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U583

Equipe 1
Génétique et thérapie des cécités rétiniennes

Equipe 2
Physiopathologie et thérapies de l’oreille interne

Equipe 3
Neurobiologie cellulaire et moléculaire du système somato-sensoriel

Equipe 4
Physiologie et approches thérapeutiques des pathologies médullaires

Equipe 5
Physiologie et thérapie des désordres vestibulaires

U844

 

 

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Jérôme Ruel
 

Function: PhD, Assistant Professor (Neuroscience) in Neurobiology of Hearing, University of Montpellier I, Faculty of Medicine.

 

Participation to educational training programs:

- Hearing Aids School (Montpellier I):

Lectures and training courses in “clinical audiometry”

Lecture in “scientific English”

Training courses in “in vivo cochlear electrophysiology”

 

- Master 1 & 2 of Audiology (Montpellier I):

Lectures in “neurophysiology basis”

Lectures in “cochlear physiology”

Lectures in “auditory pathway physiology”

 

- Faculty of Pharmacy (Montpellier I):

 Training courses in “audiometry basis”

 

- Master Neuroscience program Health and Biology (Montpellier I & II):

Lecture in Neurobiology of Hearing: “from molecular mechanisms to clinical therapy”

Training courses in “in vivo cochlear electrophysiology”

 

- University Diploma of audioprosthesis technics (Montpellier I):

Lectures in “cochlear physiology basis”

Lectures in “audiometry basis”

 

Scientific production:

 

28 peer-reviewed publications, 12 books chapters, 6 invited seminars and 43 communications or posters at national/international conferences.

 

Research interests:

 

My interests focus on the pharmacology of the synaptic neurotransmission of the inner hair cell-synaptic complex in the mammalian cochlea and the links with the occurrence of deafness and tinnitus in animal models.

 

  • In vivo animal model of genetic deafness DFNA25

Recently, we have identified SLC17A8, which encodes the vesicular glutamate transporter-3 as the gene responsible for DFNA25, an autosomal dominant form of progressive, high-frequency nonsyndromic deafness (Ruel et al., AJHG 2008b).  This finding represents the first mutation in a VGLUT associated with a human disease (with a phenotype of hearing loss at elderly).  We observed that the vesicular transporter VGLUT3 is selectively expressed in the sensory inner hair cells and that the genetic deletion of Slc17a8 in mice results in a profound deafness (Ruel et al., AJHG, 2008b). Since the phenotype of DFNA25 deafness is similar to presbycusis, analysis of Slc17a8 gene mutants is an attractive presbycusis animal model to design therapeutical treatments strategies such as in vivo gene therapy.

 

  •  In vitro and in vivo animal model of peripheral tinnitus

We previously showed using behavioral tests that tinnitus induced by salicylate or mefenamate (both cyclooxygenase blockers) involved NMDA receptors (Guitton et al., J. Neuroscience, 2003). It is well known for at least a century that a large dose of aspirin (acetylsalicylic acid) produces hearing loss and tinnitus. However, the cellular and molecular mechanism responsible for salicylate-induced tinnitus was unknown.

We showed for the first time that the synapses between IHCs and afferent auditory terminals express NMDA receptors. In vitro patch-clamp recordings of primary auditory neuron somata and two-photon calcium imaging of afferent terminals on rat cochlear slices demonstrated that salicylate and arachidonate (a substrate of cyclooxygenase) enabled calcium influx thought NMDA receptors. At the system physiology level, salicylate increased the arachidonate content in the whole cochlea (Ruel et al., J. Neuroscience, 2008a).

In vivo, we demonstrated using single unit recordings from the auditory nerve coupled with multi-intracochlear perfusions that salicylate increased vigorously the spontaneous activity of the auditory nerve fibers thought cochlear NMDA receptor activation. From these results, we propose that salicylate inhibits cochlear cyclooxygenase, which increased the arachidonate level. Arachidonate then enables NMDA receptors activation, which produces a high rate of auditory neural activity, interpreted as an incoming sound by the central nervous system (Ruel et al., J. Neuroscience, 2008a).

Our present models provide a new molecular mechanism accounting for the generation of tinnitus at the periphery of the auditory system.

 

  • In vivo pharmacology of the cochlear efferent pathway

Efferent fibers from the lateral superior olive project onto the afferent post-synaptic dendrites underneath the sensory inner hair cells. We previously demonstrated that tonic dopamine inhibition by the lateral olivocochlear (LOC) efferent pathway acts as a permanent gain control at the initialization site of the action potential to maintain the functional and morphological integrity of the primary auditory neurons (Ruel et al., European J. Neuroscience, 2001). Intracochlear perfusions of the dopamine transporter (DAT) inhibitors nomifensine and N-[1-(2-benzo[b]thiophenyl) cyclohexyl]piperidine reduced the spontaneous and the sound-evoked synchronous activity of the auditory nerve. Capillary electrophoresis with laser-induced fluorescence measurements showed that nomifensine increased extracellular dopamine levels in the cochlea (Ruel et al., J. Neurochemistry, 2006). Altogether, these results show that the DAT is essential for maintaining the spontaneous activity of auditory nerve neurons and their responsiveness to sound stimulation.

