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1. Biasing the semicircular canal cupula in excitatory direction decreases the gain of the vestibuloocular reflex for head impulses

Author: Béla Büki, Paul Avan, Dominik Obrist, László T. Tamás, Institute of Fluid Dynamics, Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA), and ENT Dept, General Hosp. Krems
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, genetic structures, [SDV]Life Sciences [q-bio], Audiology, Inhibitory postsynaptic potential, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Caloric Tests, medicine, Humans, Head Impulse Test, ComputingMilieux_MISCELLANEOUS, Vestibular system, Physics, Semicircular canal, General Neuroscience, Caloric theory, Reflex, Vestibulo-Ocular, Semicircular Canals, Sensory Systems, Electrophysiology, medicine.anatomical_structure, Otorhinolaryngology, Excitatory postsynaptic potential, Reflex, Female, Neurology (clinical), Vestibulo–ocular reflex, 030217 neurology & neurosurgery
Abstract: Background: It has been shown that cold caloric irrigation decreases the vestibulo-ocular reflex (VOR) gain in the vertically positioned lateral canal as measured by head impulse testing. This effect is most probably caused by a sustained deflection of the cupula in the inhibitory direction. Objective: The aim of the present experiment was to answer the question if a sustained excitatory deflection increases the gain of the reflex in healthy volunteers. Methods: In order to deflect the cupula, cold caloric irrigation was applied in prone (forward head hanging) position. In this position cold thermal irrigation elicited an excitatory caloric nystagmus with an ipsilateral fast phase. Results: When head impulses were applied immediately after cold caloric irrigation, the gain of the VOR decreased in comparison to the values measured before irrigation. Conclusions: Together with the previous results cited above, these data show that biasing the cupula in either direction decreases its sensitivity with respect to high acceleration stimuli. This might occur because the deviation elicits a partial mechanical and electrophysiological saturation of the cupula.
Published: 2020
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2. Otogelin, otogelin-like, and stereocilin form links connecting outer hair cell stereocilia to each other and the tectorial membrane

Author: Paul Avan, Sébastien Le Gal, Vincent Michel, Typhaine Dupont, Elisabeth Verpy, Christine Petit, Jean-Pierre Hardelin, Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique et Physiologie de l'Audition, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), This work was supported by the European Commission (ERC-2011-ADG-294570, to C.P.), Banque Nationale de Paris Paribas, Fondation pour l’Audition, Stiftung Lebenshilfewerk, and by French state funds managed by the Agence Nationale de la Recherche within the 'Investissement d’Avenir' program (ANR-15-RHUS-0001 and LabEx LifeSenses ANR-10-LABX-65) and ANR-16-CE13-0015-02., We thank Jacques Boutet de Monvel for helpful comments on the manuscript, and Jérémie Chatel-Poujade, Isabelle Perfettini, and Céline Trébeau for technical assistance., ANR-15-RHUS-0001,LIGHT4DEAF,ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER(2015), ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Chaire Génétique et physiologie cellulaire
Subjects: Tectorial Membrane, Tectorial membrane, Hearing Loss, Sensorineural, Stereocilia (inner ear), Mechanoelectrical transduction, horizontal top connector, Deafness, Stereocilia, Hair Cells, Vestibular, Mice, 03 medical and health sciences, 0302 clinical medicine, otoacoustic emission, otorhinolaryngologic diseases, medicine, Animals, Genetic Predisposition to Disease, air bundle link, Outer hair cells, tectorial membrane-attachment crown, Cochlea, 030304 developmental biology, outer hair cell, Mice, Knockout, 0303 health sciences, Membrane Glycoproteins, Multidisciplinary, Chemistry, [SCCO.NEUR]Cognitive science/Neuroscience, Biological Sciences, Cell biology, Sensory epithelium, Hair Cells, Auditory, Outer, medicine.anatomical_structure, Intercellular Signaling Peptides and Proteins, sense organs, Hair cell, 030217 neurology & neurosurgery
Abstract: International audience; The function of outer hair cells (OHCs), the mechanical actuators of the cochlea, involves the anchoring of their tallest stereocilia in the tectorial membrane (TM), an acellular structure overlying the sensory epithelium. Otogelin and otogelin-like are TM proteins related to secreted epithelial mucins. Defects in either cause the DFNB18B and DFNB84B genetic forms of deafness, respectively, both characterized by congenital mild-to-moderate hearing impairment. We show here that mutant mice lacking otogelin or otogelin-like have a marked OHC dysfunction, with almost no acoustic distortion products despite the persistence of some mechanoelectrical transduction. In both mutants, these cells lack the horizontal top connectors, which are fibrous links joining adjacent stereocilia, and the TM-attachment crowns coupling the tallest stereocilia to the TM. These defects are consistent with the previously unrecognized presence of otogelin and otogelin-like in the OHC hair bundle. The defective hair bundle cohesiveness and the absence of stereociliary imprints in the TM observed in these mice have also been observed in mutant mice lacking stereocilin, a model of the DFNB16 genetic form of deafness, also characterized by congenital mild-to-moderate hearing impairment. We show that the localizations of stereocilin, otogelin, and otogelin-like in the hair bundle are interdependent, indicating that these proteins interact to form the horizontal top connectors and the TM-attachment crowns. We therefore suggest that these 2 OHC-specific structures have shared mechanical properties mediating reaction forces to sound-induced shearing motion and contributing to the coordinated displacement of stereocilia.
Published: 2019
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3. Dual AAV-mediated gene therapy restores hearing in a DFNB9 mouse model

Author: Omar Akil, Saaid Safieddine, Jacques Boutet de Monvel, Charlotte Calvet, Frank M. Dyka, Ghizlene Lahlou, Sylvie Nouaille, Jean-Pierre Hardelin, Paul Avan, Alice Emptoz, Christine Petit, William W. Hauswirth, Lawrence R. Lustig, University of California [San Francisco] (UC San Francisco), University of California (UC), University of Florida [Gainesville] (UF), Génétique et Physiologie de l'Audition, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), ED 515 - Complexité du vivant, Sorbonne Université (SU), Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), Columbia University Medical Center (CUMC), Columbia University [New York], This work was supported by the Hearing Research Incorporation (O.A.), Fondation pour la Recherche Médicale (A.E.), Région Ile de France (DIM Thérapie génique), the European Union Seventh Framework Programme under the Grant Agreement HEALTH-F2-2010-242013 (TREAT RUSH), the French government funds managed by Agence Nationale de la Recherche (EargenCure), and LabEx Lifesenses (ANR-10-BNP Paribas Foundation, FAUN Stiftung, LHW Stiftung, and Mrs. Errera Hoechstetter)., ANR-17-CE18-0027,EARGENCURE,Restauration, par thérapie génique, de l'audition et de l'équilibre chez des souris modèles de surdités et troubles vestibulaires humains(2017), ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), European Project: 242013,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,TREATRUSH(2010), University of California [San Francisco] (UCSF), University of California, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Chaire Génétique et physiologie cellulaire
Subjects: Medical Sciences, [SDV]Life Sciences [q-bio], Genetic enhancement, Genetic Vectors, Mutant, Mice, Transgenic, Biology, law.invention, Mice, otoferlin, 03 medical and health sciences, 0302 clinical medicine, law, deafness, Complementary DNA, otorhinolaryngologic diseases, DFNB9, Animals, Humans, Coding region, Vector (molecular biology), Gene, 030304 developmental biology, 0303 health sciences, Multidisciplinary, Membrane Proteins, Genetic Therapy, Biological Sciences, Dependovirus, gene therapy, Phenotype, Cell biology, Mice, Inbred C57BL, Disease Models, Animal, Recombinant DNA, dual AAV, 030217 neurology & neurosurgery
Abstract: Significance In humans, inner ear development is completed in utero, with hearing onset at ∼20 weeks of gestation. However, genetic forms of congenital deafness are typically diagnosed during the neonatal period. Gene therapy approaches in animal models should therefore be tested after the period of hearing onset, to determine whether they can reverse an existing deafness phenotype. Here, we used a mouse model of DFNB9, a human deafness form accounting for 2–8% of all cases of congenital genetic deafness. We show that local gene therapy in the mutant mice not only prevents deafness when administered to immature hearing organs, but also durably restores hearing when administered at a mature stage, raising hopes for future gene therapy trials in DFNB9 patients., Autosomal recessive genetic forms (DFNB) account for most cases of profound congenital deafness. Adeno-associated virus (AAV)-based gene therapy is a promising therapeutic option, but is limited by a potentially short therapeutic window and the constrained packaging capacity of the vector. We focus here on the otoferlin gene underlying DFNB9, one of the most frequent genetic forms of congenital deafness. We adopted a dual AAV approach using two different recombinant vectors, one containing the 5′ and the other the 3′ portions of otoferlin cDNA, which exceed the packaging capacity of the AAV when combined. A single delivery of the vector pair into the mature cochlea of Otof−/− mutant mice reconstituted the otoferlin cDNA coding sequence through recombination of the 5′ and 3′ cDNAs, leading to the durable restoration of otoferlin expression in transduced cells and a reversal of the deafness phenotype, raising hopes for future gene therapy trials in DFNB9 patients.
Published: 2019
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4. Auditory Brainstem Changes in Timing may Underlie Hyperacusis in a Salicylate-induced Acute Rat Model

Author: Paul Avan, Julie Duron, Lénaïc Monconduit, Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), CMBN, Rutgers, The State University of New Jersey [New Brunswick] (RU), Rutgers University System (Rutgers)-Rutgers University System (Rutgers), Equipe Biophysique Neurosensorielle [Neuro-Dol], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), CCSD, Accord Elsevier, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Neuro-Dol - Clermont Auvergne (Neuro-Dol), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Université Clermont Auvergne (UCA)
Subjects: Male, 0301 basic medicine, Reflex, Startle, medicine.medical_specialty, middle-ear muscle reflex, Hearing loss, [SDV]Life Sciences [q-bio], Sodium Salicylate, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Audiology, Loudness, Rats, Sprague-Dawley, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Hearing, Moro reflex, Evoked Potentials, Auditory, Brain Stem, otorhinolaryngologic diseases, Animals, Medicine, Auditory system, ComputingMilieux_MISCELLANEOUS, Sodium salicylate, Auditory Cortex, business.industry, General Neuroscience, Hyperacusis, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Auditory Threshold, medicine.disease, loudness, Inferior Colliculi, acoustic startle reflex, 030104 developmental biology, medicine.anatomical_structure, chemistry, auditory brainstem responses, Acoustic Startle Reflex, Sensorineural hearing loss, sense organs, medicine.symptom, business, 030217 neurology & neurosurgery, hyperacusis, psychological phenomena and processes
Abstract: International audience; Hyperacusis, an exaggerated, sometimes painful perception of loudness even for soft sounds, is a poorly understood distressing condition. While the involvement of modified gain of central auditory neurons and the influence of nonauditory brain regions are well-documented, the issue of where in the auditory system these abnormalities arise remains open, particularly when hyperacusis comes without sensorineural hearing loss. Here we used acute intraperitoneal administration of sodium salicylate (150 mg/kg) in rats, enough to produce > 10-dB decrease in acoustic startle threshold with mild hearing loss at low frequencies (60 dB SPL. Candidate circuits able to act at the same time on the startle reflex, the MEMR and ABRs may be serotoninergic, as salicylate is known to increase brain serotonin and 5-HT neurons participate in MEMR and ABR circuits.
Published: 2020
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5. Noninvasive in-ear monitoring of intracranial pressure during microgravity in parabolic flights

Author: Hervé Normand, Grégory Gerenton, Pierre Denise, Fabrice Giraudet, Paul Avan, Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Cognition, Mobilités, Temporalité (COMETE), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Mobilités : Attention, Orientation et Chronobiologie (COMETE)
Subjects: Adult, Materials science, Intracranial Pressure, Weightlessness, Physiology, [SCCO.NEUR]Cognitive science/Neuroscience, Posture, Ear, 030208 emergency & critical care medicine, Middle Aged, Space Flight, Head-Down Tilt, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Physiology (medical), Pressure increase, Astronauts, Humans, Cochlear microphonic potential, ComputingMilieux_MISCELLANEOUS, 030217 neurology & neurosurgery, Monitoring, Physiologic, Biomedical engineering, Intracranial pressure
Abstract: Among possible causes of visual impairment or headache experienced by astronauts in microgravity or postflight and that hamper their performance, elevated intracranial pressure (ICP) has been invoked but never measured for lack of noninvasive methods. The goal of this work was to test two noninvasive methods of ICP monitoring using in-ear detectors of ICP-dependent auditory responses, acoustic and electric, in acute microgravity afforded by parabolic flights. The devices detecting these responses were handheld tablets routinely used in otolaryngology for hearing diagnosis, which were customized for ICP extraction and serviceable by unskilled operators. These methods had been previously validated against invasive ICP measurements in neurosurgery patients. The two methods concurred in their estimation of ICP changes with microgravity, i.e., 11.0 ± 7.7 mmHg for the acoustic method ( n = 7 subjects with valid results out of 30, auditory responses being masked by excessive in-flight noise in 23 subjects) and 11.3 ± 10.6 mmHg for the electric method ( n = 10 subjects with valid results out of 10 tested despite the in-flight noise). These results agree with recent publications using invasive access to cerebrospinal fluid in parabolic flights and suggest that acute microgravity has a moderate average effect on ICP, similar to body tilt from upright to supine, yet with some subjects undergoing large effects whereas others seem immune. The electric in-ear method would be suitable for ICP monitoring in circumstances and with subjects such that invasive measurements are excluded. NEW & NOTEWORTHY In-ear detectors of intracranial pressure-dependent auditory responses allow intracranial pressure to be monitored noninvasively during acute microgravity. The average pressure increase during 20-s long sessions in microgravity is 11 mmHg, comparable with an effect of body tilt. However, intersubject variability is large, with subjects who repeatedly experience from nothing to twice the average effect. A systematic in-flight use would allow the relationship between space adaptation syndrome and ICP to be established or dismissed.
Published: 2018
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6. New views on auditory ageing in normal subjects and patients with comorbidities

Author: Giraudet, Fabrice, Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA), and CHAUVET, Laurence
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2019

7. Pejvakin-mediated pexophagy protects auditory hair cells against noise-induced damage

Author: Sedigheh Delmaghani, Christine Petit, Alain Aghaie, Paul Avan, Isabelle Perfettini, Jean Defourny, Génétique et Physiologie de l'Audition, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), ED 515 - Complexité du vivant, Sorbonne Université (SU), Institut de la Vision, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), This work was supported by the Louis-Jeantet Foundation, Fondation Bettencourt Schueller, Fondation Agir pour l’Audition, Humanis Novalis-Taitbout, Réunica-Prévoyance, BNP Paribas, and the French Investissements d’Avenir program (ANR-10-LABX-65, to C.P.)., Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Chaire Génétique et physiologie cellulaire
Subjects: intracochlear viral transduction, pejvakin, [SDV]Life Sciences [q-bio], Peroxisome Proliferation, medicine.disease_cause, Mice, 03 medical and health sciences, 0302 clinical medicine, Hair Cells, Auditory, Macroautophagy, medicine, Animals, LC3B, Receptor, 030304 developmental biology, 0303 health sciences, Multidisciplinary, biology, Chemistry, Autophagy, Proteins, Transfection, Peroxisome, pexophagy, Cell biology, noise-induced hearing loss, PNAS Plus, Hearing Loss, Noise-Induced, Chaperone (protein), biology.protein, Microtubule-Associated Proteins, MAP1LC3B, 030217 neurology & neurosurgery, Oxidative stress
Abstract: International audience; Noise overexposure causes oxidative stress, leading to auditory hair cell damage. Adaptive peroxisome proliferation involving pejvakin, a peroxisome-associated protein from the gasdermin family, has been shown to protect against this harmful oxidative stress. However, the role of pejvakin in peroxisome dynamics and homeostasis remains unclear. Here we show that sound overstimulation induces an early and rapid selective autophagic degradation of peroxisomes (pexophagy) in auditory hair cells from wild-type, but not pejvakin-deficient (Pjvk -/-), mice. Noise overexposure triggers recruitment of the autophagosome-associated protein MAP1LC3B (LC3B; microtubule-associated protein 1 light chain 3β) to peroxisomes in wild-type, but not Pjvk -/-, mice. We also show that pejvakin-LC3B binding involves an LC3-interacting region within the predicted chaperone domain of pejvakin. In transfected cells and in vivo transduced auditory hair cells, cysteine mutagenesis experiments demonstrated the requirement for both C328 and C343, the two cysteine residues closest to the C terminus of pejvakin, for reactive oxygen species-induced pejvakin-LC3B interaction and pexophagy. The viral transduction of auditory hair cells from Pjvk -/- mice in vivo with both Pjvk and Lc3b cDNAs completely restored sound-induced pexophagy, fully prevented the development of oxidative stress, and resulted in normal levels of peroxisome proliferation, whereas Pjvk cDNA alone yielded only a partial correction of the defects. Overall, our results demonstrate that pexophagy plays a key role in noise-induced peroxisome proliferation and identify defective pexophagy as a cause of noise-induced hearing loss. They suggest that pejvakin acts as a redox-activated pexophagy receptor/adaptor, thereby identifying a previously unknown function of gasdermin family proteins.
Published: 2019
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8. An urgent need for new objective tests of auditory disorders: how to take up the challenge?

