Sensory processing of sound

Stable Identifier
Homo sapiens
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In mammals, sounds are processed in the cochlea, a spiral-shaped organ in the inner ear (reviewed in Basch et al. 2016, Fettiplace 2017, Koppl and Manley 2019). Low frequency sounds are sensed at the distal end (apex) of the cochlea; high frequency sounds are sensed at the proximal end (base) of the cochlea (reviewed in Dallos 1992, Manley 2018). Sound vibrations are transmitted from the eardrum through the three bones of the inner ear (malleus, incus, stapes) and the oval window of the cochlea to the fluids within the cochlea. Within the organ of Corti in the cochlea there are 3 rows of outer hair cells (OHCs) on the external side of the tunnel of Corti and 1 row of inner hair cells (IHCs) on the internal side (Spoendlin 1967). Each IHC synapses with approximately 20 afferent myelinated type I spiral ganglion neurons and functions as a sensory receptor to convert the energy of sound waves to secretion of glutamate neurotransmitter. Multiple OHCs synapse with each unmyelinated type II afferent neuron and OHCs are also synapsed with efferent medial olivocochlear fibers (Spoendlin 1967). The primary function of OHCs, however, is amplification of organ of Corti motions in response to sound (Ryan and Dallos 1975). Amplification is produced by changes in receptor-potential driven cell length caused by changes in the conformation of the unusual membrane protein prestin (SLC26A5, Zheng et al. 2000).
IHCs and OHCs sense the sonic vibrations by deflection of stereocilia on their apical surfaces (reviewed in Fettiplace et al. 2017, McPherson 2018). The stereocilia are arranged in rows of increasing height, with a stereocilium of one row connected to a stereocilium of another row by a tip link composed of a CDH23 dimer on the taller stereocilium joined at its N-termini to the N-termini of a PCDH15 dimer on the shorter stereocilium. CDH23 is connected to the cytoskeleton of the taller stereocilium via MYO7A (MyoVIIa), USH1C (Harmonin), and USH1G (Sans) (reviewed in Peng et al. 2011, Cosgrove and Zallocchi 2014, Barr-Gillespie 2015, Fettiplace 2017, McGrath et al. 2017, Cunningham and Müller 2019, Ó Maoiléidigh and Ricci 2019, Velez-Ortega and Frolenkov 2019) while PCDH15 on the shorter stereocilium interacts with LHFPL5, an auxiliary subunit of the mechanoelectrical transduction channel (MET channel, also known as the mechanotransduction channel), which contains at least TMC1 or TMC2, TMIE, and the auxiliary subunits LHFPL5 and CIB2 (reviewed in Fettiplace 2016, Qiu and Müller 2018, Corey et al. 2019). Deflection of stereocilia in the direction that increases tension on the tip link causes depolarization of the cell by increasing the open probability of the MET channel, which then transports calcium and potassium into the hair cell according to the gradient of those ions between the scala media (containing endolymph at 154 mM K+ and <1 mM Ca2+) at the apex of the cell and the scala tympani (containing perilymph at 7 mM K+) at the base (reviewed in Fettiplace and Kim 2014). Similarly, compression of the tip link by deflection of the stereocilia in the opposite direction decreases the open probability of the MET channel and causes hyperpolarization of the cell.
Depolarization of IHCs causes opening of voltage-gated calcium channels arrayed in stripes on the basolateral membrane close to ribbon synapses formed between the IHC and the afferent fiber of a myelinated type I spiral ganglion neuron. This results in a localized increase in cytosolic calcium ions which interact with Otoferlin (OTOF) on glutamate-containing synaptic vesicles at the ribbon structure to activate exocytosis of glutamate into the synapse formed with the afferent neuron (reviewed in Wichmann 2015, Pangrsic and Vogl 2018). Ribbon synapses are distinguished by electron-dense ribbon structures projecting from the presynaptic membrane into the cytosol and comprising at least BASSOON, RIBEYE (an isoform of CTBP2), and PICCOLINO (an isoform of PICCOLO). The ribbon structures appear to transiently bind synaptic vesicles and facilitate resupply of synaptic vesicles at active zones to refill the pool of readily releasable vesicles (reviewed in Moser et al. 2006, Moser et al. 2020).
In contrast with IHCs, OHCs mainly function in sound amplification by decreasing up to about 4% in length in response to depolarization caused by opening of the MET channel and increasing in length in response to hyperpolarization caused by channel closing, resulting in alternating compression and decompression between the reticular lamina and the basilar membrane. The changes in the length of the OHC are caused by very rapid (microseconds), voltage-sensitive changes in the conformation of the membrane protein prestin (SLC26A5). Stereociliary ATP2B2 (PMCA2) extrudes calcium ions and basally located KCNQ4 extrudes potassium ions to repolarize the OHC.
OHCs are synapsed with efferent cholinergic medial olivocochlear fibers (reviewed in Fritzsch and Elliott 2017, Fuchs and Lauer 2019). Acetylcholine released at the synapse binds an unusual, nicotine-antagonized, nicotinic receptor comprising CHRNA9 and CHRNA10. Upon binding acetylcholine, CHRNA9:CHRNA10 transports calcium ions into the OHC. The calcium activates SK2 potassium channels (KCNN2) and BK potassium channels (KCNMA1:KCNMB1) which extrude potassium ions, hyperpolarize the OHC, and inhibit activation of the OHC.
Loud sounds can cause a temporary threshold shift (temporary loss of hearing) caused by damage to stereocilia and synapses or permanent threshold shift (permanent loss of hearing) caused by damage or death of hair cells and neurons (reviewed in Kurabi et al. 2017).

