Education & Qualification
Employment
In the last years, my research work addressed several key questions regarding the molecular mechanisms by which auditory hair cells control transmitter release at their ribbon synapses, a specific type of glutamatergic synapse found in the inner ear and retina only. These ribbon synapses are built for their specific ability to sustain the challenge of high rates of stimulation over a broad range of stimulus intensities. We showed that otoferlin (in which mutations lead to nonsyndromic hearing loss DFNB9) act as a key Ca2+-sensor, synaptotagmin-like, for controlling exocytosis of the glutamatergic synaptic vesicles in auditory inner hair cells (IHCs) [1,2]. We established that the sensitivity of otoferlin is similar in vestibular and cochlear hair cells and showed that it is the topographical organization of the Cav1.3 Ca2+ channels that determines the synaptic specificity of these sensory hair cells [3]. We revealed the importance of a synaptic F-actin network in the topographical organization of the Cav1.3 channels at the IHCs active zones and showed a crucial interaction with the usher protein clarin-1 [4]. This F-actin network surrounds the active zone and controls the diffusion rate of the synaptic vesicles to the active zones. F-actin is also found to provide mechanosensitivity to the Cav1.3 channels when varying intracellular pressure. In our most recent published study, we demonstrated that various CaV1.3 channel isoforms control distinct components of the synaptic vesicle cycle in auditory inner hair cells [5] and that viral AAV-therapy is working in a mouse model of usher-syndrome [4].
Innovative techniques: Molecular biology (q-PCR) - Electrophysiological measurements of mouse Auditory Brainstem Responses - Electrophysiological patch-clamp recordings of membrane ionic currents and capacitance (exocytosis) in cochlear hair cells from mouse organ of Corti ex-vivo - High resolution Confocal Ca2+ imaging in living cochlear hair cells- Intracellular UV- Ca2+ uncaging.
References
[1] Beurg, M., Michalski, N., Safieddine, S., Bouleau, Y., Schneggenburger, R., Chapman, E. R., Petit, C., & Dulon, D. (2010). Control of Exocytosis by Synaptotagmins and Otoferlin in Auditory Hair Cells.Journal of Neuroscience,30(40), 13281–13290.
[2] Michalski, N., Goutman, J. D., Auclair, S. M., Boutet de Monvel, J., Tertrais, M., Emptoz, A., Parrin, A., Nouaille, S., Guillon, M., Sachse, M., Ciric, D., Bahloul, A., Hardelin, J.-P., Sutton, R. B., Avan, P., Krishnakumar, S. S., Rothman, J. E., Dulon, D., Safieddine, S., & Petit, C. (2017). Otoferlin acts as a Ca2+ sensor for vesicle fusion and vesicle pool replenishment at auditory hair cell ribbon synapses. eLife,6. https://doi.org/10.7554/elife.31013 .
[3] Vincent, P. F. Y., Bouleau, Y., Safieddine, S., Petit, C., & Dulon, D. (2014). Exocytotic Machineries of Vestibular Type I and Cochlear Ribbon Synapses Display Similar Intrinsic Otoferlin-Dependent Ca2+ Sensitivity But a Different Coupling to Ca2+ Channels. Journal of Neuroscience,34(33), 10853–10869.
[4] Dulon, D., Papal, S., Patni, P., Cortese, M., Vincent, P. F. Y., Tertrais, M., Emptoz, A., Tlili, A., Bouleau, Y., MCV narratives, the ichel, V., Delmaghani, S., Aghaie, A., Pepermans, E., AlegriaPrevot, O., Akil, O., Lustig, L., Avan, P., Safieddine, S., Petit, C., & El-Amraoui, A. (2018). Clarin-1 gene transfer rescues auditory synaptopathy in model of Usher syndrome. Journal of Clinical Investigation,128(8), 3382–3401.
[5] journal-article. Vincent, P. F. Y., Bouleau, Y., Charpentier, G., Emptoz, A., Safieddine, S., Petit, C., & Dulon, D. (2017). Different CaV1.3 Channel Isoforms Control Distinct Components of the Synaptic Vesicle Cycle in Auditory Inner Hair Cells.The Journal of Neuroscience,37(11), 2960–2975. https://doi.org/10.1523/jneurosci.2374-16.2017 . RCR: 1.95 *. Dimensions Link*.