Author: Avan, Paul, CHAUVET, Laurence, Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Neuro-Dol (Neuro-Dol), and Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2019

9. Targeting the TREK-1 potassium channel via riluzole to eliminate the neuropathic and depressive-like effects of oxaliplatin

Author: Jérôme Busserolles, Laura Poupon, Youssef Aissouni, Stéphane Lolignier, Nicolas Authier, David Balayssac, Nicolas Kerckhove, David André Barrière, Fabrice Giraudet, Damien Richard, Michel Lazdunski, Alain Eschalier, Mathieu Meleine, Sylvain Lamoine, Vanessa Pereira, Laetitia Prival, Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Equipe Biophysique Neurosensorielle [Neuro-Dol], Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Université Nice Sophia Antipolis (1965 - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)
Subjects: 0301 basic medicine, Male, Potassium Channels, Colorectal cancer, Cell Survival, [SDV]Life Sciences [q-bio], Pharmacology, 03 medical and health sciences, Cellular and Molecular Neuroscience, Mice, 0302 clinical medicine, Potassium Channels, Tandem Pore Domain, Cell Line, Tumor, Neoplasms, medicine, Neurotoxicity, Animals, Humans, Adverse effect, Cell Proliferation, Pain Measurement, Mice, Knockout, Riluzole, business.industry, Depression, Prevention, Cancer, Peripheral Nervous System Diseases, medicine.disease, Phenotype, Potassium channel, 3. Good health, Oxaliplatin, 030104 developmental biology, Neurotoxicity Syndromes, TREK-1 potassium channel, business, 030217 neurology & neurosurgery, medicine.drug
Abstract: International audience; Neurotoxicity remains the most common adverse effect of oxaliplatin, limiting its clinical use. In the present study, we developed a mouse model of chronic oxaliplatin-induced neuropathy, which mimics both sensory and motor deficits observed in patients, in a clinically relevant time course. Repeated oxaliplatin administration in mice induced both cephalic and extracephalic long lasting mechanical and cold hypersensitivity after the first injection as well as delayed sensorimotor deficits and a depression-like phenotype. Using this model, we report that riluzole prevents both sensory and motor deficits induced by oxaliplatin as well as the depression-like phenotype induced by cumulative chemotherapeutic drug doses. All the beneficial effects are due to riluzole action on the TREK-1 potassium channel, which plays a central role in its therapeutic action. Riluzole has no negative effect on oxaliplatin antiproliferative capacity in human colorectal cancer cells and on its anticancer effect in a mouse model of colorectal cancer. Moreover, riluzole decreases human colorectal cancer cell line viability in vitro and inhibits polyp development in vivo. The present data in mice may support the need to clinically test riluzole in oxaliplatin-treated cancer patients and state for the important role of the TREK-1 channel in pain perception.
Published: 2018
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10. Clarin-1 gene transfer rescues auditory synaptopathy in model of Usher syndrome

Author: Omar Akil, Didier Dulon, Samantha Papal, Vincent Michel, Paul Avan, Alice Emptoz, Aziz El-Amraoui, Olinda Alegria-Prévot, Sedigheh Delmaghani, Pranav Patni, Lawrence R. Lustig, Christine Petit, Alain Aghaie, Abdelaziz Tlili, Elise Pepermans, Yohan Bouleau, Saaid Safieddine, Margot Tertrais, Matteo Cortese, Philippe F.Y. Vincent, Neurophysiologie de la Synapse Auditive, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU de Bordeaux Pellegrin [Bordeaux]-Neuroscience Institute, Génétique et Physiologie de l'Audition, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), ED 515 - Complexité du vivant, Université Pierre et Marie Curie - Paris 6 (UPMC), University of California [San Francisco] (UC San Francisco), University of California (UC), Columbia University [New York], Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre National de la Recherche Scientifique (CNRS), Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), SP and MC benefited from fellowships from the Ministry of National Education, Research and Technology of France, and PP from the European Union’s Horizon 2020 Marie Sklodowska-Curie grant 665807. This work was supported by European Research Council (ERC) advanced grant 'Hair bundle' (ERC-2011-AdG 294570), the European Union Seventh Framework Programme under grant agreement HEALTH-F2-2010-242013 (TREATRUSH), the French National Research Agency (ANR) as part of the second 'Investissements d’Avenir' programme (light4deaf, ANR-15-RHUS-0001), ANR-HearInNoise-(ANR-17-CE16-0017), LHW-Stiftung, FAUN Stiftung (Suchert Foundation), LABEX Life-senses (ANR-10-LABX-65), and a grant from the Fondation Pour l’Audition to DD (2015-APA Research Grant)., We thank Jean-Pierre Hardelin and Jacques Boutet de Monvel for critical reading of the manuscript., ANR-15-RHUS-0001,LIGHT4DEAF,ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER(2015), ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), European Project: 294570,EC:FP7:ERC,ERC-2011-ADG_20110310,HAIRBUNDLE(2012), European Project: 242013,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,TREATRUSH(2010), Neuroscience Institute-Université de Bordeaux ( UB ) -CHU de Bordeaux Pellegrin [Bordeaux]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Collège de France ( CdF ) -Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Biologie du fruit et pathologie ( BFP ), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique ( INRA ) -Université Sciences et Technologies - Bordeaux 1, Laboratoire Biochimie et Biologie Moléculaire ( LBBM ), Université Hassan II, Neuro-Dol ( Neuro-Dol ), Université d'Auvergne - Clermont-Ferrand I ( UdA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université d'Auvergne - Clermont-Ferrand I ( UdA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Neuro-Dol - Clermont Auvergne ( Neuro-Dol ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Clermont Auvergne ( UCA ) -Université Clermont Auvergne ( UCA ), Comité Français de la Semoulerie Industrielle ( CFSI ), Génétique et physiologie de l'audition, This work was supported by European Research Council (ERC) advanced grant 'Hair bundle' (ERC-2011-AdG 294570), the European Union Seventh Framework Programme under grant agreement HEALTH-F2-2010-242013 (TREATRUSH), the French National Research Agency (ANR) as part of the second 'Investissements d’Avenir' programme (light4deaf, ANR-15-RHUS-0001), ANR-HearInNoise-(ANR-17-CE16-0017), LHW-Stiftung, FAUN Stiftung (Suchert Foundation), LABEX Life-senses (ANR-10-LABX-65), and a grant from the Fondation Pour l’Audition to DD (2015-APA Research Grant)., ANR-15-RHUS-0001,LIGHT4DEAF,ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER ( 2015 ), ANR-17-CE16-0017,HearInNoise,Surdité d’apparition tardive et progressive: de la physiopathologie à la thérapie ( 2017 ), ANR-11-IDEX-0004-02/10-LABX-0065,LIFESENSES,DES SENS POUR TOUTE LA VIE ( 2011 ), European Project : 294570,EC:FP7:ERC,ERC-2011-ADG_20110310,HAIRBUNDLE ( 2012 ), European Project : 242013,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,TREATRUSH ( 2010 ), Neuroscience Institute-Université de Bordeaux (UB)-CHU de Bordeaux Pellegrin [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), University of California [San Francisco] (UCSF), University of California, Chaire Génétique et physiologie cellulaire, Oficjalska, Danuta, ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER - - LIGHT4DEAF2015 - ANR-15-RHUS-0001 - RHUS - VALID, Sorbonne Universités à Paris pour l'Enseignement et la Recherche - - SUPER2011 - ANR-11-IDEX-0004 - IDEX - VALID, Assembling the puzzle of the operating auditory hair bundle - HAIRBUNDLE - - EC:FP7:ERC2012-12-01 - 2017-11-30 - 294570 - VALID, and Fighting blindness of Usher syndrome: diagnosis, pathogenesis and retinal treatment (TreatRetUsher) - TREATRUSH - - EC:FP7:HEALTH2010-02-01 - 2014-01-31 - 242013 - VALID
Subjects: 0301 basic medicine, Calcium Channels, L-Type, Usher syndrome, PDZ domain, Cell Cycle Proteins, AMPA receptor, Ribbon synapse, Biology, 03 medical and health sciences, Mice, 0302 clinical medicine, Gene therapy, Postsynaptic potential, Hair Cells, Auditory, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, otorhinolaryngologic diseases, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Receptors, AMPA, Mice, Knockout, Gene Transfer Techniques, Membrane Proteins, General Medicine, Genetic Therapy, Dependovirus, medicine.disease, Cell biology, Cytoskeletal Proteins, Disease Models, Animal, Calcium channels, 030104 developmental biology, medicine.anatomical_structure, Knockout mouse, Synapses, Synaptopathy, Human medicine, Hair cell, [ SCCO ] Cognitive science, Carrier Proteins, Usher Syndromes, 030217 neurology & neurosurgery, Research Article, Neuroscience
Abstract: Clarin-1, a tetraspan-like membrane protein defective in Usher syndrome type IIIA (USH3A), is essential for hair bundle morphogenesis in auditory hair cells. We report a new synaptic role for clarin-1 in mouse auditory hair cells elucidated by characterization of Clrn1 total (Clrn1(ex4-/-)) and postnatal hair cell-specific conditional (Clrn1(ex4fl/fl) Myo15-Cre(+/-)) knockout mice. Clrn1(ex4-/-) mice were profoundly deaf, whereas Clrn1(ex4fl/fl) Myo15-Cre(+/-) mice displayed progressive increases in hearing thresholds, with, initially, normal otoacoustic emissions and hair bundle morphology. Inner hair cell (IHC) patch-clamp recordings for the 2 mutant mice revealed defective exocytosis and a disorganization of synaptic F-actin and Ca(V)1.3 Ca2+ channels, indicative of a synaptopathy. Postsynaptic defects were also observed, with an abnormally broad distribution of AMPA receptors associated with a loss of afferent dendrites and defective electrically evoked auditory brainstem responses. Protein-protein interaction assays revealed interactions between clarin-1 and the synaptic Ca(V)1.3 Ca2+ channel complex via the Ca-V beta(2) auxiliary subunit and the PDZ domain-containing protein harmonin (defective in Usher syndrome type IC). Cochlear gene therapy in vivo, through adeno-associated virus-mediated Clrn1 transfer into hair cells, prevented the synaptic defects and durably improved hearing in Clrn1(ex4fl/fl) Myo15-Cre(+/-) mice. Our results identify clarin-1 as a key organizer of IHC ribbon synapses, and suggest new treatment possibilities for USH3A patients.
Published: 2018
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11. Vestibular-evoked myogenic potential triggered by galvanic vestibular stimulation may reveal subclinical alterations in human T-cell lymphotropic virus type 1-associated myelopathy

Author: Luiz Cláudio Ferreira Romanelli, Kyonis Rodrigues Florentino, Fabrice Giraudet, Sirley Alves da Silva Carvalho, Paul Avan, Ludimila Labanca, Denise Utsch Gonçalves, José Roberto Lambertucci, Júlia Fonseca de Morais Caporali, Bárbara Oliveira Souza, Anna Barbara de Freitas Carneiro Proietti, Universidade Federal de Minas Gerais = Federal University of Minas Gerais [Belo Horizonte, Brazil] (UFMG), Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Federal University of Minas Gerais (UFMG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Neuro-Dol (Neuro-Dol), and Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)
Subjects: 0301 basic medicine, RNA viruses, Male, Physiology, [SDV]Life Sciences [q-bio], lcsh:Medicine, Pathology and Laboratory Medicine, Gastroenterology, Nervous System, Myelopathy, White Blood Cells, 0302 clinical medicine, Animal Cells, Medicine and Health Sciences, Human T cell lymphotropic virus type 1, lcsh:Science, Spinal cord injury, Musculoskeletal System, ComputingMilieux_MISCELLANEOUS, Subclinical infection, Human T-lymphotropic virus 1, Multidisciplinary, T Cells, Muscles, Gastrocnemius Muscles, virus diseases, Middle Aged, Vestibular Evoked Myogenic Potentials, Paraparesis, Tropical Spastic, 3. Good health, Electrophysiology, medicine.anatomical_structure, Bioassays and Physiological Analysis, Spinal Cord, Medical Microbiology, Viral Pathogens, Viruses, Female, Vestibule, Labyrinth, medicine.symptom, Pathogens, Cellular Types, Anatomy, Muscle Electrophysiology, Research Article, Adult, medicine.medical_specialty, Vestibular evoked myogenic potential, Immune Cells, Immunology, Surgical and Invasive Medical Procedures, Research and Analysis Methods, Asymptomatic, Microbiology, 03 medical and health sciences, Internal medicine, Retroviruses, medicine, Humans, Galvanic vestibular stimulation, Microbial Pathogens, Blood Cells, Biology and life sciences, Functional Electrical Stimulation, business.industry, Electromyography, lcsh:R, Electrophysiological Techniques, Organisms, Htlv-1, Cell Biology, medicine.disease, Spinal cord, Electric Stimulation, Neuroanatomy, 030104 developmental biology, lcsh:Q, business, 030217 neurology & neurosurgery, Neuroscience
Abstract: Background Vestibular-evoked myogenic potential triggered by galvanic vestibular stimulation (galvanic-VEMP) evaluates the motor spinal cord and identifies subclinical myelopathies. We used galvanic-VEMP to compare spinal cord function in individuals infected with human T-cell lymphotropic virus type 1 (HTLV-1) from asymptomatic status to HTLV-1-associated myelopathy (HAM). Methodology/Principal findings This cross-sectional study with 122 individuals included 26 HTLV-1-asymptomatic carriers, 26 individuals with possible HAM, 25 individuals with HAM, and 45 HTLV-1-seronegative individuals (controls). The groups were similar regarding gender, age, and height. Galvanic stimuli (duration: 400 ms; intensity: 2 mA) were applied bilaterally to the mastoid processes and VEMP was recorded from the gastrocnemius muscle. The electromyographic parameters investigated were the latency and amplitude of the short-latency (SL) and medium-latency (ML) responses. While SL and ML amplitudes were similar between groups, SL and ML latencies were delayed in the HTLV-1 groups compared to the control group (p
Published: 2018
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12. Rapid exhaustion of auditory neural conduction in a prototypical mitochondrial disease, Friedreich ataxia

