs can sustain sufficient specific receptor types, the downstream mechanism(s) of damage, synaptic transmission to evoke low-threshold responses during and the reasons for selective vulnerability of a subset of synapses blockade of GluA2-lacking AMPARs. On individual postsynaptic den- are unknown. sities, we observed GluA2-lacking nanodomains alongside regions SGNs express a variety of glutamate receptor types, in- with robust GluA2 expression, consistent with the idea that individ- cluding N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5- + ual synapses have both CP-AMPARs and Ca2 -impermeable AMPARs. methylisoxazole-4-propionic acid (AMPA), kainate, and metabo- SGNs innervating the same IHC differ in their relative vulnerability to tropic receptors (9, 10). The AMPA type is responsible for the noise. We found local heterogeneity among synapses in the relative abundance of GluA2 subunits that may underlie such differences in Significance vulnerability. We propose a role for GluA2-lacking CP-AMPARs in noise-induced cochlear synaptopathy whereby differences among Noise can cause excitotoxic trauma to cochlear synapses by synapses account for differences in excitotoxic susceptibility. These triggering excessive release of the neurotransmitter glutamate data suggest a means of maintaining normal hearing thresholds from the auditory sensory hair cells. We report that a specific while protecting against noise-induced synaptopathy, via selective + class of glutamate receptors, Ca2 -permeable α-amino-3-hydroxy- blockade of CP-AMPARs. 5-methylisoxazole-4-propionic acid (AMPA) receptors (CP-AMPARs), is largely responsible for this trauma. Because cochlear syn- excitotoxicity | cochlear synapse | spiral ganglion neuron | noise-induced + apses are heterogenous with respect to glutamate receptors, synaptopathy | Ca2 -permeable AMPA receptor the observation that a specific class is responsible might ex- plain the variability in susceptibility to noise among synap- piral ganglion neurons (SGNs) are bipolar neurons in the ses. Selective blockade of CP-AMPARs prevents excitotoxicity Scochlea that conduct auditory information from the sensory and noise-induced cochlear synaptopathy, while other glu- hair cells to the brain. Almost all (95%) SGNs are type I and tamate receptors continue to mediate neurotransmission and synapse on inner hair cells (IHCs); the remaining 5%, type II, allow hearing. synapse on outer hair cells. (Herein, “SGN” used without quali- fication refers to type I.) Each IHC in the rodent cochlea provides Author contributions: N.H., M.A.R., and S.H.G. designed research; N.H., M.A.R., and S.H.G. the sole afferent presynaptic input to ∼10 to 20 SGNs, depending performed research; N.H., M.A.R., and S.H.G. analyzed data; and N.H., M.A.R., and S.H.G. on species and tonotopic location. Each SGN has a myelinated wrote the paper. axon with an unbranched dendritic terminal making one synapse Competing interest statement: A provisional patent application titled “Targeting Calcium-Permeable AMPA Receptors for Inner Ear Therapy with IEM-1460 and Related with one IHC. Each of these synapses consists of a single post- Compounds” was filed on 23 December 2019. Some data presented in this paper was synaptic density (PSD) apposed to a presynaptic ribbon-type active cited in the application. zone in the IHC. Each PSD includes the scaffold protein PSD95 This article is a PNAS Direct Submission. D.P.C. is a guest editor invited by the and is estimated to contain a few thousand glutamate receptors Editorial Board. receiving excitation from the IHC ribbon synapse (1, 2). Published under the PNAS license. Exposure to sounds at high levels can destroy cochlear hair 1To whom correspondence may be addressed. Email: [email protected]. cells, resulting in permanent elevation of the hearing