Retrograde facilitation of efferent synapses on cochlear hair cells.

Cochlear inner hair cells (IHCs) are temporarily innervated by efferent cholinergic fibers prior to the onset of hearing. During low-frequency firing, these efferent synapses have a relatively low probability of transmitter release but facilitate strongly with repetitive stimulation. A retrograde signal from the hair cell to the efferent terminal contributes to this facilitation. When IHCs were treated with the ryanodine receptor agonist, cyclic adenosine phosphoribose (cADPR), release probability of the efferent terminal rose. This effect was quantified by computing the quantum content from a train of 100 suprathreshold stimuli to the efferent fibers. Quantum content was sevenfold higher when IHCs were treated with 100 μM cADPR (applied in the recording pipette). Since cADPR is membrane impermeant, this result implies that an extracellular messenger travels from the hair cell to the efferent terminal. cADPR is presumed to generate this messenger by increasing cytoplasmic calcium. Consistent with this presumption, voltage-gated calcium flux into the IHC also caused retrograde facilitation of efferent transmission. Retrograde facilitation was observed in IHCs of a vesicular glutamate transporter (VGlut3) null mouse and for wild-type rat hair cells subject to wide-spectrum glutamate receptor blockade, demonstrating that glutamate was unlikely to be the extracellular messenger. Rather, bath application of nitric oxide (NO) donors caused an increase in potassium-evoked efferent transmitter release while the NO scavenger carboxy-PTIO was able to prevent retrograde facilitation produced by cADPR or IHC depolarization. Thus, hair cell activity can drive retrograde facilitation of efferent input via calcium-dependent production of NO.