Author: Alexandra Durr, Perrine Charles, T. Mom, Odile Boespflug-Tanguy, Paul Avan, Paul Deltenre, Fabrice Giraudet, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service ORL, Hôtel-Dieu, Génétique, Reproduction et Développement (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Ataxia, Adolescent, Mitochondrial disease, [SDV]Life Sciences [q-bio], Neural Conduction, Audiology, Intelligibility (communication), Nerve conduction velocity, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Time frame, Hearing, Auditory neuropathy spectrum disorder, Physiology (medical), Evoked Potentials, Auditory, Brain Stem, otorhinolaryngologic diseases, medicine, Humans, In patient, Child, ComputingMilieux_MISCELLANEOUS, business.industry, Speech Intelligibility, Auditory Threshold, Middle Aged, medicine.disease, Sensory Systems, 030104 developmental biology, Neurology, Friedreich Ataxia, Auditory Perception, Speech Perception, Audiometry, Pure-Tone, Female, sense organs, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: Objectives In patients with Friedreich ataxia (FRDA), mitochondrial failure leads to impaired cellular energetics. Since many FRDA patients have impaired hearing in noise, we investigated the objective consequences on standard auditory brainstem-evoked responses (ABRs). Methods In 37 FRDA patients, among whom 34 with abnormal standard ABRs, hearing sensitivity, speech-in-noise intelligibility and otoacoustic emissions were controlled. ABR recordings were split into four consecutive segments of the total time frame used for data collection, thus allowing the dynamics of ABR averaging to be observed. Results Most ears showed features of an auditory neuropathy spectrum disorder with flattened ABRs and impaired speech-in-noise intelligibility contrasting with near-normal hearing sensitivity and normal preneural responses. Yet split-ABRs revealed short-lived wave patterns in 26 out of 68 ears with flattened standard ABRs (38%). While averaging went on, the pattern of waves shifted so that interwave latencies increased by 35% on average. Conclusions In FRDA, the assumption of stationarity used for extracting standard ABRs is invalid. The preservation of early split-ABRs indicates no short-term dyssynchrony of action potentials. A large decrease in conduction velocity along auditory neurons occurs within seconds, attributed to fast energetic failure. Significance This model of metabolic sensory neuropathy warns against exposure of metabolically-impaired patients to sustained auditory stimulation.
Published: 2018
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13. Generalization of the primary tone phase variation method: An exclusive way of isolating the frequency-following response components

Author: Xiaoya Fan, Antoine Nonclercq, Paul Avan, Paul Deltenre, Federico Lucchetti, Fabrice Giraudet, Centre Hospitalier Universitaire Brugmann [Bruxelles] (CHU), Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Université libre de Bruxelles (ULB), Équipe Biophysique Neurosensorielle, Facultés de Médecine et de Pharmacie de Clermont-Ferrand, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Neuro-Dol (Neuro-Dol), and Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)
Subjects: Phase variation, Total harmonic distortion, Neurophysiologie, Acoustics and Ultrasonics, business.industry, [SDV]Life Sciences [q-bio], Multidisciplinary, general & others [C99] [Engineering, computing & technology], Pattern recognition, Spectral component, Stimulus (physiology), Frequency following response, 01 natural sciences, Multidisciplinaire, généralités & autres [C99] [Ingénierie, informatique & technologie], 03 medical and health sciences, 0302 clinical medicine, Amplitude, Auditory brainstem response, Arts and Humanities (miscellaneous), 0103 physical sciences, Time domain, Artificial intelligence, business, 010301 acoustics, 030217 neurology & neurosurgery, Mathematics
Abstract: The primary tone phase variation (PTPV) technique combines selective sub-averaging with systematic variation of the phases of multitone stimuli. Each response component having a known phase relationship with the stimulus components phases can be isolated in the time domain. The method was generalized to the frequency-following response (FFR) evoked by a two-tone (f1 and f2) stimulus comprising both linear and non-linear, as well as transient components. The generalized PTPV technique isolated each spectral component present in the FFR, including those sharing the same frequency, allowing comparison of their latencies. After isolation of the envelope component f2 - f1 from its harmonic distortion 2f2 - 2f1 and from the transient auditory brainstem response, a computerized analysis of instantaneous amplitudes and phases was applied in order to objectively determine the onset and offset latencies of the response components. The successive activation of two generators separated by 3.7 ms could be detected in all (N = 12) awake adult normal subjects, but in none (N = 10) of the sleeping/sedated children with normal hearing thresholds. The method offers an unprecedented way of disentangling the various FFR subcomponents. These results open the way for renewed investigations of the FFR components in both human and animal research as well as for clinical applications., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2018
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14. Transient Abnormalities in Masking Tuning Curve in Early Progressive Hearing Loss Mouse Model

Author: Souchal, Marion, Labanca, Ludimila, Alves da Silva Carvalho, Sirley, Macedo de Resende, Luciana, Blavignac, Christelle, Avan, Paul, Giraudet, Fabrice, Centre Imagerie Cellulaire Santé (CICS), Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université, Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])
Subjects: Male, 0301 basic medicine, Masking (art), medicine.medical_specialty, Article Subject, Tectorial membrane, [SDV]Life Sciences [q-bio], Otoacoustic Emissions, Spontaneous, Auditory neuropathy, Perceptual Masking, lcsh:Medicine, Audiology, General Biochemistry, Genetics and Molecular Biology, Stereocilia, Mice, 03 medical and health sciences, 0302 clinical medicine, Evoked Potentials, Auditory, Brain Stem, otorhinolaryngologic diseases, medicine, Animals, Hearing Loss, Cochlea, ComputingMilieux_MISCELLANEOUS, Absolute threshold of hearing, General Immunology and Microbiology, business.industry, lcsh:R, Auditory Threshold, General Medicine, medicine.disease, Disease Models, Animal, Hair Cells, Auditory, Outer, 030104 developmental biology, medicine.anatomical_structure, Synaptopathy, sense organs, Hair cell, business, 030217 neurology & neurosurgery, Research Article
Abstract: Damage to cochlear outer hair cells (OHCs) usually affects frequency selectivity in proportion to hearing threshold increase. However, the current clinical heuristics that attributes poor hearing performance despite near-normal auditory sensitivity to auditory neuropathy or “hidden” synaptopathy overlooks possible underlying OHC impairment. Here, we document the part played by OHCs in influencing suprathreshold auditory performance in the presence of noise in a mouse model of progressive hair cell degeneration, the CD1 strain, at postnatal day 18–30 stages when high-frequency auditory thresholds remained near-normal. Nonetheless, total loss of high-frequency distortion product otoacoustic emissions pointed to nonfunctioning basal OHCs. This “discordant profile” came with a huge low-frequency shift of masking tuning curves that plot the level of interfering sound necessary to mask the response to a probe tone, against interfering frequency. Histology revealed intense OHC hair bundle abnormalities in the basal cochlea uncharacteristically associated with OHC survival and preserved coupling with the tectorial membrane. This pattern dismisses the superficial diagnosis of “hidden” neuropathy while underpinning a disorganization of cochlear frequency mapping with optimistic high-frequency auditory thresholds perhaps because responses to high frequencies are apically shifted. The audiometric advantage of frequency transposition is offset by enhanced masking by low-frequency sounds, a finding essential for guiding rehabilitation.
Published: 2018
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15. Diagnostic and therapeutic strategy in Menière's disease. Guidelines of the French Otorhinolaryngology-Head and Neck Surgery Society (SFORL)

Author: Thierry Mom, Groupe de Travail de la Sforl, Vincent Darrouzet, Cécile Parietti-Winkler, Alain Uziel, Xavier Dubernard, Vincent Couloigner, Valérie Franco-Vidal, Jerome Nevoux, Didier Bouccara, André Chays, Service d’ORL et de chirurgie cervico-faciale [CHU Le Kremlin-Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), CHU de Bordeaux Pellegrin [Bordeaux], Réhabilitation Chirurgicale mini-Invasive et Robotisée de l'Audition, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Développement, Adaptation et Handicap. Régulations cardio-respiratoires et de la motricité. ( DevAH ), Université de Lorraine ( UL ), Service d'ORL, Hôpital Gui de Chauliac ( CHRU de Montpellier ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Centre Hospitalier Universitaire de Reims ( CHU Reims ), CHU Necker - Enfants Malades [AP-HP], Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol ( Neuro-Dol ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université d'Auvergne - Clermont-Ferrand I ( UdA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université d'Auvergne - Clermont-Ferrand I ( UdA ) -Neuro-Dol - Clermont Auvergne ( Neuro-Dol ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Clermont Auvergne ( UCA ) -Université Clermont Auvergne ( UCA ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Institut National de la Santé et de la Recherche Médicale (INSERM), Développement, Adaptation et Handicap. Régulations cardio-respiratoires et de la motricité (DevAH), Université de Lorraine (UL), Service d'Oto-Rhino-Laryngologie et de Chirurgie Cervico-Faciale [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service ORL [Hôpital Gui de Chauliac] (CHRU de Montpellier), Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Universitaire de Reims (CHU Reims), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'ORL, Hôpital Gui de Chauliac (CHRU de Montpellier), and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
Subjects: medicine.medical_specialty, Diagnostic criteria, [SDV]Life Sciences [q-bio], Disease, Otolaryngology, 03 medical and health sciences, 0302 clinical medicine, Humans, Medicine, Betahistine, Medical diagnosis, 030223 otorhinolaryngology, Meniere Disease, Societies, Medical, Therapeutic strategy, [ SDV ] Life Sciences [q-bio], business.industry, General surgery, Neurotomy, medicine.disease, Denervation, 3. Good health, Surgery, Treatment, Treatment Outcome, Otorhinolaryngology, Diagnostic tests, Head and neck surgery, France, Vestibule, Labyrinth, Otologic Surgical Procedures, business, Menière's disease, 030217 neurology & neurosurgery, medicine.drug, Meniere's disease
Abstract: Objectives The authors present the guidelines of the French Otorhinolaryngology-Head and Neck Surgery Society ( Societe francaise d’oto-rhino-laryngologie et de chirurgie de la face et du cou : SFORL) for diagnostic and therapeutic strategy in Meniere's disease. Methods A work group was entrusted with a review of the scientific literature on the above topic. Guidelines were drawn up, then read over by an editorial group independent of the work group. The guidelines were graded according to the literature analysis and recommendations grading guide published by the French National Agency for Accreditation and Evaluation in Health (January 2000). Results Meniere's disease is diagnosed in the presence of the association of four classical clinical items and after eliminating differential diagnoses on MRI. In case of partial presentation, objective audiovestibular tests are recommended. Therapy comprises medical treatment and surgery, either conservative or sacrificing vestibular function. Medical treatment is based on lifestyle improvement, betahistine, diuretics or transtympanic injection of corticosteroids or gentamicin. The main surgical treatments, in order of increasing aggressiveness, are endolymphatic sac surgery, vestibular neurotomy and labyrinthectomy.
Published: 2017
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16. CIB2, defective in isolated deafness, is key for auditory hair cell mechanotransduction and survival

Author: Michel, Vincent, Booth, Kevin T, Patni, Pranav, Cortese, Matteo, Azaiez, Hela, Bahloul, Amel, Kahrizi, Kimia, Labbé, Ménélik, Emptoz, Alice, Lelli, Andrea, Dégardin, Julie, Dupont, Typhaine, Aghaie, Asadollah, Oficjalska‐Pham, Danuta, Picaud, Serge, Najmabadi, Hossein, Smith, Richard J, Bowl, Michael R, Brown, Steven DM, Avan, Paul, Petit, Christine, El‐Amraoui, Aziz, Génétique et Physiologie de l'Audition, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), University of Iowa [Iowa City], University of Social Welfare and Rehabilitation Sciences [Tehran], Institut de la Vision, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), MRC Harwell, Laboratoire de Biophysique sensorielle, Université d'Auvergne - Clermont-Ferrand I (UdA), CHAUVET, Laurence, Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Neuro-Dol (Neuro-Dol), and Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)
Subjects: Male, Cell Survival, [SDV]Life Sciences [q-bio], Deafness, Gene Therapy & Genetic Disease, Eye, Mechanotransduction, Cellular, Polymorphism, Single Nucleotide, Retina, Mice, human and mouse deafness, otorhinolaryngologic diseases, CIB proteins, Animals, Humans, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Maze Learning, Research Articles, Mice, Knockout, Hair Cells, Auditory, Inner, Usher syndrome diagnosis Subject Categories Genetics, Behavior, Animal, Calcium-Binding Proteins, Membrane Proteins, Auditory Threshold, Pedigree, Mice, Inbred C57BL, [SDV] Life Sciences [q-bio], Disease Models, Animal, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Female, Genetics, Gene Therapy & Genetic Disease, sense organs, Usher syndrome diagnosis, Research Article, Neuroscience
Abstract: International audience; Defects of CIB2, calcium-and integrin-binding protein 2, have been reported to cause isolated deafness, DFNB48 and Usher syndrome type-IJ, characterized by congenital profound deafness, balance defects and blindness. We report here two new nonsense mutations (pGln12* and pTyr110*) in CIB2 patients displaying nonsyn-dromic profound hearing loss, with no evidence of vestibular or retinal dysfunction. Also, the generated CIB2 À/À mice display an early onset profound deafness and have normal balance and reti-nal functions. In these mice, the mechanoelectrical transduction currents are totally abolished in the auditory hair cells, whilst they remain unchanged in the vestibular hair cells. The hair bundle morphological abnormalities of CIB2 À/À mice, unlike those of mice defective for the other five known USH1 proteins, begin only after birth and lead to regression of the stereocilia and rapid hair-cell death. This essential role of CIB2 in mechanotransduction and cell survival that, we show, is restricted to the cochlea, probably accounts for the presence in CIB2 À/À mice and CIB2 patients, unlike in Usher syndrome, of isolated hearing loss without balance and vision deficits.
Published: 2017
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17. Noninvasive detection of alarming intracranial pressure changes by auditory monitoring in early management of brain injury: a prospective invasive versus noninvasive study