threshold. This article contains supporting information online at https://www.pnas.org/lookup/suppl/ Even at a sound pressure level (SPL) too low to permanently doi:10.1073/pnas.1914247117/-/DCSupplemental. impair hair cell function, exposure may impair hearing by destroying www.pnas.org/cgi/doi/10.1073/pnas.1914247117 PNAS Latest Articles | 1of11 Downloaded by guest on September 25, 2021 large fast excitatory currents necessary for synaptic transmission nerve fibers spiking at sound onset. The ABR waveform is a series at cochlear afferent synapses (11–14) and for excitotoxicity (15). of peaks with latencies corresponding to electrical activity at AMPA-type glutamate receptors are tetrameric combinations of successive levels of auditory processing in the brain. The am- GluA1, GluA2, GluA3, and GluA4 subunits, of which primarily plitude of the first peak (i.e., wave-I amplitude) is proportional the latter three are expressed in the PSDs of SGNs (9, 16). Any to the number of synchronously spiking SGNs. Synapses lost as a combination of AMPA receptor (AMPAR) subunits makes a re- consequence of NICS reduce the number of SGNs responding, + + + ceptor permeable to Na ,K ,andCa2 ions, but combinations that resulting in a reduced wave-I amplitude but, if hair cells are + include GluA2 have greatly reduced Ca2 permeability (17, 18). intact, no change in auditory threshold (27). Because GluA2 appears to be expressed at every synapse, it might The experiment was designed to allow us to establish for each + be assumed that all synapses lack Ca2 -permeable AMPAR re- mouse in each experimental group the effects of noise and the ceptors (CP-AMPARs), but this does not appear to be the case. effects of IEM-1460 while correcting for any possible effects In synapses on frog ear and fish lateral line hair cells, CP- of surgery on the cochlea (Fig. 1A). ABR was measured five AMPARs in particular appear to play a major role in synaptic times in each mouse that underwent surgery and three times in transmission and excitotoxicity (16). This is potentially significant unoperated mice. The first measurement was done before + because studies of excitotoxicity in the brain have implicated Ca2 surgery and the second was done at 3 d postsurgery, to de- influx as a key mediator of excitotoxic trauma (19), and although termine any effects on the threshold or the wave-I growth curve + NMDA-type glutamate receptors play the major role in Ca2 in- (amplitude as a function of sound level). These two measure- flux, CP-AMPARs also have a role in glutamate toxicity in the ments provided a baseline for any effects of surgery or IEM- brain (20–22). Moreover, previous in vitro (23) and in vivo (24) 1460 on the ABR. The cannula connecting the minipump to the + studies have suggested that, unlike in the brain, Ca2 entry via round window was filled with artificial perilymph (AP) only, so NMDA-type glutamate receptors is not a major contributor to that the minipump contents reached the cochlea at 3.5 d after excitotoxicity in the cochlea. Rather, we suggest that cochlear the surgical implantation. Approximately 1.5 d after the entry excitotoxicity is mediated by GluA2-lacking CP-AMPARs. To of IEM-1460 into the cochlea, a third ABR measurement was directly test this hypothesis, we used IEM-1460, a selective performed to assessed the effect of IEM-1460 itself on hearing. blocker of GluA2-lacking AMPARs (25, 26), in noise-exposed This measurement also provided the prenoise baseline for mice, with the results implicating a role of GluA2-lacking/CP- comparison to and normalization of postnoise measurements AMPARs in NICS. for each mouse. At age 13 to 14 wk and with minipump contents already pre- Results sent in the cochlea for ∼2.5 d, two groups of mice were exposed Experimental Design and Timeline of ABR Measurements.
