Experimental Otology Group, InnerEarLab, Department of Otolaryngology, University Medical Center Göttingen, Göttingen, Germany; Auditory Neuroscience Group, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
Shashank Chepurwar
Auditory Systems Physiology Group, Institute for Auditory Neuroscience, InnerEarLab, University Medical Center Göttingen, Göttingen, Germany; Collaborative Research Center 889, University of Göttingen, Göttingen, Germany
Kathrin Kusch
Functional Auditory Genomics, Institute for Auditory Neuroscience, University Medical Center Göttingen, Göttingen, Germany; Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany
Vladan Rankovic
Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany; Restorative Cochlear Genomics Group, Auditory Neuroscience and Optogenetics Laboratory, German Primate Cente, Göttingen, Germany
Sangyong Jung
Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany
Auditory Systems Physiology Group, Institute for Auditory Neuroscience, InnerEarLab, University Medical Center Göttingen, Göttingen, Germany; Collaborative Research Center 889, University of Göttingen, Göttingen, Germany
Experimental Otology Group, InnerEarLab, Department of Otolaryngology, University Medical Center Göttingen, Göttingen, Germany; Auditory Neuroscience Group, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany; Collaborative Research Center 889, University of Göttingen, Göttingen, Germany; Multiscale Bioimaging Cluster of Excellence (MBExC), University of Göttingen, Göttingen, Germany
To encode continuous sound stimuli, the inner hair cell (IHC) ribbon synapses utilize calcium-binding proteins (CaBPs), which reduce the inactivation of their CaV1.3 calcium channels. Mutations in the CABP2 gene underlie non-syndromic autosomal recessive hearing loss DFNB93. Besides CaBP2, the structurally related CaBP1 is highly abundant in the IHCs. Here, we investigated how the two CaBPs cooperatively regulate IHC synaptic function. In Cabp1/2 double-knockout mice, we find strongly enhanced CaV1.3 inactivation, slowed recovery from inactivation and impaired sustained exocytosis. Already mild IHC activation further reduces the availability of channels to trigger synaptic transmission and may effectively silence synapses. Spontaneous and sound-evoked responses of spiral ganglion neurons in vivo are strikingly reduced and strongly depend on stimulation rates. Transgenic expression of CaBP2 leads to substantial recovery of IHC synaptic function and hearing sensitivity. We conclude that CaBP1 and 2 act together to suppress voltage- and calcium-dependent inactivation of IHC CaV1.3 channels in order to support sufficient rate of exocytosis and enable fast, temporally precise and indefatigable sound encoding.