Author: Fabrice Giraudet, Aurélien Mulliez, Laurent Sakka, Bruno Pereira, Aurélie Thalamy, François Longeras, Paul Avan, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Service de Neurochirurgie [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Service de Neurochirurgie [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Gabriel Montpied [Clermont-Ferrand], and CHU Clermont-Ferrand
Subjects: 0301 basic medicine, Adult, Male, medicine.medical_specialty, Intracranial Pressure, Organ Dysfunction Scores, [SDV]Life Sciences [q-bio], Critical Care and Intensive Care Medicine, 03 medical and health sciences, 0302 clinical medicine, Cerebrospinal fluid, medicine, Humans, Prospective Studies, ComputingMilieux_MISCELLANEOUS, Intracranial pressure, Monitoring, Physiologic, integumentary system, business.industry, musculoskeletal, neural, and ocular physiology, Research, Brain, Cochlear electrophysiology, Fluid compartments, Middle Aged, humanities, 3. Good health, Surgery, nervous system diseases, Electrophysiological Phenomena, Intensive Care Units, 030104 developmental biology, ROC Curve, Brain Injuries, Breathing, Linear Models, Female, Radiology, business, Cochlear microphonic potential, Noninvasive monitoring, 030217 neurology & neurosurgery
Abstract: Background In brain-injured patients intracranial pressure (ICP) is monitored invasively by a ventricular or intraparenchymal transducer. The procedure requires specific expertise and exposes the patient to complications such as malposition, hemorrhage or infection. As inner-ear fluid compartments are connected to the cerebrospinal fluid space, ICP changes elicit subtle changes in the physiology of the inner ear. Notably, we previously demonstrated that the phase of cochlear microphonic potential (CM) generated by sound stimuli rotates with ICP. The aim of our study was to validate the monitoring of CM as a noninvasive method to follow ICP. Methods Non-invasive measure of CM-phase was compared to ICP recorded invasively in a prospective series of patients with acute brain injury managed in a neuro-intensive care unit. The study focused on patients with varying ICP and normal middle-ear function. Results In the 24 patients with less than 4 days of endotracheal ventilation and whose ICP fluctuated (50-hour data), we demonstrated close correlation between CM-phase rotation and ICP (average 1.26 degrees/mmHg). As a binary classifier, CM phase changes of 7–10 degrees signaled 7.5-mmHg ICP increases with a sensitivity of 83% and 19% fallout. Conclusion Reference methods to measure ICP require the surgical placement of a pressure transducer. Noninvasive CM-based monitoring of ICP might be beneficial to early management of brain-injured patients with initially preserved consciousness and to the diagnosis of neurological conditions, whenever invasive monitoring cannot be performed. Trial registration ClinicalTrials.gov NCT01685476, registered on 30 August 2012. Electronic supplementary material The online version of this article (doi:10.1186/s13054-017-1616-2) contains supplementary material, which is available to authorized users.
Published: 2017
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18. Non-invasive intraoperative monitoring of cochlear function by cochlear microphonics during cerebellopontine-angle surgery

Author: Toufic Khalil, Stéphane Tringali, André Chays, Paul Avan, Béatriz Madero, Xavier Dubernard, A. Bazin, Thierry Mom, Blandine Lourenço, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Service de Neurochirurgie [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Laboratoire des technologies de la microélectronique (LTM ), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Service ORL, Hôtel-Dieu, Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Service de Neurologie [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand, Centre Hospitalier Universitaire de Reims (CHU Reims), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Service de Neurochirurgie [Clermont-Ferrand], and CHU Clermont-Ferrand-CHU Gabriel Montpied [Clermont-Ferrand]
Subjects: Adult, Male, medicine.medical_specialty, Hearing loss, [SDV]Life Sciences [q-bio], Ischemia, Cerebellopontine Angle, Neurosurgical Procedures, 03 medical and health sciences, 0302 clinical medicine, Postoperative Complications, Trigeminal neuralgia, Monitoring, Intraoperative, otorhinolaryngologic diseases, medicine, Humans, Single-Blind Method, 030223 otorhinolaryngology, Hearing Loss, Intraoperative Complications, ComputingMilieux_MISCELLANEOUS, Aged, business.industry, Cochlear nerve, General Medicine, Neuroma, Acoustic, Middle Aged, medicine.disease, Cerebellopontine angle, Surgery, Cochlea, Dissection, Treatment Outcome, Otorhinolaryngology, Female, sense organs, Neurosurgery, medicine.symptom, business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: In vestibular-schwannoma (VS) surgery, hearing-preservation rate remains low. Besides damage to the cochlear nerve, intraoperative cochlear ischemia is a potential cause of hearing loss. Here, we used non-invasive cochlear microphonic (CM) recordings to detect the cochlear vascular events of VS surgery. Continuous intraoperative CM monitoring, in response to 80–95 dB SPL, 1-kHz tone-bursts, was performed in two samples of patients undergoing retrosigmoid cerebellopontine-angle surgery: one for VS (n = 31) and one for vestibular neurectomy or vasculo-neural conflict causing intractable trigeminal neuralgia, harmless to hearing (n = 19, control group). Preoperative and postoperative hearings were compared as a function of intraoperative CM changes and their chronology. Monitoring was possible throughout except for a few tens of seconds when drilling or suction noises occurred. Four patterns of CM time course were identified, eventless, fluctuating, abrupt or progressive decrease. Only the VS group displayed the last two patterns, mainly during internal-auditory-canal drilling and the ensuing tumor dissection, always with postoperative loss of hearing as an end result. Conversely, eventless and fluctuating CM patterns could be associated with postoperative hearing loss when the cochlear nerve had been reportedly damaged, an event that CM is not meant to detect. Cochlear ischemia is a frequent event in VS surgery that leads to deafness. The findings that CM decrease raised no false alarm, and that CM fluctuations, insignificant in control cases, were easily spotted, suggest that CM intraoperative monitoring is a sensitive tool that could profitably guide VS surgery.
Published: 2017
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19. Resistance of Gerbil Auditory Function to Reversible Decrease in Cochlear Blood Flow

Author: Laurent Gilain, Fabrice Giraudet, Thierry Mom, Paul Avan, Fahd El Afia, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Service ORL, Hôtel-Dieu, Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])
Subjects: Physiology, [SDV]Life Sciences [q-bio], Threshold elevation, Gerbil, Cochlear function, 03 medical and health sciences, Speech and Hearing, 0302 clinical medicine, Hearing, Cochlear blood flow, otorhinolaryngologic diseases, Animals, Auditory function, 030223 otorhinolaryngology, Cochlea, ComputingMilieux_MISCELLANEOUS, Chemistry, Auditory Threshold, Anatomy, Sensory Systems, Round Window, Ear, nervous system, Otorhinolaryngology, Regional Blood Flow, Cochlear Microphonic Potentials, sense organs, Gerbillinae, Cochlear microphonic potential, 030217 neurology & neurosurgery, circulatory and respiratory physiology, Biomedical engineering
Abstract: The objective was to design in gerbils a model of reversible decrease in cochlear blood flow (CBF) and analyze its influence on cochlear function. In Mongolian gerbils injected with ferromagnetic microbeads, a magnet placed near the porus acusticus allowed CBF to be manipulated. The cochlear microphonic potential (CM) from the basal cochlea was monitored by a round-window electrode. In 13 of the 20 successfully injected gerbils, stable CBF reduction was obtained for 11.5 min on average. The CM was affected only when CBF fell to less than 60% of its baseline, yet remained >40% of its initial level in about 2/3 of such cases. After CBF restoration, CM recovery was fast and usually complete. Reduced CM came with a 35- to 45-dB threshold elevation of neural responses determined by compound action potentials. This method allowing reversible changes of CBF confirms the robustness of cochlear function to decreased CBF. It can be used to study whether a hypovascularized cochlea is abnormally sensitive to stress.
Published: 2017
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20. Local gene therapy durably restores vestibular function in a mouse model of Usher syndrome type 1G

Author: Alice, Emptoz, Vincent, Michel, Andrea, Lelli, Omar, Akil, Jacques, Boutet de Monvel, Ghizlene, Lahlou, Anaïs, Meyer, Typhaine, Dupont, Sylvie, Nouaille, Elody, Ey, Filipa, Franca de Barros, Mathieu, Beraneck, Didier, Dulon, Jean-Pierre, Hardelin, Lawrence, Lustig, Paul, Avan, Christine, Petit, Saaid, Safieddine, Génétique et Physiologie de l'Audition, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), ED 515 - Complexité du vivant, Université Pierre et Marie Curie - Paris 6 (UPMC), University of California [San Francisco] (UC San Francisco), University of California (UC), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre de neurophysique, physiologie, pathologie (UMR 8119), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Neurophysiologie de la Synapse Auditive, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU de Bordeaux Pellegrin [Bordeaux]-Neuroscience Institute, Columbia University [New York], Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), This work was supported by Fondation pour la Recherche Médicale (A.E.), the European UnionSeventh Framework Programme under the grant agreement HEALTH-F2-2010-242013 (TREATRUSH), the European Commission (ERC-2011-ADG_294570), French state funds managed by Agence Nationale de la Recherche within theInvestissements d’Avenir Programme (ANR-15-RHUS-0001), LabEx Lifesenses(ANR-10-LABX-65), and grants from the BNP Paribas Foundation, the FAUN-Stiftung, the LHW-Stiftung, and Errera Hoechstetter., ANR-15-RHUS-0001,LIGHT4DEAF,ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER(2015), ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), European Project: 242013,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,TREATRUSH(2010), European Project: 294570,EC:FP7:ERC,ERC-2011-ADG_20110310,HAIRBUNDLE(2012), CHAUVET, Laurence, ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER - - LIGHT4DEAF2015 - ANR-15-RHUS-0001 - RHUS - VALID, Sorbonne Universités à Paris pour l'Enseignement et la Recherche - - SUPER2011 - ANR-11-IDEX-0004 - IDEX - VALID, Fighting blindness of Usher syndrome: diagnosis, pathogenesis and retinal treatment (TreatRetUsher) - TREATRUSH - - EC:FP7:HEALTH2010-02-01 - 2014-01-31 - 242013 - VALID, Assembling the puzzle of the operating auditory hair bundle - HAIRBUNDLE - - EC:FP7:ERC2012-12-01 - 2017-11-30 - 294570 - VALID, Chaire Génétique et physiologie cellulaire, University of California [San Francisco] (UCSF), University of California, Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)
Subjects: DNA, Complementary, [SDV]Life Sciences [q-bio], Genetic Vectors, Nerve Tissue Proteins, Mice, Hair Cells, Auditory, Evoked Potentials, Auditory, Brain Stem, otorhinolaryngologic diseases, Animals, Humans, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, gene, mouse, Mice, Knockout, therapy, balance, Genetic Therapy, Dependovirus, Biological Sciences, [SDV] Life Sciences [q-bio], Disease Models, Animal, Animals, Newborn, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Microscopy, Electron, Scanning, Vestibule, Labyrinth, sense organs, Usher Syndromes, Usher
Abstract: International audience; Our understanding of the mechanisms underlying inherited forms of inner ear deficits has considerably improved during the past 20 y, but we are still far from curative treatments. We investigated gene replacement as a strategy for restoring inner ear functions in a mouse model of Usher syndrome type 1G, characterized by congenital profound deafness and balance disorders. These mice lack the scaffold protein sans, which is involved both in the morphogenesis of the stereociliary bundle, the sensory antenna of inner ear hair cells, and in the mechanoelectrical transduction process. We show that a single delivery of the sans cDNA by the adenoassociated virus 8 to the inner ear of newborn mutant mice reestablishes the expression and targeting of the protein to the tips of stereocilia. The therapeutic gene restores the architecture and mechanosensi-tivity of stereociliary bundles, improves hearing thresholds, and durably rescues these mice from the balance defects. Our results open up new perspectives for efficient gene therapy of cochlear and vestibular disorders by showing that even severe dysmorphogenesis of stereociliary bundles can be corrected. gene | therapy | balance | mouse | Usher
Published: 2017
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21. Auditory cortex interneuron development requires cadherins operating hair-cell mechanoelectrical transduction

Author: Libé-Philippot, Baptiste, Vittot, Michel, Boutet de Monvel, Jacques, Le Gal, Sébastien, Dupont, Typhaine, Avan, Paul, Métin, Christine, Michalski, Nicolas, Petit, Christine, Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Institut du Fer à Moulin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de la Vision, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This work was supported by PhD funding from the French Ministry of Research allocated by the Ecole Normale Supérieure (Paris) (to B.L.-P.), the Prix Emergence and the SEIZEAR grant of the Agir Pour l’Audition foundation (to N.M.), and by grants from the ANR as part of the second Investissements d’Avenir program LIGHT4DEAF (ANR-15-RHUS-0001) and LabEx LIFESENSES (ANR-10-LABX-65), the European Research Council (ERC-2011-ADG_294570 to C.P.), BNP Paribas Foundation, FAUN-Stiftung, and LHW-Stiftung., We thank M. Bosch Grau, S. Chardenoux, A. Emptoz, C. Leclech, D. Oficjalska, M. Pedraza Boti, E. Pepermans, C. Trébeau, and D. Weil for assistance with this project, and J.-P. Hardelin for his important contribution to the writing of the manuscript. We thank S. Etienne-Manneville (Institut Pasteur, Paris) and S. Garel (Ecole Normale Supérieure, Paris) for advice. We thank G. Lepousez (Institut Pasteur, Paris) and N. Renier (Institut du Cerveau et de la Moelle Epinière, Paris) for critical reading of the manuscript. We thank C. Dehay (PrimaLyon Platform, Institut Cellule Souche et Cerveau, INSERM, Bron, France), N. Kessaris (University College London, London), and M. Sato (University of Fukui, Fukui, Japan) for sharing brain sections from macaque embryos, Nkx2.1-cre:Rosa-tdTomato mice, and Adgrv1tm1Msat mice, respectively. We acknowledge the Imagopole/Citech facility (Institut Pasteur, Paris), which is part of the France BioImaging infrastructure supported by the French Agence Nationale pour la Recherche (ANR-10-INSB-04-01, Investissements d’Avenir program), for the use of its microscopes, ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), ANR-15-RHUS-0001,LIGHT4DEAF,ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER(2015), European Project: 294570,EC:FP7:ERC,ERC-2011-ADG_20110310,HAIRBUNDLE(2012), Chaire Génétique et physiologie cellulaire, michalski, nicolas, Sorbonne Universités à Paris pour l'Enseignement et la Recherche - - SUPER2011 - ANR-11-IDEX-0004 - IDEX - VALID, ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER - - LIGHT4DEAF2015 - ANR-15-RHUS-0001 - RHUS - VALID, and Assembling the puzzle of the operating auditory hair bundle - HAIRBUNDLE - - EC:FP7:ERC2012-12-01 - 2017-11-30 - 294570 - VALID
Subjects: Auditory Cortex, Male, neuronal migration, tip links, Cadherin Related Proteins, Cell Polarity, Biological Sciences, Cadherins, Mechanotransduction, Cellular, Receptors, G-Protein-Coupled, Mice, adhesion code, nervous system, parvalbumin interneurons, Interneurons, deafness, Animals, Macaca, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Protein Precursors
Abstract: International audience; Many genetic forms of congenital deafness affect the sound reception antenna of cochlear sensory cells, the hair bundle. The resulting sensory deprivation jeopardizes auditory cortex (AC) maturation. Early prosthetic intervention should revive this process. Nevertheless, this view assumes that no intrinsic AC deficits coexist with the cochlear ones, a possibility as yet unexplored. We show here that many GABAergic interneurons, from their generation in the medial ganglionic eminence up to their settlement in the AC, express two cadherin-related (cdhr) proteins, cdhr23 and cdhr15, that form the hair bundle tip links gating the mechanoelectrical transduction channels. Mutant mice lacking either protein showed a major decrease in the number of parvalbumin interneurons specifically in the AC, and displayed audiogenic reflex seizures. Cdhr15- and Cdhr23-expressing interneuron precursors in Cdhr23(-/-) and Cdhr15(-/-) mouse embryos, respectively, failed to enter the embryonic cortex and were scattered throughout the subpallium, consistent with the cell polarity abnormalities we observed in vitro. In the absence of adhesion G protein-coupled receptor V1 (adgrv1), another hair bundle link protein, the entry of Cdhr23- and Cdhr15-expressing interneuron precursors into the embryonic cortex was also impaired. Our results demonstrate that a population of newborn interneurons is endowed with specific cdhr proteins necessary for these cells to reach the developing AC. We suggest that an "early adhesion code" targets populations of interneuron precursors to restricted neocortical regions belonging to the same functional area. These findings open up new perspectives for auditory rehabilitation and cortical therapies in patients.
Published: 2017
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22. Jugular and Portal Vein Volume, Middle Cerebral Vein Velocity, and Intracranial Pressure in Dry Immersion