Literature References
PubMed ID Title Journal Year
27410728 Is TMC1 the Hair Cell Mechanotransducer Channel?

Fettiplace, R

Biophys. J. 2016
16944206 Hair cell ribbon synapses

Moser, T, Brandt, A, Lysakowski, A

Cell Tissue Res. 2006
24987009 The physiology of mechanoelectrical transduction channels in hearing

Fettiplace, R, Kim, KX

Physiol. Rev. 2014
28915323 Hair Cell Transduction, Tuning, and Synaptic Transmission in the Mammalian Cochlea

Fettiplace, R

Compr Physiol 2017
24239741 Usher protein functions in hair cells and photoreceptors

Cosgrove, D, Zallocchi, M

Int. J. Biochem. Cell Biol. 2014
22045002 Integrating the biophysical and molecular mechanisms of auditory hair cell mechanotransduction

Peng, AW, Salles, FT, Pan, B, Ricci, AJ

Nat Commun 2011
10821263 Prestin is the motor protein of cochlear outer hair cells

Zheng, J, Shen, W, He, DZ, Long, KB, Madison, LD, Dallos, P

Nature 2000
1464757 The active cochlea

Dallos, P

J. Neurosci. 1992
27916698 Cellular mechanisms of noise-induced hearing loss

Kurabi, A, Keithley, EM, Housley, GD, Ryan, AF, Wong, AC

Hear. Res. 2017
28484373 Evolution and Development of the Inner Ear Efferent System: Transforming a Motor Neuron Population to Connect to the Most Unusual Motor Protein via Ancient Nicotinic Receptors

Fritzsch, B, Elliott, KL

Front Cell Neurosci 2017
26052920 Where hearing starts: the development of the mammalian cochlea

Basch, ML, Brown, RM, Jen, HI, Groves, AK

J. Anat. 2016
30082454 Efferent Inhibition of the Cochlea

Fuchs, PA, Lauer, AM

Cold Spring Harb Perspect Med 2019
26188105 Molecularly and structurally distinct synapses mediate reliable encoding and processing of auditory information

Wichmann, C

Hear. Res. 2015
30638948 Building and repairing the stereocilia cytoskeleton in mammalian auditory hair cells

Vélez-Ortega, AC, Frolenkov, GI

Hear. Res. 2019
30251250 Balancing presynaptic release and endocytic membrane retrieval at hair cell ribbon synapses

Pangršič, T, Vogl, C

FEBS Lett. 2018
31373863 Sensory Processing at Ribbon Synapses in the Retina and the Cochlea

Moser, T, Grabner, CP, Schmitz, F

Physiol. Rev. 2020
30181353 A Functional Perspective on the Evolution of the Cochlea

Köppl, C, Manley, GA

Cold Spring Harb Perspect Med 2019
30116889 Travelling waves and tonotopicity in the inner ear: a historical and comparative perspective

Manley, GA

J. Comp. Physiol. A Neuroethol. Sens. Neural. Behav. Physiol. 2018
30082452 Molecular Structure of the Hair Cell Mechanoelectrical Transduction Complex

Cunningham, CL, Müller, U

Cold Spring Harb Perspect Med 2019
29755320 Mechanically Gated Ion Channels in Mammalian Hair Cells

Qiu, X, Müller, U

Front Cell Neurosci 2018
1110747 Effect of absence of cochlear outer hair cells on behavioural auditory threshold

Ryan, A, Dallos, P

Nature 1975
30291150 Function and Dysfunction of TMC Channels in Inner Ear Hair Cells

Corey, DP, Akyuz, N, Holt, JR

Cold Spring Harb Perspect Med 2019
30661717 A Bundle of Mechanisms: Inner-Ear Hair-Cell Mechanotransduction

Ó Maoiléidigh, D, Ricci, AJ

Trends Neurosci. 2019
26229154 Assembly of hair bundles, an amazing problem for cell biology

Barr-Gillespie, PG

Mol. Biol. Cell 2015
29917041 Sensory Hair Cells: An Introduction to Structure and Physiology

McPherson, DR

Integr. Comp. Biol. 2018
27565685 Stereocilia morphogenesis and maintenance through regulation of actin stability

McGrath, J, Roy, P, Perrin, BJ

Semin. Cell Dev. Biol. 2017
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