Abstract
DFNA25 is an autosomal-dominant and progressive form of human deafness caused by mutations in the SLC17A8 gene, which encodes the vesicular glutamate transporter type 3 (VGLUT3). To resolve the mechanisms underlying DFNA25, we studied the phenotype of the mouse harboring the p.A221V mutation in human (corresponding to p.A224V in mouse). Using auditory brainstem response and distortion products of otoacoustic emissions, we showed that VGLUT3 A224V/A224V mouse replicates the DFNA25 progressive hearing loss with intact cochlear amplification. Scanning electron microscopy examinations demonstrated fused stereocilia bundle of the inner hair cells (IHCs) as the primary cause for DFNA25. In addition, the IHC ribbon synapses undergo structural and functional modifications at later stages. Using super-resolution microscopy, we observed oversized synaptic ribbons associated with an increase in the rate of the sustained releasable pool of exocytosis. These results indicate that the primary defect in DFNA25 stems from a failure in the mechano-transduction followed by a change in synaptic transfer. The VGLUT3 A224V/A224V mouse model opens the way to a deeper understanding and to a potential treatment of DFNA25.