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 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- haircellstothebrain.Almostall(95%)SGNsaretypeIand 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 First published February 3, 2020. 3828–3838 | PNAS | February 18, 2020 | vol. 117 | no. 7 www.pnas.org/cgi/doi/10.1073/pnas.1914247117 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 NEUROSCIENCE Experimental Design and Timeline of ABR Measurements.
Load more

Recommended publications
  • 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]
  • 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]
  • 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]
  • Dissecting the Genetic Basis of Parkinson Disease, Dystonia and Chorea
    Dissecting the Genetic Basis of Parkinson Disease, Dystonia and Chorea A thesis submitted to the University College London for the degree of Doctor of Philosophy June 2016 by Dr Niccolò Emanuele Mencacci 1 Declaration of Authorship I, Niccolò Emanuele Mencacci, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. 2 Incontenibile andare, di monte in monte, inquieti dietro un mistero che sempre ti seduce, da un’altra valle 3 Abstract In this thesis I used of a range of genetic methodologies and strategies to unravel the genetic bases of Parkinson disease (PD), myoclonus-dystonia (M-D), and chorea. First, I detail the work I performed in PD, including (1) the screening of GBA in a cohort of early-onset PD cases, which led to the identification of the allele E326K (p.Glu365Lys) as the single most frequent, clinically relevant, risk variant for PD; (2) a detailed genetic analysis in a large cohort of PD cases who underwent deep-brain stimulation treatment and a longitudinal comparison of the phenotypic features of carriers of mutations in different genes; (3) the observation that rare GCH1 coding variants, known to be responsible for the childhood-onset disorder DOPA-responsive dystonia, are a novel risk factor for PD. Then, I describe the work I performed to identify novel causes of M-D, including (1) the discovery of the missense p.Arg145His mutation in KCTD17 as a novel cause of autosomal dominant M-D; (2) the identification of tyrosine hydroxylase deficiency as a novel treatable cause of recessive M-D; and (3) the conclusive disproof of the pathogenic role of the p.Arg1389His variant in CACNA1B as a cause of M-D.
    [Show full text]
  • Synaptotoxicity in Alzheimer's Disease
    Synaptotoxicity in Alzheimer’s disease : Influence of APP processing on excitatory synapses Rebecca Powell To cite this version: Rebecca Powell. Synaptotoxicity in Alzheimer’s disease : Influence of APP processing on excitatory synapses. Neurons and Cognition [q-bio.NC]. Université Grenoble Alpes, 2019. English. NNT : 2019GREAV051. tel-02953383 HAL Id: tel-02953383 https://tel.archives-ouvertes.fr/tel-02953383 Submitted on 30 Sep 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. THÈSE Pour obtenir le grade de DOCTEUR DE LA COMMUNAUTE UNIVERSITE GRENOBLE ALPES Spécialité : Neurosciences - Neurobiologie Arrêté ministériel : 25 mai 2016 Présentée par Rebecca POWELL Thèse dirigée par Alain BUISSON, Professeur, UGA Préparée au sein du l’institut des Neurosciences de Grenoble INSERM U1216 – Equipe Neuropathologies et Dysfonctions Synaptiques Dans l'École Doctorale de Chimie et Sciences du vivant Synaptotoxicité dans la maladie d’Alzheimer : Influence du processing de l’APP sur les synapses excitatrices Thèse soutenue publiquement le 6 décembre 2019,
    [Show full text]
  • Uva-DARE (Digital Academic Repository)
    UvA-DARE (Digital Academic Repository) Phenotypes and mechanisms in myoclonus-dystonia Ritz, K.A. Publication date 2012 Link to publication Citation for published version (APA): Ritz, K. A. (2012). Phenotypes and mechanisms in myoclonus-dystonia. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:28 Sep 2021 Chapter 6Six Summary and general discussion Contents Summary Discussion Myoclonus-dystonia: a cerebellar disorder? Myoclonus-dystonia: a synaptopathy? Myoclonus-dystonia: a myoclonus-plus rather than dystonia-plus syndrome? Conclusion and future research Myoclonus-dystonia pathology Cerebellar dysfunction and myoclonus-dystonia Epsilon-sarcoglycan and synaptic vesicle turnover Identification of novel myoclonus-dystonia associated genes 92 Summary Myoclonus-dystonia (M-D) is a rare hyperkinetic movement disorder. Patients generally present with sudden, brief, shock-like jerks called myoclonus and with dystonic symptoms, which are repetitive twisting movements or abnormal postures.