Author: Kathryn Zuj, Philippe Arbeille, Hervé Normand, Loïc Treffel, Paul Avan, Pierre Denise, Nuclear Medicine and Ultrasonography [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, University of Western Ontario (UWO), Mobilités : Vieillissement, Pathologie, Santé (COMETE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Neuro-Dol (Neuro-Dol), and Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)
Subjects: Adult, Male, Intracranial Pressure, Ultrasonography, Doppler, Transcranial, [SDV]Life Sciences [q-bio], Portal vein, Fluid shift, Spaceflight, law.invention, 03 medical and health sciences, 0302 clinical medicine, Imaging, Three-Dimensional, law, Jugular vein, medicine, Humans, Fluid Shifts, Weightlessness Simulation, Intracranial pressure, business.industry, Portal Vein, Thyroid, General Medicine, Organ Size, Space Flight, 16. Peace & justice, Cerebral Veins, Healthy Volunteers, Transcranial Doppler, Cochlea, medicine.anatomical_structure, Acoustic Stimulation, 030220 oncology & carcinogenesis, Anesthesia, Aerospace Medicine, Jugular Veins, Nuclear medicine, business, 030217 neurology & neurosurgery, Blood Flow Velocity, Middle cerebral vein
Abstract: BACKGROUND The objective was to determine if short term exposure to dry immersion (DI) results in a cephalic fluid shift similar to what has been observed with spaceflight. METHODS Data were collected from 10 individuals at rest and during the first 2 h of dry immersion. Jugular vein (JV), portal vein (PV), and thyroid volume were measured using 3D echography. Middle cerebral vein velocity (MCVv) was determined using transcranial Doppler ultrasound. The cochlear response to audio stimulation was used to derive an estimate of intracranial pressure (dICP). RESULTS After 2 h of DI, there was a significant increase (mean ± SD) in JV (2.21 ± 1.10 mL), PV (1.05 ± 0.48 mL), and thyroid (0.428 ± 0.313 mL) volume. MCVv was also significantly increased with DI (3.90 ± 5.03 cm · s-1). There was no change in dICP with DI in part due to large individual variability. The range of dICP changes appeared to be related to MCVv, with participants with the largest increase in MCVv also showing increased dICP. DISCUSSION The results suggest that DI induces a significant cephalic fluid shift similar to what is observed with spaceflight. The increased thyroid volume suggests that cerebral tissue may also be subjected to similar fluid filtration, with implications for changes in intracranial pressure. However, despite all participants having an increase in JV and thyroid volume, only half showed an increase in dICP, suggesting that increased venous pooling alone is not sufficient to cause increased intracranial pressure.Arbeille P, Avan P, Treffel L, Zuj K, Normand H, Denise P. Jugular and portal vein volume, middle cerebral vein velocity, and intracranial pressure in dry immersion. Aerosp Med Hum Perform. 2017; 88(5):457-462.
Published: 2017
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23. Mice with a deletion of the major central myelin protein exhibit hypersensitivity to noxious thermal stimuli: involvement of central sensitization

Author: Fabrice Giraudet, Mélina Bégou, Bérengère Petit, Laurent Bardin, Paul Avan, Odile Boespflug-Tanguy, Céline Béchon, Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre de Recherche Pierre Fabre (Centre de R&D Pierre Fabre), PIERRE FABRE, Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de référence des leucodystrophies et leucoencéphalopathies de cause rare [AP-HP Hôpital Robert-Debré] (LEUKOFRANCE), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré
Subjects: Male, Pain Threshold, Pathology, medicine.medical_specialty, Hot Temperature, Proteolipid protein 1, Central nervous system, Neural Conduction, Pain, Motor Activity, Somatosensory system, lcsh:RC321-571, H-Reflex, Mice, Myelin, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Evoked Potentials, Somatosensory, medicine, Animals, Transgenic mice, Galanin, Myelin Proteolipid Protein, Dysmyelinating disease, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Sequence Deletion, Mice, Knockout, Central Nervous System Sensitization, business.industry, Multiple sclerosis, Age Factors, Central sensitization, Evoked Potentials, Motor, Spinal cord, medicine.disease, Sciatic Nerve, Mice, Inbred C57BL, medicine.anatomical_structure, Spinal Cord, Neurology, Hyperalgesia, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Conditioning, Operant, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Sciatic nerve, business, Neuroscience
Abstract: Null mutations in the gene encoding the major myelin protein of the central nervous system, proteolipid protein 1 ( PLP1 ), cause an X-linked form of spastic paraplegia (SPG2) associated with axonal degeneration. While motor symptoms are the best known manifestations of this condition, its somatosensory disturbances have been described but poorly characterized. We carried out a longitudinal study in an animal model of SPG2 — mice carrying a deletion of the Plp1 gene (Plp-null mice). Plp-null mice exhibited severe early-onset thermal hyperalgesia, in the absence of thermal allodynia. We first performed an electrophysiological testing which showed an early decrease in peripheral and spinal conduction velocities in Plp null mice. Such as the abnormal sensitive behaviors, this slowing of nerve conduction was observed before the development of myelin abnormalities at the spinal level, from 3 months of age, and without major morphological defects in the sciatic nerve. To understand the link between a decrease in nerve velocity and an increased response to thermal stimuli before the appearance of myelin abnormalities, we focused our attention on the dorsal horn of the spinal cord, the site of integration of somatosensory information. Immunohistochemical studies revealed an early-onset activation of astrocytes and microglia that worsened with age, associated later in age with perturbation of the expression of the sensory neuropeptides calcitonin-gene-related peptide and galanin. Taken together, these results represent complementary data supporting the hypothesis that Plp-null mice suffer from ganglionopathy associated with late onset central demyelination but with few peripheral nerve alterations, induced by the glial-cell-mediated sensitization of the spinal cord. The mechanism suggested here could underlie pain experiments in other leukodystrophies as well as in other non-genetic demyelinating diseases such as multiple sclerosis.
Published: 2014
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24. Amyloid Precursor-Like Protein 2 deletion-induced retinal synaptopathy related to congenital stationary night blindness: structural, functional and molecular characteristics

Author: Marc Abitbol, Virginie Dinet, Roberto Cappai, Yvan Arsenijevic, Na An, Francine Behar-Cohen, Mohamed El Sanharawi, Giuseppe D. Ciccotosto, Laurent Jonet, Frédéric Mascarelli, Céline Borras, Michèle Savoldelli, Kimberley Delaunay, Corinne Kostic, Caroline Pirou, Isabelle Ranchon-Cole, BMC, BMC, Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Pathology [Melbourne, Australie], University of Melbourne-Bio21 Molecular Science & Biotechnology Institute [Melbourne] (School of Chemistry), Faculty of Science [Melbourne], University of Melbourne-University of Melbourne-Faculty of Science [Melbourne], University of Melbourne, Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Unit of Gene Therapy & Stem Cell Biology [Lausanne, Suisse], Université de Lausanne = University of Lausanne (UNIL)-Fondation Asile des aveugles - Hôpital Ophtalmique Jules-Gonin [Lausanne], This work was supported by the National Health and Medical Research Council(NHMRC) to RC., Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UP7) - École pratique des hautes études (EPHE) - Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Université Pierre et Marie Curie - Paris 6 (UPMC), Bio21 Institute [Melbourne, Australie], Laboratoire de Biophysique Sensorielle, Université d'Auvergne - Clermont-Ferrand I, Unit of Gene Therapy & Stem Cell Biology, University of Lausanne, Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), University of Melbourne-Bio21 Institute [Melbourne, Australie], Neuro-Dol ( Neuro-Dol ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université d'Auvergne - Clermont-Ferrand I ( UdA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université d'Auvergne - Clermont-Ferrand I ( UdA ) -Neuro-Dol - Clermont Auvergne ( Neuro-Dol ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Clermont Auvergne ( UCA ) -Université Clermont Auvergne ( UCA ), Université de Lausanne - UML [Suisse]-Fondation Asile des aveugles - Hôpital Ophtalmique Jules-Gonin [Lausanne, Suisse], Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA), and Université de Lausanne (UNIL)-Fondation Asile des aveugles - Hôpital Ophtalmique Jules-Gonin [Lausanne]
Subjects: 0301 basic medicine, Retinal degeneration, Aging, genetic structures, Transcription, Genetic, [SDV]Life Sciences [q-bio], Ribbon synapse, Synaptic Transmission, chemistry.chemical_compound, Amyloid beta-Protein Precursor, Night Blindness, Amyloid precursor protein, Myopia, Congenital stationary night blindness, Mice, Knockout, biology, Cell Differentiation, Eye Diseases, Hereditary, Genetic Diseases, X-Linked, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Synaptopathy, Differentiation, Aging/pathology, Amacrine Cells/metabolism, Amyloid beta-Protein Precursor/chemistry, Amyloid beta-Protein Precursor/deficiency, Amyloid beta-Protein Precursor/genetics, Amyloid beta-Protein Precursor/metabolism, Animals, Animals, Newborn, Complement System Proteins/metabolism, Dendrites/metabolism, Eye Diseases, Hereditary/genetics, Eye Diseases, Hereditary/pathology, Eye Diseases, Hereditary/physiopathology, Gene Deletion, Genetic Diseases, X-Linked/genetics, Genetic Diseases, X-Linked/pathology, Genetic Diseases, X-Linked/physiopathology, Mice, Inbred C57BL, Myopia/genetics, Myopia/pathology, Myopia/physiopathology, Neurogenesis, Night Blindness/genetics, Night Blindness/pathology, Night Blindness/physiopathology, Photoreceptor Cells, Vertebrate/metabolism, Photoreceptor Cells, Vertebrate/pathology, Photoreceptor Cells, Vertebrate/ultrastructure, Presynaptic Terminals/metabolism, Presynaptic Terminals/ultrastructure, RNA, Messenger/genetics, RNA, Messenger/metabolism, Retinal Bipolar Cells/metabolism, Retinal Bipolar Cells/pathology, Retinal Bipolar Cells/ultrastructure, Transcription Factors/metabolism, Amyloid precursor-like protein 2, Synapses, Transcription, Photoreceptor Cells, Vertebrate, Retinal Bipolar Cells, Presynaptic Terminals, 03 medical and health sciences, Cellular and Molecular Neuroscience, Night vision, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, Molecular Biology, Retina, [ SDV ] Life Sciences [q-bio], Research, Retinal, Complement System Proteins, Dendrites, Inner plexiform layer, medicine.disease, 030104 developmental biology, Amacrine Cells, chemistry, biology.protein, sense organs, Neuroscience, Transcription Factors
Abstract: Background Amyloid precursor protein knockout mice (APP-KO) have impaired differentiation of amacrine and horizontal cells. APP is part of a gene family and its paralogue amyloid precursor-like protein 2 (APLP2) has both shared as well as distinct expression patterns to APP, including in the retina. Given the impact of APP in the retina we investigated how APLP2 expression affected the retina using APLP2 knockout mice (APLP2-KO). Results Using histology, morphometric analysis with noninvasive imaging technique and electron microscopy, we showed that APLP2-KO retina displayed abnormal formation of the outer synaptic layer, accompanied with greatly impaired photoreceptor ribbon synapses in adults. Moreover, APLP2-KO displayed a significant decease in ON-bipolar, rod bipolar and type 2 OFF-cone bipolar cells (36, 21 and 63 %, respectively). Reduction of the number of bipolar cells was accompanied with disrupted dendrites, reduced expression of metabotropic glutamate receptor 6 at the dendritic tips and alteration of axon terminals in the OFF laminae of the inner plexiform layer. In contrast, the APP-KO photoreceptor ribbon synapses and bipolar cells were intact. The APLP2-KO retina displayed numerous phenotypic similarities with the congenital stationary night blindness, a non-progressive retinal degeneration disease characterized by the loss of night vision. The pathological phenotypes in the APLP2-KO mouse correlated to altered transcription of genes involved in pre- and postsynatic structure/function, including CACNA1F, GRM6, TRMP1 and Gα0, and a normal scotopic a-wave electroretinogram amplitude, markedly reduced scotopic electroretinogram b-wave and modestly reduced photopic cone response. This confirmed the impaired function of the photoreceptor ribbon synapses and retinal bipolar cells, as is also observed in congenital stationary night blindness. Since congenital stationary night blindness present at birth, we extended our analysis to retinal differentiation and showed impaired differentiation of different bipolar cell subtypes and an altered temporal sequence of development from OFF to ON laminae in the inner plexiform layer. This was associated with the altered expression patterns of bipolar cell generation and differentiation factors, including MATH3, CHX10, VSX1 and OTX2. Conclusions These findings demonstrate that APLP2 couples retina development and synaptic genes and present the first evidence that APLP2 expression may be linked to synaptic disease. Electronic supplementary material The online version of this article (doi:10.1186/s13041-016-0245-z) contains supplementary material, which is available to authorized users.
Published: 2016
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25. Class III myosins shape the auditory hair bundles by limiting microvilli and stereocilia growth

Author: Asadollah Aghaie, Typhaine Dupont, Paul Avan, Matteo Cortese, Christine Petit, Andrea Lelli, Jacques Boutet de Monvel, Vincent Michel, Montserrat Bosch-Grau, Isabelle Perfettini, Aziz El-Amraoui, Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), Institut de la Vision, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), This research was funded by the European Research Council (advanced grant 'Hair bundle,' ERC-2011-AdG294570), the Agence Nationale de la Recherche (ANR, grant EARMEC, ANR-11-BSV5-0011), ANR program 'Investissements d'Avenir' (grant ANR-10-LABX-65), Errera Hoechstetter, and the Foundation BNP Paribas., ANR-11-BSV5-0011,EARMEC,Propriétés mécaniques, actives et passives, de la touffe ciliaire des cellules mécano-sensorielles ciliées le long de l'axe tonotopique de la cochlée des mammifères.(2011), ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), European Project: 294570,EC:FP7:ERC,ERC-2011-ADG_20110310,HAIRBUNDLE(2012), Chaire Génétique et physiologie cellulaire, Oficjalska, Danuta, BLANC - Propriétés mécaniques, actives et passives, de la touffe ciliaire des cellules mécano-sensorielles ciliées le long de l'axe tonotopique de la cochlée des mammifères. - - EARMEC2011 - ANR-11-BSV5-0011 - BLANC - VALID, Sorbonne Universités à Paris pour l'Enseignement et la Recherche - - SUPER2011 - ANR-11-IDEX-0004 - IDEX - VALID, and Assembling the puzzle of the operating auditory hair bundle - HAIRBUNDLE - - EC:FP7:ERC2012-12-01 - 2017-11-30 - 294570 - VALID
Subjects: 0301 basic medicine, Physiology, [SDV]Life Sciences [q-bio], Molecular Sequence Data, Morphogenesis, Reviews, audition, Biology, Myosin IIIA, Deafness, Stereocilia, 03 medical and health sciences, Mice, 0302 clinical medicine, unconventional myosins, Myosin, Hair Cells, Auditory, otorhinolaryngologic diseases, Animals, Humans, Myosin Type III, Amino Acid Sequence, 030304 developmental biology, Body Patterning, Mice, Knockout, Stereocilium, 0303 health sciences, Microvilli, Myosin Heavy Chains, Microfilament Proteins, Comment, Membrane Proteins, Cell Biology, Anatomy, Microfilament Protein, Mice, Mutant Strains, Cell biology, [SDV] Life Sciences [q-bio], 030104 developmental biology, HEK293 Cells, Mechanosensitive channels, sense organs, 030217 neurology & neurosurgery
Abstract: International audience; The precise architecture of hair bundles, the arrays of mechanosensitive microvilli-like stereocilia crowning the auditory hair cells, is essential to hearing. Myosin IIIa, defective in the late-onset deafness form DFNB30, has been proposed to transport espin-1 to the tips of stereocilia, thereby promoting their elongation. We show that Myo3a(-/-)Myo3b(-/-) mice lacking myosin IIIa and myosin IIIb are profoundly deaf, whereas Myo3a-cKO Myo3b(-/-) mice lacking myosin IIIb and losing myosin IIIa postnatally have normal hearing. Myo3a(-/-)Myo3b(-/-) cochlear hair bundles display robust mechanoelectrical transduction currents with normal kinetics but show severe embryonic abnormalities whose features rapidly change. These include abnormally tall and numerous microvilli or stereocilia, ungraded stereocilia bundles, and bundle rounding and closure. Surprisingly, espin-1 is properly targeted to Myo3a(-/-)Myo3b(-/-) stereocilia tips. Our results uncover the critical role that class III myosins play redundantly in hair-bundle morphogenesis; they unexpectedly limit the elongation of stereocilia and of subsequently regressing microvilli, thus contributing to the early hair bundle shaping.
Published: 2016
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26. Hypervulnerability to Sound Exposure through Impaired Adaptive Proliferation of Peroxisomes

