Abstract
Mammalian hearing involves the mechanoelectrical transduction (MET) of sound-induced fluid waves in the cochlea. Essential to this process are the specialised sensory cochlear cells, the inner (IHCs) and outer hair cells (OHCs). While genetic hearing loss is highly heterogeneous, understanding the requirement of each gene will lead to a better understanding of the molecular basis of hearing and also to therapeutic opportunities for deafness. The Neuroplastin (Nptn) gene, which encodes two protein isoforms Np55 and Np65, is required for hearing, and homozygous loss-of-function mutations that affect both isoforms lead to profound deafness in mice. Here we have utilised several distinct mouse models to elaborate upon the spatial, temporal, and functional requirement of Nptn for hearing. While we demonstrate that both Np55 and Np65 are present in cochlear cells, characterisation of a Np65-specific mouse knockout shows normal hearing thresholds indicating that Np65 is functionally redundant for hearing. In contrast, we find that Nptn-knockout mice have significantly reduced maximal MET currents and MET channel open probabilities in mature OHCs, with both OHCs and IHCs also failing to develop fully mature basolateral currents. Furthermore, comparing the hearing thresholds and IHC synapse structure of Nptn-knockout mice with those of mice that lack Nptn only in IHCs and OHCs shows that the majority of the auditory deficit is explained by hair cell dysfunction, with abnormal afferent synapses contributing only a small proportion of the hearing loss. Finally, we show that continued expression of Neuroplastin in OHCs of adult mice is required for membrane localisation of Plasma Membrane Ca2+ ATPase 2 (PMCA2), which is essential for hearing function. Moreover, Nptn haploinsufficiency phenocopies Atp2b2 (encodes PMCA2) mutations, with heterozygous Nptn-knockout mice exhibiting hearing loss through genetic interaction with the Cdh23ahl allele. Together, our findings provide further insight to the functional requirement of Neuroplastin for mammalian hearing.
Highlights
The mammalian cochlea is an extremely complex and organised structure consisting of multiple cell types that act in concert to convert sound into neuronal signals
We have shown that two types of Neuroplastin protein are both expressed within the cochlea, only one of these isoforms needs to be expressed for normal hearing
We demonstrate that the hearing loss caused by the absence of Neuroplastin is made worse when combined with a common mutation within a gene called Cadherin 23 (Cdh23ahl)
Summary
The mammalian cochlea is an extremely complex and organised structure consisting of multiple cell types that act in concert to convert sound into neuronal signals. Within the organ of Corti are two functionally distinct sensory cells: the inner hair cells (IHCs), which relay sound stimuli to the brain via the release of glutamate from ribbon synapses onto type I spiral ganglion neurons; and the outer hair cells (OHCs) which mechanically amplify sound stimuli through the generation of voltage-dependent axial forces on the organ of Corti. The function of both IHCs and OHCs is driven by mechanoelectrical transduction (MET) channels located at the tips of modified microvilli called stereocilia at the apex of each cell, activated following deflection of the stereocilia bundle. Coordinated Ca2+-signaling is required for the maturation of afferent synapses on both IHCs [3] and OHCs [4], and in mature IHCs, the influx of Ca2+, primarily through CaV1.3 channels located at each active zone, facilitates the release of vesicles onto the afferent terminals
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