    [Show full text]
  • Poster Contributions: 13Th Göttingen Meeting, 20-23 March 2019
    Poster Contributions: 13th Göttingen Meeting, 20-23 March 2019 Explanation of Abstract Numbers There are two poster sessions on Wednesday, Thursday, Friday and Saturday. Posters with poster numbers ending with an A are displayed on Wednesday, posters with a poster number ending with a B are displayed on Thursday, posters with a poster number ending with a C are displayed on Friday and posters with a poster number ending with a D are displayed on Saturday. Each poster session (90 min) is divided into two parts (each 45 min): odd and even serial numbers. In the first part of the first session of a day posters with odd serial numbers will be discussed. In the second 45 min of the first session of a day posters with even serial numbers will be discussed. In the second session of a day posters with odd serial poster numbers will be discussed again in the first 45 min and in the second 45 min of the same session posters with even serial numbers will be discussed once more. Example T21-2B T = poster to a poster topic 21 = the poster topic is No. 21, i.e. Motor Systems 2 = serial number (even number, i.e. second hours of each session) B = indicates the day, i.e. Thursday This means: poster T21-2B is a poster belonging to the topic “Motor Systems” and is presented on Thursday, March 21, 10:45 -11:30 h and 17:15 -18:00 h in the poster area 21. Postersessions Postersessions A: Wednesday, March 20 13.00 - 14.30 and 16.30 - 18.00 Postersessions B: Thursday, March 21 10.00 - 11.30 and 16.30 - 18.00 Postersessions C: Friday, March 22 10.00 - 11.30 and
    [Show full text]
  • UK Neuromuscular Translational Research Conference 26-27 March
    UK Neuromuscular Translational Research Conference 26 -27 March 2009 International Centre for Life Times Square Newcastle Upon Tyne NE1 4EP Contents Welcome from the MRC Centre for Neuromuscular Diseases and from the Muscular Dystrophy Campaign .....................................................................................................................................2 About the MRC Centre for Neuromuscular Diseases and the Muscular Dystrophy Campaign ...4 Patient Organisations....................................................................................................................7 Programme....................................................................................................................................8 Speaker abstracts........................................................................................................................11 Poster list.....................................................................................................................................18 Poster abstracts...........................................................................................................................21 Clinical Trials...............................................................................................................................48 Delegate list.................................................................................................................................54 MRC Centre for Neuromuscular Diseases staff list.....................................................................58
    [Show full text]
  • The Role of Alpha-Synuclein and Other Parkinson's Genes in Neurodevelopmental and Neurodegenerative Disorders
    International Journal of Molecular Sciences Review The Role of Alpha-Synuclein and Other Parkinson’s Genes in Neurodevelopmental and Neurodegenerative Disorders C. Alejandra Morato Torres 1, Zinah Wassouf 2,3, Faria Zafar 1, Danuta Sastre 1, Tiago Fleming Outeiro 2,3,4,5 and Birgitt Schüle 1,* 1 Department Pathology, Stanford University School of Medicine, Stanford, CA 94304, USA; [email protected] (C.A.M.T.); [email protected] (F.Z.); [email protected] (D.S.) 2 German Center for Neurodegenerative Diseases, 37075 Göttingen, Germany; [email protected] (Z.W.); [email protected] (T.F.O.) 3 Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, 37075 Göttingen, Germany 4 Max Planck Institute for Experimental Medicine, 37075 Göttingen, Germany 5 Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Framlington Place, Newcastle Upon Tyne NE2 4HH, UK * Correspondence: [email protected]; Tel.: +1-650-721-1767 Received: 13 July 2020; Accepted: 8 August 2020; Published: 10 August 2020 Abstract: Neurodevelopmental and late-onset neurodegenerative disorders present as separate entities that are clinically and neuropathologically quite distinct. However, recent evidence has highlighted surprising commonalities and converging features at the clinical, genomic, and molecular level between these two disease spectra. This is particularly striking in the context of autism spectrum disorder (ASD) and Parkinson’s disease (PD). Genetic causes and risk factors play a central role in disease pathophysiology and enable the identification of overlapping mechanisms and pathways. Here, we focus on clinico-genetic studies of causal variants and overlapping clinical and cellular features of ASD and PD.
    [Show 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).
    [Show full text]
  • Dendritic Spines in Alzheimer's Disease: How the Actin
    International Journal of Molecular Sciences Review Dendritic Spines in Alzheimer’s Disease: How the Actin Cytoskeleton Contributes to Synaptic Failure Silvia Pelucchi, Ramona Stringhi and Elena Marcello * Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milan, Italy; [email protected] (S.P.); [email protected] (R.S.) * Correspondence: [email protected]; Tel.: +39-02-50318314 Received: 24 December 2019; Accepted: 26 January 2020; Published: 30 January 2020 Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by Aβ-driven synaptic dysfunction in the early phases of pathogenesis. In the synaptic context, the actin cytoskeleton is a crucial element to maintain the dendritic spine architecture and to orchestrate the spine’s morphology remodeling driven by synaptic activity. Indeed, spine shape and synaptic strength are strictly correlated and precisely governed during plasticity phenomena in order to convert short-term alterations of synaptic strength into long-lasting changes that are embedded in stable structural modification. These functional and structural modifications are considered the biological basis of learning and memory processes. In this review we discussed the existing evidence regarding the role of the spine actin cytoskeleton in AD synaptic failure. We revised the physiological function of the actin cytoskeleton in the spine shaping and the contribution of actin dynamics in the endocytosis mechanism. The internalization process is implicated in different aspects of AD since it controls both glutamate receptor membrane levels and amyloid generation. The detailed understanding of the mechanisms controlling the actin cytoskeleton in a unique biological context as the dendritic spine could pave the way to the development of innovative synapse-tailored therapeutic interventions and to the identification of novel biomarkers to monitor synaptic loss in AD.
    [Show full text]