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

Yang, Y.; Jeng, J.-Y.; Murtha, K.; Climer, L.; Ceriani, F. E.; Sese, W. D.; Hornak, A. J.; Liberman, M. C.; Marcotti, W.; Simmons, D. D.

doi:10.1101/2024.06.10.598303

bioRxiv · 10.1101/2024.06.10.598303

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

Yang, Y.·Jeng, J.-Y.·Murtha, K.·Climer, L.·Ceriani, F. E.·Sese, W. D.·Hornak, A. J.·Liberman, M. C.·Marcotti, W.·Simmons, D. D.

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Abstract

Tight regulation of Ca2+ is crucial for the function of cochlear outer hair cells (OHCs). Dysregulation of Ca2+ homeostasis in OHCs is associated with impaired hearing and contributes to increased vulnerability to insults such as 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 the control of intracellular Ca2+ 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 Ca2+ 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 Ca2+ 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 Ca2+ homeostasis likely contribute to early onset hearing loss in the Ocm-/- mice.

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Yang, Y., Jeng, J.-Y., Murtha, K., Climer, L., Ceriani, F. E., Sese, W. D., Hornak, A. J., Liberman, M. C., Marcotti, W., Simmons, D. D.. 2024-06-10. Lack of Oncomodulin Increases ATP-Dependent Calcium Signaling and Susceptibility to Noise in Adult Mice. https://doi.org/10.1101/2024.06.10.598303

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