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

Autores
Taranda, Julian; Maison, Stéphane F.; Ballestero, Jimena Andrea; Katz, Eleonora; Savino, Jessica; Vetter, Douglas E.; Boulter, Jim; Liberman, M. Charles; Fuchs, Paul A.; Elgoyhen, Ana Belen
Año de publicación
2009
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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 of knockin mice with a threonine for leucine change (L9′T) at position 9′ of the second transmembrane domain of the α9 nicotinic cholinergic subunit, rendering α9-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 α9α10 hair cell nicotinic receptor. Importantly, relative to their wild-type littermates, Chrna9L9′T/L9′T mice showed less permanent hearing loss following exposure to intense noise. Thus, a point mutation designed to alter α9α10 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.
Fil: Taranda, Julian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Tufts University School of Medicine; Estados Unidos
Fil: Maison, Stéphane F.. Massachusetts Eye and Ear Infirmary; Estados Unidos
Fil: Ballestero, Jimena Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Katz, Eleonora. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Savino, Jessica. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Vetter, Douglas E.. Tufts University School of Medicine; Estados Unidos
Fil: Boulter, Jim. University of California at Los Angeles; Estados Unidos
Fil: Liberman, M. Charles. Massachusetts Eye and Ear Infirmary; Estados Unidos
Fil: Fuchs, Paul A.. The Johns Hopkins University School of Medicine; Estados Unidos
Fil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; Argentina
Materia
KNOCK-IN MOUSE
NICOTINIC CHOLINERGIC RECEPTORS
NOISE PROTECTION
EFFERENT FEEDBACK
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/79632
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/79632
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling A point mutation in the hair cell nicotinic cholinergic receptor prolongs cochlear inhibition and enhances noise protectionTaranda, JulianMaison, Stéphane F.Ballestero, Jimena AndreaKatz, EleonoraSavino, JessicaVetter, Douglas E.Boulter, JimLiberman, M. CharlesFuchs, Paul A.Elgoyhen, Ana BelenKNOCK-IN MOUSENICOTINIC CHOLINERGIC RECEPTORSNOISE PROTECTIONEFFERENT FEEDBACKhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The 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 of knockin mice with a threonine for leucine change (L9′T) at position 9′ of the second transmembrane domain of the α9 nicotinic cholinergic subunit, rendering α9-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 α9α10 hair cell nicotinic receptor. Importantly, relative to their wild-type littermates, Chrna9L9′T/L9′T mice showed less permanent hearing loss following exposure to intense noise. Thus, a point mutation designed to alter α9α10 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.Fil: Taranda, Julian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Tufts University School of Medicine; Estados UnidosFil: Maison, Stéphane F.. Massachusetts Eye and Ear Infirmary; Estados UnidosFil: Ballestero, Jimena Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Katz, Eleonora. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Savino, Jessica. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Vetter, Douglas E.. Tufts University School of Medicine; Estados UnidosFil: Boulter, Jim. University of California at Los Angeles; Estados UnidosFil: Liberman, M. Charles. Massachusetts Eye and Ear Infirmary; Estados UnidosFil: Fuchs, Paul A.. The Johns Hopkins University School of Medicine; Estados UnidosFil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; ArgentinaPublic Library of Science2009-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/79632Taranda, Julian; Maison, Stéphane F.; Ballestero, Jimena Andrea; Katz, Eleonora; Savino, Jessica; et al.; A point mutation in the hair cell nicotinic cholinergic receptor prolongs cochlear inhibition and enhances noise protection; Public Library of Science; PLoS Biology; 7; 1; 1-2009; 71-831544-9173CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.1000018info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pbio.1000018info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:41:10Zoai:ri.conicet.gov.ar:11336/79632instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:41:10.699CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv A point mutation in the hair cell nicotinic cholinergic receptor prolongs cochlear inhibition and enhances noise protection
title A point mutation in the hair cell nicotinic cholinergic receptor prolongs cochlear inhibition and enhances noise protection
spellingShingle A point mutation in the hair cell nicotinic cholinergic receptor prolongs cochlear inhibition and enhances noise protection
Taranda, Julian
KNOCK-IN MOUSE
NICOTINIC CHOLINERGIC RECEPTORS
NOISE PROTECTION
EFFERENT FEEDBACK
title_short A point mutation in the hair cell nicotinic cholinergic receptor prolongs cochlear inhibition and enhances noise protection
title_full A point mutation in the hair cell nicotinic cholinergic receptor prolongs cochlear inhibition and enhances noise protection
title_fullStr A point mutation in the hair cell nicotinic cholinergic receptor prolongs cochlear inhibition and enhances noise protection
title_full_unstemmed A point mutation in the hair cell nicotinic cholinergic receptor prolongs cochlear inhibition and enhances noise protection
title_sort A point mutation in the hair cell nicotinic cholinergic receptor prolongs cochlear inhibition and enhances noise protection
dc.creator.none.fl_str_mv Taranda, Julian
Maison, Stéphane F.