Author: Sylvie Dartevelle, Asadollah Aghaie, Maryline Beurg, E. Sylvester Vizi, Sedigheh Delmaghani, Isabelle Perfettini, Jean Pierre Hardelin, Nicolas Thelen, Alice Emptoz, Guillaume Soubigou, Máté Aller, Didier Dulon, Michel Leibovici, Marc Thiry, Christine Petit, Fabrice Giraudet, Anaïs Meyer, Paul Avan, Tibor Zelles, Saaid Safieddine, Jean Defourny, Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), Syndrome de Usher et autres atteintes rétino-cochléaires, Institut de la Vision, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neurophysiologie de la Synapse Auditive, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU de Bordeaux Pellegrin [Bordeaux]-Neuroscience Institute, Unit of Cell and Tissue Biology, GIGA-Neurosciences, Université de Liège-CHU Sart Tilman, Institute of Experimental Medicine [Budapest] (KOKI), Hungarian Academy of Sciences (MTA), Department of Pharmacology and Pharmacotherapy, Semmelweis University [Budapest], Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ingénierie des Anticorps (plate-forme) - Antibody Engineering (Platform), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Transcriptome et Epigénome (PF2), Institut Pasteur [Paris] (IP), This work was supported by the Louis-Jeantet Foundation, ANR-NKTH 'HearDeafTrheareat' (2010-INTB-1402-23 01 and TÉT_10-1-2011- 0421), Fondation Bettencourt Schueller, Fondation Agir pour l’Audition, Humanis Novalis- Taitbout, Réunica-Prévoyance, BNP Paribas, and the French state program ‘‘Investissements d’Avenir’’ (ANR-10-LABX-65) (to C.P.)., ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), ANR-10-INTB-0002,HearDeafTreat,Audition et surdité: Mécanismes moléculaires et approches thérapeutiques(2010), Petit, Christine, Sorbonne Universités à Paris pour l'Enseignement et la Recherche - - SUPER2011 - ANR-11-IDEX-0004 - IDEX - VALID, Audition et surdité: Mécanismes moléculaires et approches thérapeutiques - - HearDeafTreat2010 - ANR-10-INTB-0002 - Blanc international 2010 - VALID, Génétique et Physiologie de l'Audition, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), ED 515 - Complexité du vivant, Université Pierre et Marie Curie - Paris 6 (UPMC), This work was supported by the Louis-Jeantet Foundation, Fondation BettencourtSchueller, Fondation Agir pour l’Audition, Humanis Novalis-Taitbout, Reunica-Pre´ voyance, BNP Paribas, Chaire Génétique et physiologie cellulaire, CHU Sart Tilman-Université de Liège, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], and Institut Pasteur [Paris]
Subjects: Auditory Pathways, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Peroxisome Proliferation, Stimulation, Nerve Tissue Proteins, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, medicine.disease_cause, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Sound exposure, Mice, 0302 clinical medicine, Transcription (biology), Hair Cells, Auditory, medicine, Peroxisomes, otorhinolaryngologic diseases, Auditory system, Animals, Humans, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, 030304 developmental biology, Mice, Knockout, Neurons, 0303 health sciences, Biochemistry, Genetics and Molecular Biology(all), fungi, Proteins, food and beverages, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Anatomy, Peroxisome, Phenotype, Cell biology, Oxidative Stress, medicine.anatomical_structure, Hearing Loss, Noise-Induced, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, 030217 neurology & neurosurgery, Oxidative stress
Abstract: International audience; A deficiency in pejvakin, a protein of unknown function, causes a strikingly heterogeneous form of human deafness. Pejvakin-deficient (Pjvk(-/-)) mice also exhibit variable auditory phenotypes. Correlation between their hearing thresholds and the number of pups per cage suggest a possible harmful effect of pup vocalizations. Direct sound or electrical stimulation show that the cochlear sensory hair cells and auditory pathway neurons of Pjvk(-/-) mice and patients are exceptionally vulnerable to sound. Subcellular analysis revealed that pejvakin is associated with peroxisomes and required for their oxidative-stress-induced proliferation. Pjvk(-/-) cochleas display features of marked oxidative stress and impaired antioxidant defenses, and peroxisomes in Pjvk(-/-) hair cells show structural abnormalities after the onset of hearing. Noise exposure rapidly upregulates Pjvk cochlear transcription in wild-type mice and triggers peroxisome proliferation in hair cells and primary auditory neurons. Our results reveal that the antioxidant activity of peroxisomes protects the auditory system against noise-induced damage.
Published: 2015
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27. Abnormal fast fluctuations of electrocochleography and otoacoustic emissions in Menière's disease

Author: Thierry Mom, Fabrice Giraudet, Y. Pavier, Grégory Gerenton, Idir Djennaoui, Laurent Gilain, Paul Avan, Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), and UNICANCER
Subjects: Adult, Male, medicine.medical_specialty, Time Factors, Stereocilia (inner ear), Hydrostatic pressure, Otoacoustic Emissions, Spontaneous, Posture, Audiology, Young Adult, Tilt-Table Test, otorhinolaryngologic diseases, medicine, Humans, Endolymphatic Hydrops, Cochlea, ComputingMilieux_MISCELLANEOUS, Meniere Disease, Aged, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, Auditory Threshold, Extratympanic electrocochleography, Electrocochleography, Middle Aged, medicine.disease, Normal limit, Sensory Systems, Electrophysiology, Acoustic Stimulation, Case-Control Studies, Audiometry, Pure-Tone, Female, sense organs, business, Meniere's disease
Abstract: The responses of cochlear hair cells to sound stimuli depend on the resting position of their stereocilia bundles, which is sensitive to the chemical and mechanical environment. Cochlear hydrops, a hallmark of Menière's disease (MD), which is likely to come with disruption of this environment, results in hearing symptoms and electrophysiological signs, such as excessive changes in the cochlear summating potential (SP) and in the postural shifts of distortion-product otoacoustic emissions (DPOAEs). Here, SP from the basal part of the cochlea and DPOAEs from the apical part of the cochlea were recorded concomitantly in 73 patients with a definite MD, near an attack (n = 40) or between attacks with no clinical symptoms (n = 33), to compare their sensitivities to posture and evaluate their stability. The phase of the 2f1-f2 DPOAEs was monitored during body tilt, with stimuli f1 = 1 kHz and f2 = 1.2 kHz at 72 dB SPL. Extratympanic electrocochleography was performed in response to 95-dBnHL clicks. The normal limits of the DPOAE phase shift with body tilt, [-18°, +38°], and of the SP to action-potential (AP) ratio,0.40, were exceeded in 75% and 60% of patients, respectively, near an attack. In these patients, but not in the asymptomatic ones, both tests reveal fluctuating cochlear responses from one data sample to the next. They emphasize how hydrops hinders normal hair-cell operation and may generate fast fluctuations in inner-ear functioning. If these fluctuations also occur on shorter time scales, it might explain the imperfect diagnostic sensitivity of SP and DPOAE tests, as averaging procedures would tend to level out transient fluctuations characteristic of hydrops.
Published: 2015
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28. An unusually powerful mode of low-frequency sound interference due to defective hair bundles of the auditory outer hair cells

Author: Christine Petit, Fabrice Giraudet, Aziz El-Amraoui, Isabelle Foucher, Elisabeth Verpy, Samantha Papal, Sébastien Le Gal, Brigitte Riederer, Isabelle Perfettini, Ursula Seidler, Vincent Michel, Kazusaku Kamiya, Weiliang Xia, Paul Avan, Maria-Magdalena Georgescu, Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), Department of Otorhinolaryngology, Juntendo University School of Medicine, Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School [Hannover] (MHH), School of Management, Northwestern Polytechnical University [Xi'an] (NPU), Department of Neuro-Oncology, The University of Texas M.D. Anderson Cancer Center [Houston], This work was supported by the Japan Society for the Promotion of Science and Uehara Memorial Foundation (K.K.), EuropeanResearch Council (ERC)-HairBundle (ERC-2011-ADG_20110310), LABEX Lifesenses (ANR-10-LABX-65), Réunica-Prévoyance, Novalis Taitbout, BNP-Paribas, and Fondation Voir et Entendre (C.P.), ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), European Project: 294570,EC:FP7:ERC,ERC-2011-ADG_20110310,HAIRBUNDLE(2012), Chaire Génétique et physiologie cellulaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Neuro-Dol (Neuro-Dol), and Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)
Subjects: Auditory perception, Masking (art), medicine.medical_specialty, Sodium-Hydrogen Exchangers, Tectorial membrane, Infrasound, Nherf2, Audiology, 03 medical and health sciences, Mice, 0302 clinical medicine, medicine, otorhinolaryngologic diseases, Animals, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Cochlea, 030304 developmental biology, Audio frequency, Mice, Knockout, 0303 health sciences, Multidisciplinary, Chemistry, hearing impairment, Biological Sciences, Phosphoproteins, Hair Cells, Auditory, Outer, off-frequency detection, medicine.anatomical_structure, Sound, Auditory Perception, sense organs, tail hypersensitivity, Cochlear microphonic potential, Auditory fatigue, Usher syndrome, 030217 neurology & neurosurgery
Abstract: A detrimental perceptive consequence of damaged auditory sensory hair cells consists in a pronounced masking effect exerted by low-frequency sounds, thought to occur when auditory threshold elevation substantially exceeds 40 dB. Here, we identified the submembrane scaffold protein Nherf1 as a hair-bundle component of the differentiating outer hair cells (OHCs). Nherf1(-/-) mice displayed OHC hair-bundle shape anomalies in the mid and basal cochlea, normally tuned to mid- and high-frequency tones, and mild (22-35 dB) hearing-threshold elevations restricted to midhigh sound frequencies. This mild decrease in hearing sensitivity was, however, discordant with almost nonresponding OHCs at the cochlear base as assessed by distortion-product otoacoustic emissions and cochlear microphonic potentials. Moreover, unlike wild-type mice, responses of Nherf1(-/-) mice to high-frequency (20-40 kHz) test tones were not masked by tones of neighboring frequencies. Instead, efficient maskers were characterized by their frequencies up to two octaves below the probe-tone frequency, unusually low intensities up to 25 dB below probe-tone level, and growth-of-masker slope (2.2 dB/dB) reflecting their compressive amplification. Together, these properties do not fit the current acknowledged features of a hypersensitivity of the basal cochlea to lower frequencies, but rather suggest a previously unidentified mechanism. Low-frequency maskers, we propose, may interact within the unaffected cochlear apical region with midhigh frequency sounds propagated there via a mode possibly using the persistent contact of misshaped OHC hair bundles with the tectorial membrane. Our findings thus reveal a source of misleading interpretations of hearing thresholds and of hypervulnerability to low-frequency sound interference.
Published: 2014
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29. The CD2 isoform of protocadherin-15 is an essential component of the tip-link complex in mature auditory hair cells

Author: Richard J. Goodyear, Typhaine Dupont, Mohamed Makrelouf, Paul Avan, Jean-Pierre Hardelin, Muriel Holder, Elise Pepermans, Amel Bahloul, Souad Gherbi, Samia Abdi, Vincent Michel, Christine Petit, Sandrine Marlin, Guy P. Richardson, Akila Zenati, Crystel Bonnet, Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), School of Life Sciences, University of Sussex, Syndrome de Usher et autres atteintes rétino-cochléaires, Institut de la Vision, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique et Biologie, Université Saâd Dahlab Blida 1 (UB1)- Centre Hospitalo-Universitaire de Blida (CHU Blida), Centre de référence des Surdités Génétiques [CHU Necker, Paris], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique clinique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de Biochimie Génétique, CHU de Bab El Oued-Université d'Alger 1, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Equipe Biophysique Neurosensorielle [Neuro-Dol], Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), EP wassupported by a fellowship from the Fondation Raymonde et Guy Strittmatter.This work was supported by ERC-Hair bundle (ERC-2011-ADG_294570), FoundationBNP Paribas and LHW-Stiftung to CP, Tassili project funding to CP andAZ and Wellcome Trust programme grant (WT087377) to GR. This workperformed in the frame of the LABEX LIFESENSES [reference ANR-10-LABX-65]was supported by French state funds managed by the ANR within the Investissementsd’Avenir programme under reference ANR-11-IDEX-0004-02., ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), European Project: 294570,EC:FP7:ERC,ERC-2011-ADG_20110310,HAIRBUNDLE(2012), Chaire Génétique et physiologie cellulaire, Université de Saâd Dahlab [Blida] (USDB )- Centre Hospitalo-Universitaire de Blida (CHU Blida), Centre de référence des Surdités Génétiques, Petit, Christine, Sorbonne Universités à Paris pour l'Enseignement et la Recherche - - SUPER2011 - ANR-11-IDEX-0004 - IDEX - VALID, and Assembling the puzzle of the operating auditory hair bundle - HAIRBUNDLE - - EC:FP7:ERC2012-12-01 - 2017-11-30 - 294570 - VALID
Subjects: Gene isoform, Male, protocadherin-15, tip-link, Protocadherin, Cadherin Related Proteins, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Gene Therapy & Genetic Disease, Mechanotransduction, Cellular, Frameshift mutation, Mice, Report, deafness, Conditional gene knockout, Hair Cells, Auditory, medicine, otorhinolaryngologic diseases, Animals, Humans, Protein Isoforms, Inner ear, Protein Precursors, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Child, Frameshift Mutation, stereocilia, Genetics, Mice, Knockout, tip-link Subject Categories Genetics, auditory mechano-electrical transduction, [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], Cadherins, Cell biology, medicine.anatomical_structure, [SDV.BBM.MN] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Mutation, Molecular Medicine, Female, Hair cell, Human medicine, Tip link, PCDH15, Neuroscience
Abstract: International audience; Protocadherin-15 (Pcdh15) is a component of the tip-links, the extracellular filaments that gate hair cell mechano-electrical transduction channels in the inner ear. There are three Pcdh15 splice isoforms (CD1, CD2 and CD3), which only differ by their cyto-plasmic domains; they are thought to function redundantly in mechano-electrical transduction during hair-bundle development, but whether any of these isoforms composes the tip-link in mature hair cells remains unknown. By immunolabelling and both morphological and electrophysiological analyses of post-natal hair cell-specific conditional knockout mice (Pcdh15 ex38-fl/ex38-fl Myo15-cre +/À) that lose only this isoform after normal hair-bundle development, we show that Pcdh15-CD2 is an essential component of tip-links in mature auditory hair cells. The finding, in the homozygous or compound heterozygous state, of a PCDH15 frameshift mutation (p.P1515Tfs*4) that affects only Pcdh15-CD2, in profoundly deaf children from two unrelated families, extends this conclusion to humans. These results provide key information for identification of new components of the mature auditory mechano-electrical trans-duction machinery. This will also serve as a basis for the development of gene therapy for deafness caused by PCDH15 defects.
Published: 2014
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30. Hearing is normal without connexin30