Load more

Recommended publications
  • View Full Page
    8358 • The Journal of Neuroscience, June 11, 2014 • 34(24):8358–8372 Cellular/Molecular Specialized Postsynaptic Morphology Enhances Neurotransmitter Dilution and High-Frequency Signaling at an Auditory Synapse Cole W. Graydon,1,2* Soyoun Cho,3* Jeffrey S. Diamond,1 Bechara Kachar,2 Henrique von Gersdorff,3 and William N. Grimes1,4 1Synaptic Physiology Section, National Institute of Neurological Disorders and Stroke, and 2Section on Structural Cell Biology, National Institute on Deafness and Other Communication Disorders, Bethesda, Maryland 20892, 3Vollum Institute, Oregon Health & Science University, Portland, Oregon 97239, and 4Howard Hughes Medical Institute/University of Washington, Department of Biophysics and Physiology, Seattle, Washington 98195 Sensory processing in the auditory system requires that synapses, neurons, and circuits encode information with particularly high temporalandspectralprecision.Intheamphibianpapillia,soundfrequenciesupto1kHzareencodedalongatonotopicarrayofhaircells and transmitted to afferent fibers via fast, repetitive synaptic transmission, thereby promoting phase locking between the presynaptic and postsynaptic cells. Here, we have combined serial section electron microscopy, paired electrophysiological recordings, and Monte Carlo diffusion simulations to examine novel mechanisms that facilitate fast synaptic transmission in the inner ear of frogs (Rana catesbeiana and Rana pipiens). Three-dimensional anatomical reconstructions reveal specialized spine-like contacts between individual afferent fibers and
    [Show full text]
  • Intrinsically Different Retinal Progenitor Cells Produce Specific Types Of
    PERSPECTIVES These clonal data demonstrated that OPINION RPCs are generally multipotent. However, these data could not determine whether Intrinsically different retinal the variability in clones was due to intrinsic differences among RPCs or extrinsic and/ progenitor cells produce specific or stochastic effects on equivalent RPCs or their progeny. Furthermore, the fates identi- fied within a clone demonstrated an RPC’s types of progeny ‘potential’ but not the ability of an RPC to make a specific cell type at a specific devel- Connie Cepko opmental time or its ‘competence’ (BOX 2). Moreover, although many genes that regu- Abstract | Lineage studies conducted in the retina more than 25 years ago late the development of retinal cell types demonstrated the multipotency of retinal progenitor cells (RPCs). The number have been studied, using the now classical and types of cells produced by individual RPCs, even from a single time point in gain- and loss‑of‑function approaches18,19, development, were found to be highly variable. This raised the question of the precise roles of such regulators in defin- whether this variability was due to intrinsic differences among RPCs or to extrinsic ing an RPC’s competence or potential have not been well elucidated, as most studies and/or stochastic effects on equivalent RPCs or their progeny. Newer lineage have examined the outcome of a perturba- studies that have made use of molecular markers of RPCs, retrovirus-mediated tion on the development of a cell type but lineage analyses of specific RPCs and live imaging have begun to provide answers not the stage and/or cell type in which such a to this question.
    [Show full text]
  • The Glutamate–Aspartate Transporter GLAST Mediates Glutamate Uptake at Inner Hair Cell Afferent Synapses in the Mammalian Cochlea
    The Journal of Neuroscience, July 19, 2006 • 26(29):7659–7664 • 7659 Brief Communications The Glutamate–Aspartate Transporter GLAST Mediates Glutamate Uptake at Inner Hair Cell Afferent Synapses in the Mammalian Cochlea Elisabeth Glowatzki,1 Ning Cheng,2 Hakim Hiel,1 Eunyoung Yi,1 Kohichi Tanaka,4 Graham C. R. Ellis-Davies,5 Jeffrey D. Rothstein,3 and Dwight E. Bergles1,2 Departments of 1Otolaryngology–Head and Neck Surgery, 2Neuroscience, and 3Neurology, Johns Hopkins University, Baltimore, Maryland 21205, 4Laboratory of Molecular Neuroscience, School of Biomedical Science and Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113- 8510, Japan, and 5Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102 Ribbon synapses formed between inner hair cells (IHCs) and afferent dendrites in the mammalian cochlea can sustain high rates of release, placing strong demands on glutamate clearance mechanisms. To investigate the role of transporters in glutamate removal at these synapses, we made whole-cell recordings from IHCs, afferent dendrites, and glial cells adjacent to IHCs [inner phalangeal cells (IPCs)] in whole-mount preparations of rat organ of Corti. Focal application of the transporter substrate D-aspartate elicited inward currents in IPCs, which were larger in the presence of anions that permeate the transporter-associated anion channel and blocked by the transporter antagonist D,L-threo-␤-benzyloxyaspartate. These currents were produced by glutamate–aspartate transporters (GLAST) (excitatory amino acid transporter 1) because they were weakly inhibited by dihydrokainate, an antagonist of glutamate transporter-1 Ϫ/Ϫ (excitatory amino acid transporter 2) and were absent from IPCs in GLAST cochleas.