Ballestero, Jimena Andrea
Katz, Eleonora
Savino, Jessica
Vetter, Douglas E.
Boulter, Jim
Liberman, M. Charles
Fuchs, Paul A.
Elgoyhen, Ana Belen
author Taranda, Julian
author_facet Taranda, Julian
Maison, Stéphane F.
Ballestero, Jimena Andrea
Katz, Eleonora
Savino, Jessica
Vetter, Douglas E.
Boulter, Jim
Liberman, M. Charles
Fuchs, Paul A.
Elgoyhen, Ana Belen
author_role author
author2 Maison, Stéphane F.
Ballestero, Jimena Andrea
Katz, Eleonora
Savino, Jessica
Vetter, Douglas E.
Boulter, Jim
Liberman, M. Charles
Fuchs, Paul A.
Elgoyhen, Ana Belen
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv KNOCK-IN MOUSE
NICOTINIC CHOLINERGIC RECEPTORS
NOISE PROTECTION
EFFERENT FEEDBACK
topic KNOCK-IN MOUSE
NICOTINIC CHOLINERGIC RECEPTORS
NOISE PROTECTION
EFFERENT FEEDBACK
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv 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 of knockin mice with a threonine for leucine change (L9′T) at position 9′ of the second transmembrane domain of the α9 nicotinic cholinergic subunit, rendering α9-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 α9α10 hair cell nicotinic receptor. Importantly, relative to their wild-type littermates, Chrna9L9′T/L9′T mice showed less permanent hearing loss following exposure to intense noise. Thus, a point mutation designed to alter α9α10 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.
Fil: Taranda, Julian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Tufts University School of Medicine; Estados Unidos
Fil: Maison, Stéphane F.. Massachusetts Eye and Ear Infirmary; Estados Unidos
Fil: Ballestero, Jimena Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Katz, Eleonora. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Savino, Jessica. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Vetter, Douglas E.. Tufts University School of Medicine; Estados Unidos
Fil: Boulter, Jim. University of California at Los Angeles; Estados Unidos
Fil: Liberman, M. Charles. Massachusetts Eye and Ear Infirmary; Estados Unidos
Fil: Fuchs, Paul A.. The Johns Hopkins University School of Medicine; Estados Unidos
Fil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; Argentina
description 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 of knockin mice with a threonine for leucine change (L9′T) at position 9′ of the second transmembrane domain of the α9 nicotinic cholinergic subunit, rendering α9-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 α9α10 hair cell nicotinic receptor. Importantly, relative to their wild-type littermates, Chrna9L9′T/L9′T mice showed less permanent hearing loss following exposure to intense noise. Thus, a point mutation designed to alter α9α10 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.
publishDate 2009
dc.date.none.fl_str_mv 2009-01
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/79632
Taranda, Julian; Maison, Stéphane F.; Ballestero, Jimena Andrea; Katz, Eleonora; Savino, Jessica; et al.; A point mutation in the hair cell nicotinic cholinergic receptor prolongs cochlear inhibition and enhances noise protection; Public Library of Science; PLoS Biology; 7; 1; 1-2009; 71-83
1544-9173
CONICET Digital
CONICET
url http://hdl.handle.net/11336/79632
identifier_str_mv Taranda, Julian; Maison, Stéphane F.; Ballestero, Jimena Andrea; Katz, Eleonora; Savino, Jessica; et al.; A point mutation in the hair cell nicotinic cholinergic receptor prolongs cochlear inhibition and enhances noise protection; Public Library of Science; PLoS Biology; 7; 1; 1-2009; 71-83
1544-9173
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.1000018
info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pbio.1000018
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Public Library of Science
publisher.none.fl_str_mv Public Library of Science
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.070432

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