Author: Paul Avan, Anne-Cécile Boulay, Martine Cohen-Salmon, Christian Giaume, Ghislaine Hamard, Fabrice Giraudet, Francisco J. del Castillo, Christine Petit, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ecole doctorale Cerveau Cognition et Comportement [Paris] (ED 158 - 3C), Sorbonne Université (SU), Génétique et Physiologie de l'Audition, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Plateforme Recombinaison Homologue, Transfert d'Embryons et Cryoconservation [Institut Cochin] (PRHTEC), Institut Cochin (IC UM3 (UMR 8104 / U1016)), and Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: medicine.medical_specialty, Mice, 129 Strain, Genotype, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Mutant, Blotting, Western, Connexin, Audiology, Deafness, Polymerase Chain Reaction, Connexins, Mice, Hearing, medicine, otorhinolaryngologic diseases, Connexin 30, Evoked Potentials, Auditory, Brain Stem, Animals, Inner ear, Gene, Mice, Knockout, Gap junction protein, biology, General Neuroscience, DNA, Cell biology, Cochlea, Connexin 26, Mice, Inbred C57BL, medicine.anatomical_structure, Mutation, biology.protein, Isolated Deafness, Brief Communications, GJB6
Abstract: Gjb2andGjb6,two contiguous genes respectively encoding the gap junction protein connexin26 (Cx26) and connexin 30 (Cx30) display overlapping expression in the inner ear. Both have been linked to the most frequent monogenic hearing impairment, the recessive isolated deafness DFNB1. Although there is robust evidence for the direct involvement of Cx26 in cochlear functions, the contribution of Cx30 is unclear since deletion ofCx30strongly downregulatesCx26both in human and in mouse. Thus, it is imperative that any role of Cx30 in audition be clearly evaluated. Here, we developed a newCx30knock-out mouse model (Cx30Δ/Δ) in which half ofCx26expression was preserved. Our results show thatCx30andCx26coordinated expression is dependent on the spacing of their surrounding chromosomic region, and thatCx30Δ/Δmutants display normal hearing. Thus, in deaf patients withGJB6deletion as well as in the previousCx30knock-out mouse model, defectiveCx26expression is the likely cause of deafness, and in contrast to current opinion, Cx30 is dispensable for cochlear functions.
Published: 2013
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31. Usher type 1G protein sans is a critical component of the tip-link complex, a structure controlling actin polymerization in stereocilia

Author: Dominique Weil, Sébastien Chardenoux, Paul Avan, Vincent Michel, Nicolas Michalski, Olinda Alegria-Prévot, Marcio Do Cruzeiro, Isabelle Perfettini, Guy P. Richardson, Richard J. Goodyear, Isabelle Foucher, Elisa Caberlotto, Jean-Pierre Hardelin, Amel Bahloul, Christine Petit, Elise Pepermans, Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), Université Pierre et Marie Curie - Paris 6 (UPMC), Génétique des Déficits Sensoriels, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), School of Life Sciences, University of Sussex, Plateforme Recombinaison Homologue, Transfert d'Embryons et Cryoconservation [Institut Cochin] (PRHTEC), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), This work was supported by FAUN Stiftung (Suchert Foundation), Fondation Raymonde and Guy Strittmatter,LHW-Stiftung, the Conny Maeva Charitable Foundation, Fondation Orange, and the Louis-Jeantet Foundation. R.J.G. and G.P.R. are supported by The Wellcome Trust, Chaire Génétique et physiologie cellulaire, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), michalski, nicolas, Génétique et Physiologie de l'Audition, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Collège de France ( CdF ) -Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Plateforme Recombinaison Homologue, Transfert d'Embryons et Cryoconservation [Institut Cochin] ( PRHTEC ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Neuro-Dol ( Neuro-Dol ), Université d'Auvergne - Clermont-Ferrand I ( UdA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université d'Auvergne - Clermont-Ferrand I ( UdA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Neuro-Dol - Clermont Auvergne ( Neuro-Dol ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Clermont Auvergne ( UCA ) -Université Clermont Auvergne ( UCA ), and Collège de France ( CdF )
Subjects: Scaffold protein, MESH: Signal Transduction, MESH: Protein Precursors, MESH : Immunohistochemistry, [SDV]Life Sciences [q-bio], MESH : Actins, Fluorescent Antibody Technique, MESH : Analysis of Variance, MESH: Mice, Knockout, MESH: Cadherins, Polymerization, Mice, 0302 clinical medicine, MESH: Genetic Vectors, MESH: Hair Cells, Auditory, MESH : Polymerization, MESH: Animals, MESH: Nerve Tissue Proteins, Mechanotransduction, MESH : Protein Precursors, MESH : Nerve Tissue Proteins, MESH: Fluorescent Antibody Technique, Mice, Knockout, 0303 health sciences, Multidisciplinary, MESH: Electrophysiology, Cilium, Biological Sciences, Cadherins, Immunohistochemistry, MESH : Genetic Vectors, Cell biology, [SDV] Life Sciences [q-bio], Electrophysiology, medicine.anatomical_structure, MESH: Polymerization, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH : Cadherins, Transduction (physiology), Engineering sciences. Technology, Signal Transduction, MESH : Microscopy, Electron, Scanning, MESH: Microscopy, Electron, Scanning, Genetic Vectors, Cadherin Related Proteins, Nerve Tissue Proteins, Biology, MESH: Actins, MESH : Cilia, 03 medical and health sciences, MESH : Electrophysiology, MESH: Cilia, MESH: Analysis of Variance, MESH : Mice, Hair Cells, Auditory, medicine, otorhinolaryngologic diseases, Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cilia, Protein Precursors, MESH : Hair Cells, Auditory, MESH: Mice, Actin, 030304 developmental biology, MESH : Signal Transduction, Analysis of Variance, [ SDV ] Life Sciences [q-bio], Stereocilia, MESH: Immunohistochemistry, Actins, MESH : Fluorescent Antibody Technique, Cytoplasm, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Microscopy, Electron, Scanning, MESH : Mice, Knockout, MESH : Animals, sense organs, Tip link, 030217 neurology & neurosurgery
Abstract: The mechanotransducer channels of auditory hair cells are gated by tip-links, oblique filaments that interconnect the stereocilia of the hair bundle. Tip-links stretch from the tips of stereocilia in the short and middle rows to the sides of neighboring, taller stereocilia. They are made of cadherin-23 and protocadherin-15, products of the Usher syndrome type 1 genes USH1D and USH1F, respectively. In this study we address the role of sans, a putative scaffold protein and product of the USH1G gene. In Ush1g −/− mice, the cohesion of stereocilia is disrupted, and both the amplitude and the sensitivity of the transduction currents are reduced. In Ush1g fl/fl Myo15-cre +/− mice, the loss of sans occurs postnatally and the stereocilia remain cohesive. In these mice, there is a decrease in the amplitude of the total transducer current with no loss in sensitivity, and the tips of the stereocilia in the short and middle rows lose their prolate shape, features that can be attributed to the loss of tip-links. Furthermore, stereocilia from these rows undergo a dramatic reduction in length, suggesting that the mechanotransduction machinery has a positive effect on F-actin polymerization. Sans interacts with the cytoplasmic domains of cadherin-23 and protocadherin-15 in vitro and is absent from the hair bundle in mice defective for either of the two cadherins. Because sans localizes mainly to the tips of short- and middle-row stereocilia in vivo, we conclude that it belongs to a molecular complex at the lower end of the tip-link and plays a critical role in the maintenance of this link.
Published: 2011
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32. Genetic dissection of the function of hindbrain axonal commissures

Author: Marc Tessier-Lavigne, Alain Chédotal, Chris I. De Zeeuw, Nicolas Renier, Paul Avan, Martijn Schonewille, Aleksandra Badura, Fabrice Giraudet, Institut de la Vision, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Neuroscience, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Genentech, Inc. [San Francisco], his project is supported by grants from the 'fondation pour le recherche médicale' (programme Equipe FRM), the Association Française contre les Myopathies (AFM, ASS-SUB06-00123), and the Agence Nationale de la Recherche (ANR-08-MNPS-030-01) to AC. The group of CIDZ was supported by the Dutch Organization for Medical Sciences (ZON-MW), Life Sciences (NWO-ALW), Senter (Neuro-Bsik), Prinses Beatrix Fonds, and the European Community (EEC)., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA), Autard, Delphine, Netherlands Institute for Neuroscience (NIN), and Neurosciences
Subjects: Eye Movements, MESH: Rotarod Performance Test, MESH: Mice, Knockout, Mice, Ocular Motility Disorders, 0302 clinical medicine, MESH: Eye Movements, MESH: Behavior, Animal, Developmental Biology/Developmental Molecular Mechanisms, MESH: Animals, MESH: Nerve Tissue Proteins, Biology (General), Mice, Knockout, 0303 health sciences, Movement Disorders, Neuroscience/Behavioral Neuroscience, Behavior, Animal, General Neuroscience, Horizontal gaze palsy, MESH: Rhombencephalon, Climbing fiber, Anatomy, Commissure, Neuroscience/Neurodevelopment, MESH: Motor Activity, Ophthalmology/Inherited Eye Disorders, MESH: Evoked Potentials, Auditory, medicine.anatomical_structure, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Evoked Potentials, Auditory, MESH: Membrane Proteins, General Agricultural and Biological Sciences, Research Article, MESH: Body Patterning, MESH: Axons, Genetics and Genomics/Animal Genetics, QH301-705.5, Recombinant Fusion Proteins, Central nervous system, Rhombomere, Nerve Tissue Proteins, Receptors, Cell Surface, Hindbrain, Motor Activity, Biology, Neurological Disorders, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, MESH: Mice, Inbred C57BL, medicine, MESH: Recombinant Fusion Proteins, Animals, Humans, MESH: Ocular Motility Disorders, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, MESH: Mice, Body Patterning, 030304 developmental biology, MESH: Humans, General Immunology and Microbiology, MESH: Embryo, Mammalian, Membrane Proteins, Embryo, Mammalian, medicine.disease, Axons, Mice, Inbred C57BL, Rhombencephalon, Developmental Biology/Neurodevelopment, nervous system, Rotarod Performance Test, Forebrain, Axon guidance, 030217 neurology & neurosurgery, MESH: Movement Disorders
Abstract: The Robo3 receptor controls midline crossing by axons. Deleting Robo3 in specific commissural neurons with a conditional knockout reveals their contribution to sensory and motor integration, and models human neurological conditions., In Bilateria, many axons cross the midline of the central nervous system, forming well-defined commissures. Whereas in mammals the functions of commissures in the forebrain and in the visual system are well established, functions at other axial levels are less clearly understood. Here, we have dissected the function of several hindbrain commissures using genetic methods. By taking advantage of multiple Cre transgenic lines, we have induced site-specific deletions of the Robo3 receptor. These lines developed with the disruption of specific commissures in the sensory, motor, and sensorimotor systems, resulting in severe and permanent functional deficits. We show that mice with severely reduced commissures in rhombomeres 5 and 3 have abnormal lateral eye movements and auditory brainstem responses, respectively, whereas mice with a primarily uncrossed climbing fiber/Purkinje cell projection are strongly ataxic. Surprisingly, although rerouted axons remain ipsilateral, they still project to their appropriate neuronal targets. Moreover, some Cre;Robo3 lines represent potential models that can be used to study human syndromes, including horizontal gaze palsy with progressive scoliosis (HGPPS). To our knowledge, this study is one of the first to link defects in commissural axon guidance with specific cellular and behavioral phenotypes., Author Summary Coordination of the left and right sides of the body requires the action of neurons whose axons cross the nervous system midline. The precise contributions of “commissural” neurons to sensory and motor functions remain poorly understood. To probe these crossing circuits, we took advantage of the recent finding that the Robo3 axon guidance receptor is required for midline crossing by axons at most axial levels. A Robo3 conditional knockout mouse line was generated, allowing Robo3 to be deleted in selective neuronal populations. This led to disruption of specific commissures in the sensory, motor, and sensorimotor systems, and resulted in severe but specific functional deficits. Surprisingly, although rerouted axons do not cross the midline, they still project to their appropriate neuronal targets, suggesting that midline crossing is not required to complete the axonal guidance program of those neurons. Moreover, some of the mouse lines represent good models for human syndromes, including horizontal gaze palsy with progressive scoliosis (HGPPS), which is characterized by deficits in coordinated eye movements. This study links defects in commissural axon guidance with specific and dramatic behavioral phenotypes.
Published: 2010
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33. Vezatin, an integral membrane protein of adherens junctions, is required for the sound resilience of cochlear hair cells

Author: Dominique Weil, Paolo Gasparini, Isabelle Perfettini, Jean-Pierre Hardelin, Christine Petit, Vincent Michel, Paul Avan, Amel Bahloul, Sylvie Nouaille, Michel Leibovici, Danilo Licastro, Jian Zuo, Cristina Zadro, Isabelle Roux, Marie-Christine Simmler, Bahloul, A, Simmler, Mc, Michel, V, Leibovici, M, Perfettini, I, Roux, I, Weil, D, Nouaille, S, Zuo, J, Zadro, C, Licastro, D, Gasparini, Paolo, Avan, P, Hardelin, Jp, Petit, C., Génétique des Déficits Sensoriels, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), Département de neurobiologie du développement, recherche de l'Hôpital St. Jude Children's, St Jude Children's Research Hospital, Unité de génétique médicale, Département des sciences de la reproduction et le développement, IRCCS de l'Université de Trieste, Università degli studi di Trieste = University of Trieste, Department of Physics, RISSC-Lab-University of Naples Federico II = Università degli studi di Napoli Federico II, Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Région Ile-de-France du projet, Grant Numéro: Sésame 2002-E1666 Pasteur-Weizmann Programme commun de recherche (2006-2007), ANR-05-MRAR-0015,Usher type I,Physiopathologie du syndrome de Usher de type I : de la structure de la myosine VIIa et de l'harmonine à leur fonction dans les cellules ciliées auditives(2005), European Project, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique et Physiologie de l'Audition, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]-Collège de France (CdF)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université de Trieste, Università degli studi di Napoli Federico II-RISSC-Lab, Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol - Clermont Auvergne (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Université Clermont Auvergne (UCA), Collège de France (CDF), Collège de France (CdF), Agence française de recherche national (ANR-Maladies Rares), Nombre de subventions: ANR-05-MRAR-015-01 - Agence française de recherche national (ANR-Maladies Neurologiques et Psychiatriques),Agence française de recherche national (ANR-Maladies Rares), Nombre de subventions: ANR-05-MRAR-015-01 - Agence française de recherche national (ANR-Maladies Neurologiques et Psychiatriques), and Chaire Génétique et physiologie cellulaire
Subjects: mouse model, Deafness, Biology, Polymorphism, Single Nucleotide, adherens junction, Adherens junction, Mice, 03 medical and health sciences, 0302 clinical medicine, Stress, Physiological, Radixin, medicine, otorhinolaryngologic diseases, Animals, Inner ear, Research Articles, Cochlea, 030304 developmental biology, 0303 health sciences, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Anatomy, medicine.disease, Cell biology, noise-induced hearing loss, Intercellular Junctions, medicine.anatomical_structure, Hearing Loss, Noise-Induced, Membrane protein, Organ of Corti, vezatin, Molecular Medicine, Hair cell, organ of Corti, Noise, Gene Deletion, 030217 neurology & neurosurgery, Noise-induced hearing loss
Abstract: International audience; Loud sound exposure is a significant cause of hearing loss worldwide. We asked whether a lack of vezatin, an ubiquitous adherens junction protein, could result in noise-induced hearing loss. Conditional mutant mice bearing non-functional vezatin alleles only in the sensory cells of the inner ear (hair cells) indeed exhibited irreversible hearing loss after only one minute exposure to a 105 dB broadband sound. In addition, mutant mice spontaneously underwent late onset progressive hearing loss and vestibular dysfunction related to substantial hair cell death. We establish that vezatin is an integral membrane protein with two adjacent transmembrane domains, and cytoplasmic N- and C-terminal regions. Late recruitment of vezatin at junctions between MDCKII cells indicates that the protein does not play a role in the formation of junctions, but rather participates in their stability. Moreover, we show that vezatin directly interacts with radixin in its actin-binding conformation. Accordingly, we provide evidence that vezatin associates with actin filaments at cell-cell junctions. Our results emphasize the overlooked role of the junctions between hair cells and their supporting cells in the auditory epithelium resilience to sound trauma.
Published: 2009
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34. Otoferlin, defective in a human deafness form, is essential for exocytosis at the auditory ribbon synapse

