Lack of Oncomodulin Increases ATP-Dependent Calcium Signaling and Susceptibility to Noise in Adult Mice

Abstract Tight regulation of Ca 2+ is crucial for the function of cochlear outer hair cells (OHCs). Dysregulation of Ca 2+ homeostasis in OHCs is associated with impaired hearing and contributes to increased vulnerability to insults such as noise exposure. Ca 2+ signaling in developing OHCs is modulated by oncomodulin (OCM), an EF-hand calcium-binding protein. Here, we investigated whether the lack of OCM disrupts the control of intracellular Ca 2+ in mature OHCs, and influences vulnerability to acoustic injury. Using young adult CBA/CaJ mice, we found that OHCs from Ocm -knockout ( Ocm -/- ) mice showed normal biophysical profiles, electromotile responses, and synaptic innervation compared to littermate controls. Moderate noise exposure (95 dB SPL, 2 hrs) caused temporary threshold shifts in Ocm +/+ and Ocm -/- mice. However, while Ocm +/+ fully recovered thresholds 2 weeks after noise exposure, Ocm -/- mice showed permanent threshold shifts. Additionally, Ocm -/- mice had auditory brainstem responses with highly variable latencies and amplitudes both before and after noise exposure compared to Ocm +/+ mice. Using a genetically encoded Ca 2+ sensor (GCaMP6s) expressed in Ocm +/+ and Ocm -/- OHCs, we found that prolonged noise exposure (95 dB SPL, 9 hrs) significantly increased GCaMP6s fluorescence, ATP-induced Ca 2+ signaling and also caused greater threshold shifts in Ocm -/- compared to Ocm +/+ OHCs. However, prolonged noise exposure had no significant change in the number of presynaptic OHC ribbons in either Ocm +/+ or Ocm -/- mice. We assessed whether the ATP-induced responses were due to changes in P2X2 receptor expression. Prior to noise exposure, P2X2 expression was higher in the cochlea of Ocm -/- mice compared to Ocm +/+ mice. Following prolonged noise, P2X2 receptors were upregulated in the cochlea of Ocm +/+ but not in the Ocm -/- mice, which retained their pre-noise expression level. We propose that the lack of OCM increases susceptibility to cochlear pathology and that purinergic signaling and dysregulation of cytosolic Ca 2+ homeostasis likely contribute to early onset hearing loss in the Ocm -/- mice.