Multifaceted role of RIMBP2 in promoting hearing in murine cochlear hair cells

Chai, R.; Li, G.-L.; Li, H.; Liao, M.; Chen, X.; Lu, L.; Guo, R.; Zhang, P.; Li, Y.; Zhang, Y.; Fang, Q.; Hu, Y.; Cai, J.; Tang, M.; Gao, X.; He, S.

doi:10.1101/2022.05.03.490398

bioRxiv · 10.1101/2022.05.03.490398

Multifaceted role of RIMBP2 in promoting hearing in murine cochlear hair cells

Chai, R.·Li, G.-L.·Li, H.·Liao, M.·Chen, X.·Lu, L.·Guo, R.·Zhang, P.·Li, Y.·Zhang, Y.·Fang, Q.·Hu, Y.·Cai, J.·Tang, M.·Gao, X.·He, S.

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Abstract

In peripheral, the mammalian cochlea is a remarkable sensory apparatus, owning to its outer and inner hair cells (OHCs and IHCs) that amplify and transmit auditory signals to the brain, respectively. Rab3-interacting molecular (RIM) binding protein 2 (RIMBP2) is widely expressed in receptor cells and neurons, specifically in the active zones for exocytosis of synaptic vesicles (SVs), but its exact functions in the cochlea are not very well understood. We therefore generated a Rimbp2 knockout mouse model (Rimbp2-/-), which exhibited severely impaired hearing with not only elevated hearing thresholds but also increased latencies and reduced amplitudes in the Wave I of their auditory brainstem responses (ABRs). Consistent with the threshold elevation, we found significant loss of OHCs, likely through apoptosis, in the Rimbp2-/- cochlea. Consistent with changes observed in the ABR Wave I, we found greatly reduced exocytosis, both spontaneously and upon stimulation, in Rimbp2-/- IHCs. Specifically, our patch-clamp analysis on IHCs and postsynaptic spiral ganglion neurons (SGNs) revealed not only reduced readily releasable pool (RRP) of SVs but also reduced sustained release rate, along with complete blockade of fast endocytosis, in Rimbp2-/- IHCs. Lastly, with immunostaining of whole-mounted cochleae, we found that while the number of ribbon synapses in Rimbp2-/- IHCs was unchanged, their localization moved subtly but significantly towards the basal pole of IHCs. Taken together, we uncovered an unexpected role of RIMBP2 for OHC survival and a more extensive role in promoting IHC exocytosis than previously believed.

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Chai, R., Li, G.-L., Li, H., Liao, M., Chen, X., Lu, L., Guo, R., Zhang, P., Li, Y., Zhang, Y., Fang, Q., Hu, Y., Cai, J., Tang, M., Gao, X., He, S.. 2022-05-04. Multifaceted role of RIMBP2 in promoting hearing in murine cochlear hair cells. https://doi.org/10.1101/2022.05.03.490398

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