Journal
JOURNAL OF NEUROSCIENCE
Volume 29, Issue 34, Pages 10730-10740Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1577-09.2009
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Funding
- Deutsche Forschungsgemeinschaft
- European Community
- Bundesministerium fur Bildung und Forschung
- University of Gottingen Medical School
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Hearing relies on Ca2+ influx-triggered exocytosis in cochlear inner hair cells (IHCs). Here we studied the role of the Ca2+ channel subunit Ca-V beta(2) in hearing. Of the Ca-V beta(1-4) mRNAs, IHCs predominantly contained Ca-V beta(2). Hearing was severely impaired in mice lacking Ca-V beta(2) in extracardiac tissues (Ca-V beta(-/-)(2)). This involved deficits in cochlear amplification and sound encoding. Otoacoustic emissions were reduced or absent in Ca-V beta(-/-)(2) mice, which showed strongly elevated auditory thresholds in single neuron recordings and auditory brainstem response measurements. Ca-V beta(-/-)(2) IHCs showed greatly reduced exocytosis (by 68%). This was mostly attributable to a decreased number of membrane-standing Ca(V)1.3 channels. Confocal Ca2+ imaging revealed presynaptic Ca2+ microdomains albeit with much lower amplitudes, indicating synaptic clustering of fewer Ca(V)1.3 channels. The coupling of the remaining Ca2+ influx to IHC exocytosis appeared unaffected. Extracellular recordings of sound-evoked spiking in the cochlear nucleus and auditory nerve revealed reduced spike rates in the Ca-V beta(-/-)(2) mice. Still, sizable onset and adapted spike rates were found during suprathreshold stimulation in Ca-V beta 2(-/-) mice. This indicated that residual synaptic sound encoding occurred, although the number of presynaptic Ca(V)1.3 channels and exocytosis were reduced to one-third. The normal developmental upregulation, clustering, and gating of large-conductance Ca2+ activated potassium channels in IHCs were impaired in the absence of Ca-V beta(2). Moreover, we found the developmental efferent innervation to persist in Ca-V beta(2)-deficient IHCs. In summary, Ca-V beta(2) has an essential role in regulating the abundance and properties of Ca(V)1.3 channels in IHCs and, thereby, is critical for IHC development and synaptic encoding of sound.
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