    [Show full text]
  • Lack of Fractalkine Receptor on Macrophages Impairs Spontaneous Recovery of Ribbon Synapses After Moderate Noise Trauma in C57BL/6 Mice Tejbeer Kaur
    Washington University School of Medicine Digital Commons@Becker Open Access Publications 2019 Lack of fractalkine receptor on macrophages impairs spontaneous recovery of ribbon synapses after moderate noise trauma in C57BL/6 mice Tejbeer Kaur Anna C. Clayman Andrew J. Nash Angela D. Schrader Mark E. Warchol See next page for additional authors Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Authors Tejbeer Kaur, Anna C. Clayman, Andrew J. Nash, Angela D. Schrader, Mark E. Warchol, and Kevin K. Ohlemiller fnins-13-00620 June 12, 2019 Time: 17:26 # 1 ORIGINAL RESEARCH published: 13 June 2019 doi: 10.3389/fnins.2019.00620 Lack of Fractalkine Receptor on Macrophages Impairs Spontaneous Recovery of Ribbon Synapses After Moderate Noise Trauma in C57BL/6 Mice Tejbeer Kaur1*, Anna C. Clayman2, Andrew J. Nash2, Angela D. Schrader1, Mark E. Warchol1 and Kevin K. Ohlemiller1,2 1 Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO, United States, 2 Program in Audiology and Communication Sciences, Washington University School of Medicine, St. Louis, MO, United States Noise trauma causes loss of synaptic connections between cochlear inner hair cells (IHCs) and the spiral ganglion neurons (SGNs). Such synaptic loss can trigger slow and progressive degeneration of SGNs. Macrophage fractalkine signaling is critical for neuron survival in the injured cochlea, but its role in cochlear synaptopathy is Edited by: unknown. Fractalkine, a chemokine, is constitutively expressed by SGNs and signals Isabel Varela-Nieto, via its receptor CX3CR1 that is expressed on macrophages. The present study Spanish National Research Council characterized the immune response and examined the function of fractalkine signaling (CSIC), Spain in degeneration and repair of cochlear synapses following noise trauma.
    [Show full text]
  • Review of Hair Cell Synapse Defects in Sensorineural Hearing Impairment
    Otology & Neurotology 34:995Y1004 Ó 2013, Otology & Neurotology, Inc. Review of Hair Cell Synapse Defects in Sensorineural Hearing Impairment *†‡Tobias Moser, *Friederike Predoehl, and §Arnold Starr *InnerEarLab, Department of Otolaryngology, University of Go¨ttingen Medical School; ÞSensory Research Center SFB 889, þBernstein Center for Computational Neuroscience, University of Go¨ttingen, Go¨ttingen, Germany; and §Department of Neurology, University of California, Irvine, California, U.S.A. Objective: To review new insights into the pathophysiology of are similar to those accompanying auditory neuropathy, a group sensorineural hearing impairment. Specifically, we address defects of genetic and acquired disorders of spiral ganglion neurons. of the ribbon synapses between inner hair cells and spiral ganglion Genetic auditory synaptopathies include alterations of glutamate neurons that cause auditory synaptopathy. loading of synaptic vesicles, synaptic Ca2+ influx or synaptic Data Sources and Study Selection: Here, we review original vesicle turnover. Acquired synaptopathies include noise-induced publications on the genetics, animal models, and molecular hearing loss because of excitotoxic synaptic damage and subse- mechanisms of hair cell ribbon synapses and their dysfunction. quent gradual neural degeneration. Alterations of ribbon synapses Conclusion: Hair cell ribbon synapses are highly specialized to likely also contribute to age-related hearing loss. Key Words: enable indefatigable sound encoding with utmost temporal precision. GeneticsVIon
    [Show full text]
  • The Genetic Relationship Between Paroxysmal Movement Disorders and Epilepsy