Removal of this tonic dopamine inhibition results in the development of early signs of excitotoxicity. LOC system may maintain the adequate firing of the auditory nerve fibers and protect them against glutamate receptor overstimulation occurring under physiopathological conditions such as acoustic trauma.

 

 

Techniques: functional model of cochlear slices ex vivo, gross cochlear and auditory nerve single unit recordings coupled with intracochlear perfusions in vivo.

 

Keywords: glutamate, cochlear AMPA & NMDA receptors, vesicular glutamate transporters (VGLUT3), synaptic transmission, dopamine modulation, excitotoxicity, genetic deafness (DFNA25), tinnitus and inner ear therapy.

 

Patent:  

- Inserm/NeuroSystec, WO2004/022069A1: “Delivery of modulators of glutamate-mediated neurotransmission to the inner ear".

- Inserm/Auris Medical, WO2005/5094799: “Use of an NMDA receptor antagonist for the treatment of tinnitus induced by excitotoxicity”.

 

Pharmacology and electrophysiology of the cochlear inner hair cell-synaptic complex

 

 

Selected publications:

 

C.G. d’Aldin, J. Ruel, R. Assié, R. Pujol, J.L. Puel (1997). Implication of NMDA type glutamate receptors in neural regeneration and neoformation of synapses after excitotoxic injury in the guinea pig cochlea.  International Journal of Developmental Neuroscience, 15: 619-629.

 

J.L. Puel, J. Ruel, C.G. d’Aldin, R. Pujol (1998). Excitotoxicity and repair of cochlear synapses after noise-trauma induced hearing loss.  NeuroReport, 9: 2109-2114.

 

J. Ruel, C. Chen, R. Pujol, R.P. Bobbin, J.L. Puel (1999). AMPA-preferring glutamate receptors in cochlear physiology of adult guinea pig.  Journal of Physiology (London), 518: 667-680.

 

J. Ruel, R.P. Bobbin, D. Vidal, R. Pujol, J.L. Puel (2000). The selective AMPA receptor antagonist GYKI 53784 blocks action potential generation and excitotoxicity in the guinea pig cochlea.  Neuropharmacology, 39: 1959-1973.

 

J. Ruel, R. Nouvian, C. Gervais d’Aldin, R. Pujol, M. Eybalin, J.L. Puel (2001). Dopamine inhibition of the auditory nerve activity in the adult mammalian cochlea.  European Journal of Neuroscience, 14: 977-986.

 

J.L. Puel, J. Ruel, M. Guitton, J. Wang, R. Pujol (2002). The inner hair cell synaptic complex: physiology, pharmacology and new therapeutic strategies.  Audiology & Neuro-Otology, 7: 49-54.

 

J. Ruel, M.J. Guitton, J.L. Puel (2002). Negative allosteric modulation of AMPA-preferring receptors by the selective isomer GYKI 53784 (LY303070), a specific non-competitive AMPA antagonist.  CNS Drug Reviews, 8: 235-254.

 

G. Rebillard, J. Ruel, R. Nouvian, H. Saleh, R. Pujol, Y. Dehnes, J. Raymond, J.L. Puel, G. Devau (2003). Glutamate transporters in the guinea pig cochlea: partial mRNA sequences, cellular expression and functional implications.  European Journal of Neuroscience, 17:83-92.

 

M.J. Guitton., J. Caston, J. Ruel, R.M. Johnson, R. Pujol, J.L. Puel (2003). Salicylate induces tinnitus through activation of cochlear NMDA receptors.  Journal of Neuroscience, 23:3944-3952.

 

R. Nouvian, J. Ruel, J. Wang, M.J. Guitton, R. Pujol, J.L. Puel (2003). Degeneration of sensory outer hair cells following pharmacological blockade of cochlear KCNQ channels in the adult guinea pig. European Journal of Neuroscience, 17: 2553-2562.

 

S. Boyer, J. Ruel, J.L. Puel, C. Chabbert (2004). A procedure to label inner ear afferent nerve endings for calcium imaging. Brain Res. Protoc., 13:91-8.

 

B. Delprat, J. Ruel, M.J. Guitton, G. Hamard, M. Lenoir, R. Pujol, J.L. Puel, P. Brabet, C.P. Hamel (2005). Deafness and cochlear fibrocyte alterations in mice deficient for the inner ear protein otospiralin. Molecular Cellular Biology, 25:847-53.

 

J. Ruel, J. Wang, R. Pujol, A. Hameg, M. Dib, J.L. Puel (2005). Neuroprotective effect of riluzole in acute noise-induced hearing loss.  NeuroReport, 13;16:1087-90.

