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A point mutation in the hair cell nicotinic cholinergic receptor prolongs cochlear inhibition and enhances noise protection.

Taranda J, Maison SF, Ballestero JA, Katz E, Savino J, Vetter DE, Boulter J, Liberman MC, Fuchs PA, Elgoyhen AB - PLoS Biol. (2009)

Bottom Line: The transduction of sound in the auditory periphery, the cochlea, is inhibited by efferent cholinergic neurons projecting from the brainstem and synapsing directly on mechanosensory hair cells.One fundamental question in auditory neuroscience is what role(s) this feedback plays in our ability to hear.The Chrna9L9'T allele produced a 3-fold prolongation of efferent synaptic currents in vitro.

View Article: PubMed Central - PubMed

Affiliation: Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina.

ABSTRACT
The transduction of sound in the auditory periphery, the cochlea, is inhibited by efferent cholinergic neurons projecting from the brainstem and synapsing directly on mechanosensory hair cells. One fundamental question in auditory neuroscience is what role(s) this feedback plays in our ability to hear. In the present study, we have engineered a genetically modified mouse model in which the magnitude and duration of efferent cholinergic effects are increased, and we assess the consequences of this manipulation on cochlear function. We generated the Chrna9L9'T line of knockin mice with a threonine for leucine change (L9'T) at position 9' of the second transmembrane domain of the alpha9 nicotinic cholinergic subunit, rendering alpha9-containing receptors that were hypersensitive to acetylcholine and had slower desensitization kinetics. The Chrna9L9'T allele produced a 3-fold prolongation of efferent synaptic currents in vitro. In vivo, Chrna9L9'T mice had baseline elevation of cochlear thresholds and efferent-mediated inhibition of cochlear responses was dramatically enhanced and lengthened: both effects were reversed by strychnine blockade of the alpha9alpha10 hair cell nicotinic receptor. Importantly, relative to their wild-type littermates, Chrna9(L9'T/L9'T) mice showed less permanent hearing loss following exposure to intense noise. Thus, a point mutation designed to alter alpha9alpha10 receptor gating has provided an animal model in which not only is efferent inhibition more powerful, but also one in which sound-induced hearing loss can be restrained, indicating the ability of efferent feedback to ameliorate sound trauma.

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Schematics Showing the Central Origin (A) and Peripheral Projections (B) of the MOC Fibers and the Cholinergic Synapse onto OHCs in the Mature Organ of Corti (C)MOC efferent neurons are located in the superior olivary complex of the brainstem and project to the cochlea, where they make direct synaptic contacts at the base of the OHCs. At this synapse, ACh is released. It binds to α9α10 receptors present at the OHCs, leading to Ca2+ influx and the subsequent activation of Ca2+-dependent SK2 K+ channels and hair cell hyperpolarization. The black arrow in (A) indicates the place of electrical stimulation to activate the MOC fibers. The white arrow in (B) indicates the afferent fibers that bring the information from the IHCs to the central nervous system, and the red arrow indicates the MOC fibers. For approximately 10 d after birth (before the onset of hearing), cholinergic efferents temporarily synapse directly with IHCs (not shown in the figure) and provide a useful experimental target for the study of altered α9α10 receptors.
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pbio-1000018-g001: Schematics Showing the Central Origin (A) and Peripheral Projections (B) of the MOC Fibers and the Cholinergic Synapse onto OHCs in the Mature Organ of Corti (C)MOC efferent neurons are located in the superior olivary complex of the brainstem and project to the cochlea, where they make direct synaptic contacts at the base of the OHCs. At this synapse, ACh is released. It binds to α9α10 receptors present at the OHCs, leading to Ca2+ influx and the subsequent activation of Ca2+-dependent SK2 K+ channels and hair cell hyperpolarization. The black arrow in (A) indicates the place of electrical stimulation to activate the MOC fibers. The white arrow in (B) indicates the afferent fibers that bring the information from the IHCs to the central nervous system, and the red arrow indicates the MOC fibers. For approximately 10 d after birth (before the onset of hearing), cholinergic efferents temporarily synapse directly with IHCs (not shown in the figure) and provide a useful experimental target for the study of altered α9α10 receptors.

Mentions: The medial olivocochlear (MOC) efferents (Figure 1A) originate in the medial portion of the superior olivary complex and project to outer hair cells (OHCs; Figure 1B) of the organ of Corti, where large synaptic contacts are formed [2]. In contrast to IHCs, OHCs act as biological motors to amplify the sound-evoked motions of the organ of Corti through a type of somatic electromotility generated by a specialized membrane protein known as prestin. Activation of the MOC pathway, either by sound or by shock trains delivered to the bundle at the floor of the IVth ventricle (Figure 1A), reduces cochlear sensitivity through the action of the neurotransmitter acetylcholine (ACh) on nicotinic receptors (nAChRs) at the base of OHCs (Figure 1C) [3]. Although significant progress has been made in defining the cellular mechanisms of hair cell inhibition [3], the functional role(s) of this sound-evoked feedback system, including control of the dynamic range of hearing [2], improvement of signal detection in background noise [4–6], mediating selective attention [7,8], and protection from acoustic injury [9], remain controversial.