Author: Philippe Rostaing, Christine Petit, M'hamed Grati, Ghislaine Hamard, Régis Nouvian, Saaid Safieddine, Marie-Christine Simmler, Amel Bahloul, Antoine Triller, Isabelle Roux, Isabelle Perfettini, Paul Avan, Morgane Le Gall, Tobias Moser, Génétique des Déficits Sensoriels, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Otolaryngology and Center for Molecular Physiology of the Brain, Georg-August-University = Georg-August-Universität Göttingen, The Wellcome Trust Sanger Institute [Cambridge], Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Plateforme Recombinaison Homologue, Transfert d'Embryons et Cryoconservation [Institut Cochin] (PRHTEC), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biologie cellulaire de la synapse normale et pathologique, Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), Foundation Louis-Jeantet and the French Ministry of Research (ACI 'Biologie du Développement et Physiologie intégrative') , the European Commission FP6 Integrated Project EuroHear LSHG-CT-2004-512063, Human Frontiers Science Program, the Deutsche Forschungsgemeinschaft, (Center for Molecular Physiology of the Brain), MENRT, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Georg-August-Universität Göttingen, Institut Jacques Monod ( IJM ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Plateforme Recombinaison Homologue, Transfert d'Embryons et Cryoconservation [Institut Cochin] ( PRHTEC ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), École normale supérieure - Paris ( ENS Paris ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Neuro-Dol ( Neuro-Dol ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université d'Auvergne - Clermont-Ferrand I ( UdA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université d'Auvergne - Clermont-Ferrand I ( UdA ) -Neuro-Dol - Clermont Auvergne ( Neuro-Dol ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Clermont Auvergne ( UCA ) -Université Clermont Auvergne ( UCA ), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Georg-August-University [Göttingen], École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Chaire Génétique et physiologie cellulaire, Laboratoire d'Electronique et Systèmes de Télécommunications (LEST), Université de Brest (UBO)-Ecole Nationale Supérieure des Télécommunications de Bretagne-Centre National de la Recherche Scientifique (CNRS), Université de Brest (UBO), This work was supported by grants from the FoundationLouis-Jeantet and the French Ministry of Research (ACI ‘‘Biologie duDeveloppement et Physiologie integrative’’) to C.P., Human Frontiers Science Program to T.M. and S.S., and the Deutsche Forschungsgemeinschaft to T.M. (Centerfor Molecular Physiology of the Brain)., École normale supérieure - Paris (ENS Paris)-École normale supérieure - Paris (ENS Paris)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Neuro-Dol - Clermont Auvergne (Neuro-Dol), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Université Clermont Auvergne (UCA)
Subjects: Auditory Pathways, Time Factors, [SDV]Life Sciences [q-bio], MESH: Synaptosomal-Associated Protein 25, Synaptogenesis, Syntaxin 1, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Ribbon synapse, Deafness, MESH : Synaptosomal-Associated Protein 25, Membrane Fusion, Synaptic Transmission, MESH: Mice, Knockout, MESH: Synapses, Mice, 0302 clinical medicine, MESH: Syntaxin 1, MESH: Cochlea, OTOF, MESH: Animals, Mice, Knockout, 0303 health sciences, MESH : Synaptic Transmission, MESH: Exocytosis, MESH : Hair Cells, Inner, MESH : Evoked Potentials, Auditory, Brain Stem, SNAP25, Anatomy, Cell biology, Cochlea, Synaptic vesicle exocytosis, medicine.anatomical_structure, MESH: Auditory Pathways, MESH: Calcium, MESH : Synaptic Vesicles, Hair cell, Synaptic Vesicles, MESH: Membrane Proteins, MESH : Synapses, MESH : Time Factors, MESH : Cochlea, MESH : Deafness, Synaptosomal-Associated Protein 25, MESH: Deafness, MESH : Mice, Inbred C57BL, Biology, MESH: Membrane Fusion, Synaptic vesicle, General Biochemistry, Genetics and Molecular Biology, Exocytosis, MESH : Exocytosis, 03 medical and health sciences, MESH: Mice, Inbred C57BL, MESH : Membrane Fusion, MESH : Mice, medicine, Evoked Potentials, Auditory, Brain Stem, MESH: Synaptic Transmission, Animals, Humans, MESH : Calcium, MESH: Mice, 030304 developmental biology, Hair Cells, Auditory, Inner, MESH: Humans, Biochemistry, Genetics and Molecular Biology(all), MESH : Humans, MESH: Time Factors, [ SDV.BC.BC ] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Membrane Proteins, MESH : Syntaxin 1, MESH: Synaptic Vesicles, MESH: Hair Cells, Inner, Mice, Inbred C57BL, MESH : Membrane Proteins, Synapses, MESH : Mice, Knockout, MESH: Evoked Potentials, Auditory, Brain Stem, Calcium, MESH : Animals, MESH : Auditory Pathways, sense organs, 030217 neurology & neurosurgery
Abstract: International audience; The auditory inner hair cell (IHC) ribbon synapse operates with an exceptional temporal precision and maintains a high level of neurotransmitter release. However, the molecular mechanisms underlying IHC synaptic exocytosis are largely unknown. We studied otoferlin, a predicted C2-domain transmembrane protein, which is defective in a recessive form of human deafness. We show that otoferlin expression in the hair cells correlates with afferent synaptogenesis and find that otoferlin localizes to ribbon-associated synaptic vesicles. Otoferlin binds Ca(2+) and displays Ca(2+)-dependent interactions with the SNARE proteins syntaxin1 and SNAP25. Otoferlin deficient mice (Otof(-/-)) are profoundly deaf. Exocytosis in Otof(-/-) IHCs is almost completely abolished, despite normal ribbon synapse morphogenesis and Ca(2+) current. Thus, otoferlin is essential for a late step of synaptic vesicle exocytosis and may act as the major Ca(2+) sensor triggering membrane fusion at the IHC ribbon synapse.
Published: 2006
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35. Déficits auditifs : recherches émergentes et applications chez l'enfant

Author: Avan, Paul, Cazals, Yves, Dauman, René, Denoyelle, Françoise, Hardelin, Jean-Pierre, Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Physiologie neurovégétative - PNV (PNP), Université Paul Cézanne - Aix-Marseille 3-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Groupe hospitalier Pellegrin, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Génétique des Déficits Sensoriels, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut national de la santé et de la recherche médicale(INSERM), ORANGE, Colette, Service d'ORL et de Chirurgie Cervicofaciale, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Neuro-Dol - Clermont Auvergne (Neuro-Dol), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Université Clermont Auvergne (UCA)
Subjects: Otoémissions acoustiques, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Surdité congénitale, OEA, PEAA, Audition, Surdité, Dépistage, Dépistage néonatal, Physiologie de l'audition, Réhabilitation auditive, Diagnostic, Potentiels évoqués auditifs automatisés, Génétique, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: La déficience auditive est le déficit sensoriel le plus fréquent chez l’enfant.Ses conséquences sur le développement du langage et de la communicationsont importantes.Les surdités peuvent être classées selon le degré de perte auditive (moyennesur les fréquences 500, 1 000, 2 000 et 4 000 Hz de la meilleure oreille) ensurdités légères, moyennes, sévères et profondes. Les surdités sévères et profondescorrespondent à une déficience auditive qui, sans réhabilitation,entraîne l’absence d’acquisition du langage oral. Même les surdités moyennes,qui représentent 50 % des surdités, ont un impact sur les apprentissagesscolaires, le développement cognitif et l’adaptation sociale qui ne doit pasêtre sous-estimée.Les surdités peuvent être également classées selon l’emplacement du défautprimaire (oreille externe, moyenne, interne). À partir de l’audiogrammeobtenu chez l’enfant (comparaison des courbes de conduction aérienne etosseuse), on distingue les surdités de perception (oreille interne, nerf auditif,voies auditives centrales) et les surdités de transmission (oreille moyenneessentiellement).Les surdités de l’enfant peuvent être isolées (non syndromiques) ou syndromiques(c’est-à-dire associées à des anomalies d’autres organes). La prévalencede la surdité augmente avec l’âge. Certains types de surdité, enparticulier les surdités génétiques, apparaissent durant l’enfance ou même àl’âge adulte. La répartition des surdités prélinguales (c’est-à-dire survenantavant l’âge d’apparition du langage) dans les pays développés est aujourd’huiestimée à 10-15 % de surdités syndromiques héréditaires, 60-65 % de surditésisolées héréditaires et 20-25 % de surdités d’autre origine (infections,médicaments, complication de la prématurité…).L’identification des gènes responsables constitue un axe récent de recherchesur l’origine des déficits auditifs. Ces gènes codent pour des protéines quisont impliquées dans les processus cellulaires du fonctionnement de lacochlée, organe de l’audition dans l’oreille interne. Leur connaissance présenteun intérêt pour la pratique clinique quotidienne car elle peut permettrede cibler un diagnostic moléculaire pour le conseil génétique etpronostique.En France, il n’existe pas encore d’organisation générale permettant de réalisersystématiquement le dépistage à la naissance. La rubrique « dépistagenéonatal de la surdité » figure néanmoins dans le carnet de santé depuis 1970. Des outils non invasifs chez le nouveau-né existent depuis quelquesannées (otoémissions acoustiques, potentiels évoqués auditifs automatisés).Si une anomalie est décelée par un test de dépistage en maternité, des testsplus complexes à visée diagnostique doivent être réalisés en milieu spécialisépour évaluer précisément le niveau auditif.Par ailleurs, on sait que la prise en charge doit être précoce afin de se situerpendant la période critique (liée à la plasticité cérébrale), durant laquelle lelangage oral s’organise à partir des sons entendus. Les possibilités de prise encharge évoluent profondément, avec en particulier la réhabilitation des surditésprofondes par implant cochléaire. Toutes ces avancées peuvent contribuerà réduire fortement le handicap lié à cette déficience.De nouveaux défis se posent donc à l’acoustique, discipline déjà ancienne,pour l’amélioration du dépistage, du diagnostic et de la prise en charge qu’ils’agisse d’appareillages prothétiques ou d’implants cochléaires qui présententencore des imperfections multiples dans un environnement bruyant.(...)
Published: 2006

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35 results on '"Equipe Biophysique Neurosensorielle [Neuro-Dol]"'

1. Biasing the semicircular canal cupula in excitatory direction decreases the gain of the vestibuloocular reflex for head impulses

2. Otogelin, otogelin-like, and stereocilin form links connecting outer hair cell stereocilia to each other and the tectorial membrane

3. Dual AAV-mediated gene therapy restores hearing in a DFNB9 mouse model

4. Auditory Brainstem Changes in Timing may Underlie Hyperacusis in a Salicylate-induced Acute Rat Model

5. Noninvasive in-ear monitoring of intracranial pressure during microgravity in parabolic flights

6. New views on auditory ageing in normal subjects and patients with comorbidities

7. Pejvakin-mediated pexophagy protects auditory hair cells against noise-induced damage

8. An urgent need for new objective tests of auditory disorders: how to take up the challenge?

9. Targeting the TREK-1 potassium channel via riluzole to eliminate the neuropathic and depressive-like effects of oxaliplatin

10. Clarin-1 gene transfer rescues auditory synaptopathy in model of Usher syndrome

11. Vestibular-evoked myogenic potential triggered by galvanic vestibular stimulation may reveal subclinical alterations in human T-cell lymphotropic virus type 1-associated myelopathy

12. Rapid exhaustion of auditory neural conduction in a prototypical mitochondrial disease, Friedreich ataxia

13. Generalization of the primary tone phase variation method: An exclusive way of isolating the frequency-following response components

14. Transient Abnormalities in Masking Tuning Curve in Early Progressive Hearing Loss Mouse Model

15. Diagnostic and therapeutic strategy in Menière's disease. Guidelines of the French Otorhinolaryngology-Head and Neck Surgery Society (SFORL)

16. CIB2, defective in isolated deafness, is key for auditory hair cell mechanotransduction and survival

17. Noninvasive detection of alarming intracranial pressure changes by auditory monitoring in early management of brain injury: a prospective invasive versus noninvasive study

18. Non-invasive intraoperative monitoring of cochlear function by cochlear microphonics during cerebellopontine-angle surgery

19. Resistance of Gerbil Auditory Function to Reversible Decrease in Cochlear Blood Flow

20. Local gene therapy durably restores vestibular function in a mouse model of Usher syndrome type 1G

21. Auditory cortex interneuron development requires cadherins operating hair-cell mechanoelectrical transduction

22. Jugular and Portal Vein Volume, Middle Cerebral Vein Velocity, and Intracranial Pressure in Dry Immersion

23. Mice with a deletion of the major central myelin protein exhibit hypersensitivity to noxious thermal stimuli: involvement of central sensitization

24. Amyloid Precursor-Like Protein 2 deletion-induced retinal synaptopathy related to congenital stationary night blindness: structural, functional and molecular characteristics

25. Class III myosins shape the auditory hair bundles by limiting microvilli and stereocilia growth

26. Hypervulnerability to Sound Exposure through Impaired Adaptive Proliferation of Peroxisomes

27. Abnormal fast fluctuations of electrocochleography and otoacoustic emissions in Menière's disease

28. An unusually powerful mode of low-frequency sound interference due to defective hair bundles of the auditory outer hair cells

29. The CD2 isoform of protocadherin-15 is an essential component of the tip-link complex in mature auditory hair cells

30. Hearing is normal without connexin30

31. Usher type 1G protein sans is a critical component of the tip-link complex, a structure controlling actin polymerization in stereocilia

32. Genetic dissection of the function of hindbrain axonal commissures

33. Vezatin, an integral membrane protein of adherens junctions, is required for the sound resilience of cochlear hair cells

34. Otoferlin, defective in a human deafness form, is essential for exocytosis at the auditory ribbon synapse

35. Déficits auditifs : recherches émergentes et applications chez l'enfant

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35 results on '"Equipe Biophysique Neurosensorielle [Neuro-Dol]"'

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