Mechanotransduction is required for establishing and maintaining mature inner hair cells and regulating efferent innervation

AbstractThe auditory system in many mammals is immature at birth but precisely organized in adults. Spontaneous activity in the inner ear plays a critical role in guiding this process. This is shaped by an efferent pathway that descends from the brainstem and makes transient direct synaptic contacts with inner hair cells (IHCs). In this work, we used an α9 cholinergic receptor knock-in mouse model (of either sex) with enhanced medial efferent activity (Chrna9L9’T, L9’T) to understand the role of the olivocochlear system in the correct establishment of auditory circuits. Wave III of auditory brainstem responses (which represents synchronized activity of synapses within the superior olivary complex) were smaller in L9’T mice, suggesting a central dysfunction. The mechanism underlying this functional alteration was analysed in brain slices containing the medial nucleus of the trapezoid body (MNTB), where neurons are topographically organized along a medio-lateral axis. The topographic organization of MNTB physiological properties observed in WT mice was abolished in the L9’T mice. Additionally, electrophysiological recordings in slices evidenced MNTB synaptic alterations, which were further supported by morphological alterations. The present results suggest that the transient cochlear efferent innervation to IHCs during the critical period before the onset of hearing is involved in the refinement of topographic maps as well as in setting the correct synaptic transmission at central auditory nuclei.Significance StatementCochlear inner hair cells of altricial mammals display spontaneous electrical activity before hearing onset. The pattern and firing rate of these cells is crucial for the correct maturation of the central auditory pathway. A descending efferent innervation from the central nervous system contacts hair cells during this developmental window. The function of this transient efferent innervation remains an open question. The present work shows that the genetic enhancement of efferent function disrupts the orderly topographic distribution at the medial nucleus of the trapezoid body level and causes severe synaptic dysfunction. Thus, the transient efferent innervation to the cochlea is necessary for the correct establishment of the central auditory circuitry.

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Biophysical and morphological changes in inner hair cells and their efferent innervation in the ageing mouse cochlea

The Journal of Physiology ◽

10.1113/jp280256 ◽

2020 ◽

Vol 599 (1) ◽

pp. 269-287

Author(s):

Jing‐Yi Jeng ◽

Adam J. Carlton ◽

Stuart L. Johnson ◽

Steve D. M. Brown ◽

Matthew C. Holley ◽

...

Keyword(s):

Hair Cells ◽

Morphological Changes ◽

Efferent Innervation ◽

Inner Hair Cells

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Faculty Opinions recommendation of Inner hair cells are not required for survival of spiral ganglion neurons in the adult cochlea.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13483964.14861062 ◽

2012 ◽

Author(s):

Andy Groves

Keyword(s):

Hair Cells ◽

Spiral Ganglion ◽

Spiral Ganglion Neurons ◽

Inner Hair Cells ◽

Ganglion Neurons

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Faculty Opinions recommendation of LRRC52 regulates BK channel function and localization in mouse cochlear inner hair cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.736503545.793580199 ◽

2020 ◽

Author(s):

Tobias Moser

Keyword(s):

Hair Cells ◽

Bk Channel ◽

Inner Hair Cells ◽

Channel Function

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Inner hair cell stereocilia are embedded in the tectorial membrane

Nature Communications ◽

10.1038/s41467-021-22870-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Pierre Hakizimana ◽

Anders Fridberger

Keyword(s):

Electron Microscopy ◽

Hair Cell ◽

Mechanical Stimulation ◽

Hair Cells ◽

Viscous Drag ◽

Tectorial Membrane ◽

Inner Hair Cell ◽

Inner Hair Cells ◽

Inward Currents

AbstractMammalian hearing depends on sound-evoked displacements of the stereocilia of inner hair cells (IHCs), which cause the endogenous mechanoelectrical transducer channels to conduct inward currents of cations including Ca2+. Due to their presumed lack of contacts with the overlaying tectorial membrane (TM), the putative stimulation mechanism for these stereocilia is by means of the viscous drag of the surrounding endolymph. However, despite numerous efforts to characterize the TM by electron microscopy and other techniques, the exact IHC stereocilia-TM relationship remains elusive. Here we show that Ca2+-rich filamentous structures, that we call Ca2+ ducts, connect the TM to the IHC stereocilia to enable mechanical stimulation by the TM while also ensuring the stereocilia access to TM Ca2+. Our results call for a reassessment of the stimulation mechanism for the IHC stereocilia and the TM role in hearing.

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The efferents interconnecting auditory inner hair cells

Hearing Research ◽

10.1016/0378-5955(94)90059-0 ◽

1994 ◽

Vol 75 (1-2) ◽

pp. 81-92 ◽

Cited By ~ 19

Author(s):

H.M. Sobkowicz ◽

S.M. Slapnick

Keyword(s):

Hair Cells ◽

Inner Hair Cells

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Calcium- and Calmodulin-Dependent Inactivation of Calcium Channels in Inner Hair Cells of the Rat Cochlea

Journal of Neurophysiology ◽

10.1152/jn.01174.2007 ◽

2008 ◽

Vol 99 (5) ◽

pp. 2183-2193 ◽

Cited By ~ 34

Author(s):

Lisa Grant ◽

Paul Fuchs

Keyword(s):

Calcium Channels ◽

Hair Cells ◽

Calcium Currents ◽

Resting Potential ◽

Resting Membrane Potential ◽

Inner Hair Cells ◽

Voltage Gated ◽

Voltage Gated Calcium Channels ◽

Dependent Inactivation ◽

Calcium Buffering

Modulation of voltage-gated calcium channels was studied in inner hair cells (IHCs) in an ex vivo preparation of the apical turn of the rat organ of Corti. Whole cell voltage clamp in the presence of potassium channel blockers showed inward calcium currents with millisecond activation and deactivation kinetics. When temperature was raised from 22 to 37°C, the calcium currents of immature IHCs [<12 days postnatal (P12)] increased threefold in amplitude, and developed more pronounced inactivation. This was determined to be calcium-dependent inactivation (CDI) on the basis of its reliance on external calcium (substitution with barium), sensitivity to internal calcium-buffering, and voltage dependence (reflecting the calcium driving force). After the onset of hearing at P12, IHC calcium current amplitude and the extent of inactivation were greatly reduced. Although smaller than in prehearing IHCs, CDI remained significant in the mature IHC near the resting membrane potential. CDI in mature IHCs was enhanced by application of the endoplasmic calcium pump blocker, benzo-hydroquinone. Conversely, CDI in immature IHCs was reduced by calmodulin inhibitors. Thus voltage-gated calcium channels in mammalian IHCs are subject to a calmodulin-mediated process of CDI. The extent of CDI depends on the balance of calcium buffering mechanisms and may be regulated by calmodulin-specific processes. CDI provides a means for the rate of spontaneous transmitter release to be adjusted to variations in hair cell resting potential and steady state calcium influx.

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