    Review article pISSN 2635-909X • eISSN 2635-9103 Ann Child Neurol 2020;28(3):76-87 https://doi.org/10.26815/acn.2020.00073 The Genetic Relationship between Paroxysmal Movement Disorders and Epilepsy Hyunji Ahn, MD, Tae-Sung Ko, MD Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea Received: May 1, 2020 Revised: May 12, 2020 Seizures and movement disorders both involve abnormal movements and are often difficult to Accepted: May 24, 2020 distinguish due to their overlapping phenomenology and possible etiological commonalities. Par- oxysmal movement disorders, which include three paroxysmal dyskinesia syndromes (paroxysmal Corresponding author: kinesigenic dyskinesia, paroxysmal non-kinesigenic dyskinesia, paroxysmal exercise-induced dys- Tae-Sung Ko, MD kinesia), hemiplegic migraine, and episodic ataxia, are important examples of conditions where Department of Pediatrics, Asan movement disorders and seizures overlap. Recently, many articles describing genes associated Medical Center Children’s Hospital, University of Ulsan College of with paroxysmal movement disorders and epilepsy have been published, providing much infor- Medicine, 88 Olympic-ro 43-gil, mation about their molecular pathology. In this review, we summarize the main genetic disorders Songpa-gu, Seoul 05505, Korea that results in co-occurrence of epilepsy and paroxysmal movement disorders, with a presenta- Tel: +82-2-3010-3390 tion of their genetic characteristics, suspected pathogenic mechanisms, and detailed descriptions Fax: +82-2-473-3725 of paroxysmal movement disorders and seizure types. E-mail: [email protected] Keywords: Dyskinesias; Movement disorders; Seizures; Epilepsy Introduction ies, and paroxysmal dyskinesias [3,4]. Paroxysmal dyskinesias are an important disease paradigm asso- Movement disorders often arise from the basal ganglia nuclei or ciated with overlapping movement disorders and seizures [5].
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • Genes Involved in the Development and Physiology of Both the Peripheral and Central Auditory Systems Nicolas Michalski, Christine Petit
    Genes Involved in the Development and Physiology of Both the Peripheral and Central Auditory Systems Nicolas Michalski, Christine Petit To cite this version: Nicolas Michalski, Christine Petit. Genes Involved in the Development and Physiology of Both the Peripheral and Central Auditory Systems. Annual Review of Neuroscience, Annual Reviews, 2019, 42, pp.67-86. 10.1146/annurev-neuro-070918-050428. pasteur-02874563 HAL Id: pasteur-02874563 https://hal-pasteur.archives-ouvertes.fr/pasteur-02874563 Submitted on 6 Jul 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution - NonCommercial| 4.0 International License Genes Involved in the Development and Physiology of both the Peripheral and Central Auditory Systems 1,2,3,# 1,2,3,4,5,# Nicolas Michalski & Christine Petit 1 Unité de Génétique et Physiologie de l’Audition, Institut Pasteur, 75015 Paris, France 2 UMRS 1120, Institut National de la Santé et de la Recherche Médicale (INSERM), 75015 Paris, France 3 Sorbonne Universités, UPMC Université Paris 06, Complexité
    [Show full text]
  • March 22 – 25, 2017 2 0 17 Program Program
    Program y t Göttingen Meeting h t 2 of the German Neuroscience Socie 1 7 12th Göttingen Meeting of the 1 0 2 German Neuroscience Society March 22 – 25, 20 17 Program Blueprint for Exceptional Customer Service 7-11 July 2018 | Berlin, Germany Organised by the Federation of European Neuroscience Societies (FENS) Hosted by The German Neuroscience Society Since the inception of Fine Science Tools in 1974, it has been our goal to provide the highest quality surgical and microsurgical instruments to meet your research needs. To be sure we meet your high standards, every product we sell comes with our 100% satisfaction guarantee. If, for any reason, you are not completely satisfied with your purchase, you may return it for a full refund. th The 20 Anniversary of FENS Where European neuroscience meets the world SAVE THE DATE Five good reasons • State-of-the-art neuroscience to attend the • Europe’s foremost neuroscience event Forum in Berlin: • Exchange ideas and network with neuroscientists worldwide • A diverse scientific programme with world-renowned speakers • Visit Berlin - Germany’s capital and cultural centre www.fens.org/2018 FINE SURGICAL INSTRUMENTS FOR RESEARCHTM Visit us at finescience.de or call +49 6221 90 50 50 Program 12th GÖTTINGEN MEETING OF THE GERMAN NEUROSCIENCE SOCIETY 36th GÖTTINGEN NEUROBIOLOGY CONFERENCE March 22 - 25, 2017 1 FiberOptoMeter Anzeige: npi 1 Optogenetic Stimulation & Fluorescence Measurement via the Same Fiber Ca2+ fluorescence signals (OGB-1) Data kindly provided by Dr. A. Stroh and M. Schwalm npi electronic