 

J. Ruel, J. Wang, D. Demêmes, S. Gobaille, J.L. Puel, G. Rebillard (2006). Dopamine transporter is essential for the maintenance of spontaneous activity of auditory nerve neurons and their responsiveness to sound stimulation. Journal of Neurochemistry, 97: 190-200.

 

F. Venail, J. Wang, J. Ruel, E. Ballana, G. Rebillard, M. Eybalin, M. Arbones, A. Bosch, J.L. Puel (2007). Coxsackie adenovirus receptor and anb3/anb5integrins in adenovirus gene transfer of rat cochlea. Gene Therapy, 14: 30-37.

 

J. Ruel, J. Wang, G. Rebillard, M. Eybalin, R. Lloyd, R. Pujol, J.L. Puel (2007). Physiology, pharmacology and plasticity at the inner hair cell synaptic complex. Hearing Research, 227: 19-27.

 

J. Wang, J. Ruel, S. Ladrech, C. Bonny, T. R. Van De Water, J.L. Puel (2007). Inhibition of the JNK-mediated mitochondrial cell death pathway restores auditory function in sound exposed animals. Molecular Pharmacology, 71: 654-666.

 

J. Ruel, C. Chabbert, R. Nouvian, R. Bendris, M. Eybalin, C.L. Léger, J. Bourien, M. Mersel, J.L. Puel (2008). Salicylate enables cochlear arachidonic acid sensitive NMDA receptor responses. Journal of Neuroscience, 28(29): 7313-7323.

 

J. Ruel, S. Emery, R. Nouvian, T. Bersot, B. Amilhon, J. M. Van Rybroek, G. Rebillard, M. Lenoir, M. Eybalin, B. Delprat, T. A. Sivakumaran, B. Giros, S. El Mestikawy, T. Moser, R. J. H. Smith, M. M. Lesperance, J.L. Puel (2008). Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice. American Journal of Human Genetics, 83: 1-15.

 

 

 

Selected international communications:

 

J. Ruel, A. Caicedo, R. Pujol, J.L. Puel. Modulation of desensitization at AMPA versus kainate receptors by cyclothiazide and concanavalin A in cochlear physiology.  Association for Research in Otolaryngology, St Petersburg Beach, Florida, (USA), February 15-19 1998.

 

J. Ruel, C. d’Aldin, R. Pujol, J.L. Puel. Dopamine modulates excitatory neurotransmission in the guinea pig cochlea. Association for Research in Otolaryngology, St Petersburg Beach, Florida, (USA), February 13-18 1999.

 

J. Ruel, R. Nouvian, R.P. Bobbin, R. Pujol, J.L. Puel. Effect of the selective non-competitive AMPA receptor antagonist GYKI 53784 on cochlear physiology and excitotoxicity in the guinea pig cochlea.  Association for Research in Otolaryngology, St Petersburg Beach, Florida, (USA), February 20-24 2000.

 

J. Ruel, J.L. Puel, M. Guitton, J. Wang, R. Pujol. The inner hair cell synaptic complex: physiology, pharmacology and new therapeutic strategies.  “Auditory Function and Dysfunction: Molecular and Physiological Mechanisms” Satellite Meeting.  Auckland (New Zealand) August 19-22 2001.

 

J. Ruel, G. Rebillard, D. Demêmes, S. Gobaille, J. Wang, J.L. Puel. Localization and function of dopamine transporter in the mammalian cochlea. Association for Research in Otolaryngology, 29th Mid-Winter Meeting, Baltimore, (USA), February 5-9, 2006.

 

J. Ruel, R. Nouvian, G. Rebillard, M. Eybalin, J.L. Puel. Dual function of the lateral olivocochlear efferent pathway in the mammalian cochlea. Association for Research in Otolaryngology, 30th Mid-Winter Meeting, Denver Colorado, (USA), February 10-15, 2007.

 

J. Ruel, C. Chabbert, N. Nouvian, C.L. Léger, J. Bourien, M. Mersel, J.L. Puel. Mechanism by which high-dose of salicylate induces tinnitus. Association for Research in Otolaryngology, 31st Mid-Winter Meeting, Phoenix Arizona, (USA), February 16-21, 2008.

 

J. Ruel, S. Emery, R. Nouvian, T. Bersot, B. Amilhon, J. M. Van Rybroek, G. Rebillard, M. Lenoir, M. Eybalin, B. Delprat, T. A. Sivakumaran, B. Giros, S. El Mestikawy, T. Moser, R. J. H. Smith, M. M. Lesperance, J.L. Puel. Impairment of SLC17A8 encoding vesicular glutamate transporter-3 (VGLUT3) underlies profound deafness and inner hair cell dysfunction in null mice.  Inner Ear Biology Workshop. Ferrarra (Italy) September 2008.

 

 

 

Contact: jerome.ruel(at)inserm.fr

 

 

 

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