Lack of oncomodulin increases ATP-dependent calcium signaling and susceptibility to noise in adult mice

Dysregulation of Ca2+ homeostasis in cochlear outer hair cells (OHCs) is associated with impaired hearing following noise exposure. Ca2+ signaling in developing OHCs is modulated by oncomodulin (OCM), an EF-hand calcium-binding protein. Here, we investigated whether the lack of OCM disrupts Ca2+ signaling in mature OHCs and influences vulnerability to moderate noise. Using young adult CBA/CaJ mice of either sex, we found that OHCs from Ocm knock-out (Ocm−/−) mice showed comparable electromotile responses and synaptic innervation compared with littermate controls. Prior to noise exposure, Ocm−/− mice had auditory brainstem responses with highly variable latencies and amplitudes compared with Ocm+/+ mice. Moderate noise exposure (95 dB SPL, 2 h) caused temporary threshold shifts in wild-type (Ocm+/+) mice but PTS in Ocm−/− mice. Using a genetically encoded Ca2+ sensor (GCaMP6s) expressed in OHCs, we found increased GCaMP6s fluorescence and ATP-induced Ca2+ signaling in Ocm−/− OHCs. Using GCaMP6s mice of either sex, P2X2 expression was also higher throughout the cochlea of Ocm−/− mice compared with Ocm+/+ mice. Prolonged noise exposure (95 dB SPL, 9 h) led to greater threshold shifts in Ocm−/− mice and upregulated expression of P2X2 receptors in the cochlea of Ocm+/+ but not in the Ocm−/− mice. Prolonged noise exposure did not change the number of presynaptic OHC ribbons. We propose that the lack of OCM leads to a noise-exposed phenotype that increases susceptibility to cochlear pathology. Additionally, the combination of increased purinergic signaling and dysregulation of cytosolic Ca2+ homeostasis likely contributes to early-onset hearing loss in Ocm−/− mice.