    [Show full text]
  • The Integrity of Cochlear Hair Cells Is Established and Maintained
    Ninoyu et al. Cell Death and Disease (2020) 11:536 https://doi.org/10.1038/s41419-020-02743-z Cell Death & Disease ARTICLE Open Access The integrity of cochlear hair cells is established and maintained through the localization of Dia1 at apical junctional complexes and stereocilia Yuzuru Ninoyu1,2, Hirofumi Sakaguchi2, Chen Lin1, Toshiaki Suzuki 1, Shigeru Hirano2,YasuoHisa2, Naoaki Saito1 and Takehiko Ueyama 1 Abstract Dia1, which belongs to the diaphanous-related formin family, influences a variety of cellular processes through straight actin elongation activity. Recently, novel DIA1 mutants such as p.R1213X (p.R1204X) and p.A265S, have been reported to cause an autosomal dominant sensorineural hearing loss (DFNA1). Additionally, active DIA1 mutants induce progressive hearing loss in a gain-of-function manner. However, the subcellular localization and pathological function of DIA1(R1213X/R1204X) remains unknown. In the present study, we demonstrated the localization of endogenous Dia1 and the constitutively active DIA1 mutant in the cochlea, using transgenic mice expressing FLAG-tagged DIA1 (R1204X) (DIA1-TG). Endogenous Dia1 and the DIA1 mutant were regionally expressed at the organ of Corti and the spiral ganglion from early life; alongside cochlear maturation, they became localized at the apical junctional complexes (AJCs) between hair cells (HCs) and supporting cells (SCs). To investigate HC vulnerability in the DIA1-TG mice, we exposed 4-week-old mice to moderate noise, which induced temporary threshold shifts with cochlear synaptopathy and ultrastructural changes in stereocilia 4 weeks post noise exposure. Furthermore, we established a knock-in (KI) fi 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; mouse line expressing AcGFP-tagged DIA1(R1213X) (DIA1-KI) and con rmed mutant localization at AJCs and the tips of stereocilia in HCs.
    [Show full text]
  • Autism Spectrum Disorder Causes, Mechanisms, and Treatments: Focus on Neuronal Synapses
    REVIEW ARTICLE published: 05 August 2013 MOLECULAR NEUROSCIENCE doi: 10.3389/fnmol.2013.00019 Autism spectrum disorder causes, mechanisms, and treatments: focus on neuronal synapses Hyejung Won 1,WonMah1,2 and Eunjoon Kim 1,2* 1 Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, South Korea 2 Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon, South Korea Edited by: Autism spectrum disorder (ASD) is a group of developmental disabilities characterized Nicola Maggio, The Chaim Sheba by impairments in social interaction and communication and restricted and repetitive Medical Center, Israel interests/behaviors. Advances in human genomics have identified a large number of Reviewed by: genetic variations associated with ASD. These associations are being rapidly verified by a Carlo Sala, CNR Institute of Neuroscience, Italy growing number of studies using a variety of approaches, including mouse genetics. These Lior Greenbaum, Hadassah Medical studies have also identified key mechanisms underlying the pathogenesis of ASD, many Center, Israel of which involve synaptic dysfunctions, and have investigated novel, mechanism-based *Correspondence: therapeutic strategies. This review will try to integrate these three key aspects of ASD Eunjoon Kim, Center for Synaptic research: human genetics, animal models, and potential treatments. Continued efforts in Brain Dysfunctions, Institute for Basic Science, and Department of this direction should ultimately reveal core mechanisms that account
    [Show full text]