A point mutation in the hair cell nicotinic cholinergic receptor prolongs cochlear inhibition and enhances noise protection.

Taranda J, Maison SF, Ballestero JA, Katz E, Savino J, Vetter DE, Boulter J, Liberman MC, Fuchs PA, Elgoyhen AB - PLoS Biol. (2009)

Schematics Showing the Central Origin (A) and Peripheral Projections (B) of the MOC Fibers and the Cholinergic Synapse onto OHCs in the Mature Organ of Corti (C)MOC efferent neurons are located in the superior olivary complex of the brainstem and project to the cochlea, where they make direct synaptic contacts at the base of the OHCs. At this synapse, ACh is released. It binds to α9α10 receptors present at the OHCs, leading to Ca2+ influx and the subsequent activation of Ca2+-dependent SK2 K+ channels and hair cell hyperpolarization. The black arrow in (A) indicates the place of electrical stimulation to activate the MOC fibers. The white arrow in (B) indicates the afferent fibers that bring the information from the IHCs to the central nervous system, and the red arrow indicates the MOC fibers. For approximately 10 d after birth (before the onset of hearing), cholinergic efferents temporarily synapse directly with IHCs (not shown in the figure) and provide a useful experimental target for the study of altered α9α10 receptors.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2628405&req=5

pbio-1000018-g001: Schematics Showing the Central Origin (A) and Peripheral Projections (B) of the MOC Fibers and the Cholinergic Synapse onto OHCs in the Mature Organ of Corti (C)MOC efferent neurons are located in the superior olivary complex of the brainstem and project to the cochlea, where they make direct synaptic contacts at the base of the OHCs. At this synapse, ACh is released. It binds to α9α10 receptors present at the OHCs, leading to Ca2+ influx and the subsequent activation of Ca2+-dependent SK2 K+ channels and hair cell hyperpolarization. The black arrow in (A) indicates the place of electrical stimulation to activate the MOC fibers. The white arrow in (B) indicates the afferent fibers that bring the information from the IHCs to the central nervous system, and the red arrow indicates the MOC fibers. For approximately 10 d after birth (before the onset of hearing), cholinergic efferents temporarily synapse directly with IHCs (not shown in the figure) and provide a useful experimental target for the study of altered α9α10 receptors.
Mentions: The medial olivocochlear (MOC) efferents (Figure 1A) originate in the medial portion of the superior olivary complex and project to outer hair cells (OHCs; Figure 1B) of the organ of Corti, where large synaptic contacts are formed [2]. In contrast to IHCs, OHCs act as biological motors to amplify the sound-evoked motions of the organ of Corti through a type of somatic electromotility generated by a specialized membrane protein known as prestin. Activation of the MOC pathway, either by sound or by shock trains delivered to the bundle at the floor of the IVth ventricle (Figure 1A), reduces cochlear sensitivity through the action of the neurotransmitter acetylcholine (ACh) on nicotinic receptors (nAChRs) at the base of OHCs (Figure 1C) [3]. Although significant progress has been made in defining the cellular mechanisms of hair cell inhibition [3], the functional role(s) of this sound-evoked feedback system, including control of the dynamic range of hearing [2], improvement of signal detection in background noise [4–6], mediating selective attention [7,8], and protection from acoustic injury [9], remain controversial.

Bottom Line: The transduction of sound in the auditory periphery, the cochlea, is inhibited by efferent cholinergic neurons projecting from the brainstem and synapsing directly on mechanosensory hair cells.One fundamental question in auditory neuroscience is what role(s) this feedback plays in our ability to hear.The Chrna9L9'T allele produced a 3-fold prolongation of efferent synaptic currents in vitro.

View Article: PubMed Central - PubMed

Affiliation: Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina.

ABSTRACT
The transduction of sound in the auditory periphery, the cochlea, is inhibited by efferent cholinergic neurons projecting from the brainstem and synapsing directly on mechanosensory hair cells. One fundamental question in auditory neuroscience is what role(s) this feedback plays in our ability to hear. In the present study, we have engineered a genetically modified mouse model in which the magnitude and duration of efferent cholinergic effects are increased, and we assess the consequences of this manipulation on cochlear function. We generated the Chrna9L9'T line of knockin mice with a threonine for leucine change (L9'T) at position 9' of the second transmembrane domain of the alpha9 nicotinic cholinergic subunit, rendering alpha9-containing receptors that were hypersensitive to acetylcholine and had slower desensitization kinetics. The Chrna9L9'T allele produced a 3-fold prolongation of efferent synaptic currents in vitro. In vivo, Chrna9L9'T mice had baseline elevation of cochlear thresholds and efferent-mediated inhibition of cochlear responses was dramatically enhanced and lengthened: both effects were reversed by strychnine blockade of the alpha9alpha10 hair cell nicotinic receptor. Importantly, relative to their wild-type littermates, Chrna9(L9'T/L9'T) mice showed less permanent hearing loss following exposure to intense noise. Thus, a point mutation designed to alter alpha9alpha10 receptor gating has provided an animal model in which not only is efferent inhibition more powerful, but also one in which sound-induced hearing loss can be restrained, indicating the ability of efferent feedback to ameliorate sound trauma.

Show MeSH
Related in: MedlinePlus