Our laboratory is working on research projects, with the two linked goals: (i) to decipher the cellular and molecular mechanisms that underlie the development and functioning of the auditory system; and (ii) to identify the defective genes responsible for human hearing impairment as means of elucidating the pathogenesis of the corresponding forms of deafness. To date our work has focused mainly on the sensory organ, the cochlea, but recently the activity has extended into new areas of auditory processing

Progress in 2006 included the following:

- The identification of the causative gene for the DFNB59 deafness form, and the mouse model generated revealed that this gene encodes a novel cytosolic protein, called pejvakin. Pejvakin is expressed in spiral ganglion and auditory brainstem neurons and is involved in their synchronized firing. DFNB59 is the first form of inherited isolated deafness not due to a cochlear defect but an auditory neuronopathy, thereby possibly providing an entry point to understanding post-synaptic processes.

- We have shown that otoferlin, encoded by DFNB9, is a synaptic vesicle transmembrane protein composed of six C2 domains, and expressed by the inner hair cells. These synapses have distinct morphological features (ribbons), physiological properties (high temporal precision and sustained exocytosis) and molecular composition (L-type Ca²⁺ channels and no synapsins nor synaptotagmins I and II). We found that otoferlin binds, and in a Ca²⁺-dependent manner, two SNARE proteins, syntaxin 1 and SNAP25, as does synaptotagmin I. By combining EM analyses, capacitance measurements and direct stimulation of the spiral ganglion neurons in otoferlin null mice, we conclude that otoferlin is essential for a late step of synaptic vesicle exocytosis. It may act as the major Ca²⁺ sensor triggering membrane fusion at the IHC ribbon synapse and thereby “substitute” for the missing synaptotagmin I.

- The hair bundle, the mechano-electrical transduction organelle, works as a single functional unit. We previously proposed that Usher syndrome type I (USH1) (deafness associated to blindness) genes will enlighten the mechanisms underlying the hair bundle cohesion. Work performed in 2006 fully supports our hypothesis.

- The endocochlear potential (EP), produced by the stria vascularis (SV) of the cochlea, provides more than half of the current driving force for transduction in auditory hair cells. By studying deaf mice defective in the gap junction protein connexin 30, that fail to develop EP, we have uncovered a novel pathogenic process for deafness, the blood barrier disruption of the capillaries supplying the stria vascularis compartment. This anomaly, by creating an electrical shunt into the SV, could readily explain the absence of EP.