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For normal cochlear function, outer hair cells (OHCs) require a precise control of intracellular Ca 2+ levels. In the absence of regulatory elements such as proteinaceous buffers or extrusion pumps, OHCs degenerate, leading to profound hearing impairment. Influx of Ca 2+ occurs both at the stereocilia tips and the basolateral membrane. In this latter compartment, two different origins for Ca 2+ influx have been poorly explored: voltage-gated L-type Ca 2+ channels (VGCCs) at synapses with Type II afferent neurons, and α9α10 cholinergic nicotinic receptors at synapses with medio-olivochlear complex (MOC) neurons. Using functional imaging in mouse OHCs, we dissected Ca 2+ influx individually through each of these sources, either by applying step depolarizations to activate VGCC, or stimulating MOC axons. Ca 2+ ions originated in MOC synapses, but not by VGCC activation, was confined by Ca 2+ -ATPases most likely present in nearby synaptic cisterns. Although Ca 2+ currents in OHCs are small, VGCC Ca 2+ signals were comparable in size to those elicited by α9α10 receptors, and were potentiated by ryanodine receptors (RyRs). In contrast, no evidence of potentiation by RyRs was found for MOC Ca 2+ signals over a wide range of presynaptic stimulation strengths. Our study shows that despite the fact that these two Ca 2+ entry sites are closely positioned, they differ in their regulation by intracellular cisterns and/or organelles, suggesting the existence of well-tuned mechanisms to separate the two different OHC synaptic functions. SIGNIFICANCE STATEMENT Outer hair cells (OHCs) are sensory cells in the inner ear operating under very special constraints. Acoustic stimulation leads to fast changes both in membrane potential and in the intracellular concentration of metabolites such as Ca 2+ Tight mechanisms for Ca 2+ control in OHCs have been reported. Interestingly, Ca 2+ is crucial for two important synaptic processes: inhibition by efferent cholinergic neurons, and glutamate release onto Type II afferent fibers. In the current study we functionally imaged Ca 2+ at these two different synapses, showing close positioning within the basolateral compartment of OHCs. In addition, we show differential regulation of these two Ca 2+ sources by synaptic cisterns and/or organelles, which could result crucial for functional segregation during normal hearing.

Synaptic Contributions to Cochlear Outer Hair Cell Ca2+ Dynamics

Synaptic Contributions to Cochlear Outer Hair Cell Ca²⁺ Dynamics