Functional and developmental changes in the inner hair cell ribbon synapses caused by Myosin VI knockout and deafness-inducing point mutation

Hearing loss is one of the most common neurosensory disorders in humans, and above half of hearing loss is caused by gene mutations. Among more than 100 genes that cause non-syndromic hearing loss, myosin VI (MYO6) is typical in terms of the complexity of underlying mechanisms, which are not well understood. In this study, we used both knock-out (Myo6 ^−/−) and point mutation (Myo6 ^C442Y) mice as animal models, performed whole-cell patch-clamp recording and capacitance measurement in the inner hair cells (IHCs) in the cochlea, and sought to reveal potential functional and developmental changes in their ribbon synapses. In Myo6 ^−/− cochleae of both before (P8-10) and after hearing onset (P18-20), exocytosis from IHCs, measured in whole-cell capacitance change (ΔC_m), was significantly reduced, Ca²⁺ current amplitude (I_Ca) was unchanged, but Ca²⁺ voltage dependency was differently altered, causing significant increase in Ca²⁺ influx in mature IHCs but not in immature IHCs. In immature IHCs of Myo6 ^C442Y/C442Y cochleae, neither ΔC_m nor I_Ca was altered, but both were reduced in mature IHCs of the same animal model. Furthermore, while the reduction of exocytosis was caused by a combination of the slower rate of depleting readily releasable (RRP) pool of synaptic vesicles and slower sustained release rate (SRR) in Myo6 ^−/− immature IHCs, it was likely due to smaller RRP and slower SRR in mature IHCs of both animal models. These results expand our understanding of the mechanisms of deafness caused by MYO6 mutations, and provide a solid theoretical and scientific basis for the diagnosis and treatment of deafness.