Increased activity of D5R-Kv1.3 pathway in cholinergic interneurons contributes to the hypercholinergic state of parkinsonism and dyskinesias

Autores
Tubert, Cecilia; Paz, Rodrigo Manuel; Stahl, Agostina Mónica; Rela, Lorena; Murer, Mario Gustavo
Año de publicación
2021
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
Balanced actions of dopamine (DA) and acetylcholine (ACh) shape striatal function. Striatal cholinergic interneurons (ChIs) are the main striatal ACh source. In Parkinson´s disease (PD), DAergic nigrostriatal neurons degenerate, leading to a hypercholinergic state. L-dopa treatment can induce dyskinesias (LID). Previously, we found that ChIs are hyperexcitable in a mouse model of PD as result of a reduced Kv1.3 current, and, recently, that ChIs from LID mice are even more hyperexcitable. Our aim is to identify the mechanisms underlying this hyperexcitability, which are potential new therapeutic targets for Parkinson?s disease and dyskinesias. Since hyperexcitability occurs in the absence of DA or L-dopa treatment, we hypothesize that physiologic activation of D5R, which results in increased excitability, reduces Kv1.3 current. Because the D5R, which has constitutive (ligand-independent) activity, excites ChIs in physiological conditions, we hypothesize that an alteration of D5R signaling causes ChIs hyperexcitability in PD. With ex-vivo electrophysiological recordings, we found that D5R increases ChIs excitability by reducing a Kv1.3 current through a cAMP dependent signaling cascade. Moreover, in PD and LID mouse models, elevated levels of cAMP contribute to ChIs hyperexcitability. Finally, preliminary results suggest that this pathway is overactive due to an increased constitutive activation of D5R that entails an increased cAMP production followed by a reduction in Kv1.3 current, resulting in ChIs hyperexcitability.
Fil: Tubert, Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina
Fil: Paz, Rodrigo Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina
Fil: Stahl, Agostina Mónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina
Fil: Rela, Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina
Fil: Murer, Mario Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina
XXXV Reunión Anual de la Sociedad Argentina de Investigación en Neurociencias
Ciudad Autónoma de Buenos Aires
Argentina
Sociedad Argentina de Investigación en Neurociencias
Materia
ENFERMEDAD DE PARKINSON
DISCINESIAS
INTERNEURONAS COLINÉRGICAS ESTRIATALES
ACTIVIDAD CONSTITUTIVA
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:11336/203648
Acceder
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network_acronym_str CONICETDig
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network_name_str CONICET Digital (CONICET)
spelling Increased activity of D5R-Kv1.3 pathway in cholinergic interneurons contributes to the hypercholinergic state of parkinsonism and dyskinesiasTubert, CeciliaPaz, Rodrigo ManuelStahl, Agostina MónicaRela, LorenaMurer, Mario GustavoENFERMEDAD DE PARKINSONDISCINESIASINTERNEURONAS COLINÉRGICAS ESTRIATALESACTIVIDAD CONSTITUTIVAhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Balanced actions of dopamine (DA) and acetylcholine (ACh) shape striatal function. Striatal cholinergic interneurons (ChIs) are the main striatal ACh source. In Parkinson´s disease (PD), DAergic nigrostriatal neurons degenerate, leading to a hypercholinergic state. L-dopa treatment can induce dyskinesias (LID). Previously, we found that ChIs are hyperexcitable in a mouse model of PD as result of a reduced Kv1.3 current, and, recently, that ChIs from LID mice are even more hyperexcitable. Our aim is to identify the mechanisms underlying this hyperexcitability, which are potential new therapeutic targets for Parkinson?s disease and dyskinesias. Since hyperexcitability occurs in the absence of DA or L-dopa treatment, we hypothesize that physiologic activation of D5R, which results in increased excitability, reduces Kv1.3 current. Because the D5R, which has constitutive (ligand-independent) activity, excites ChIs in physiological conditions, we hypothesize that an alteration of D5R signaling causes ChIs hyperexcitability in PD. With ex-vivo electrophysiological recordings, we found that D5R increases ChIs excitability by reducing a Kv1.3 current through a cAMP dependent signaling cascade. Moreover, in PD and LID mouse models, elevated levels of cAMP contribute to ChIs hyperexcitability. Finally, preliminary results suggest that this pathway is overactive due to an increased constitutive activation of D5R that entails an increased cAMP production followed by a reduction in Kv1.3 current, resulting in ChIs hyperexcitability.Fil: Tubert, Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Paz, Rodrigo Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Stahl, Agostina Mónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Rela, Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Murer, Mario Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaXXXV Reunión Anual de la Sociedad Argentina de Investigación en NeurocienciasCiudad Autónoma de Buenos AiresArgentinaSociedad Argentina de Investigación en NeurocienciasSociedad Argentina de Neurociencias2021info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectReuniónBookhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/203648Increased activity of D5R-Kv1.3 pathway in cholinergic interneurons contributes to the hypercholinergic state of parkinsonism and dyskinesias; XXXV Reunión Anual de la Sociedad Argentina de Investigación en Neurociencias; Ciudad Autónoma de Buenos Aires; Argentina; 2020; 1-1CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://csan2020.saneurociencias.org.ar/info:eu-repo/semantics/altIdentifier/url/https://csan2020.saneurociencias.org.ar/wp-content/uploads/2021/06/EBOOK-2020.pdfNacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:36:28Zoai:ri.conicet.gov.ar:11336/203648instacron: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 09:36:29.005CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Increased activity of D5R-Kv1.3 pathway in cholinergic interneurons contributes to the hypercholinergic state of parkinsonism and dyskinesias
title Increased activity of D5R-Kv1.3 pathway in cholinergic interneurons contributes to the hypercholinergic state of parkinsonism and dyskinesias
spellingShingle Increased activity of D5R-Kv1.3 pathway in cholinergic interneurons contributes to the hypercholinergic state of parkinsonism and dyskinesias
Tubert, Cecilia
ENFERMEDAD DE PARKINSON
DISCINESIAS
INTERNEURONAS COLINÉRGICAS ESTRIATALES
ACTIVIDAD CONSTITUTIVA
title_short Increased activity of D5R-Kv1.3 pathway in cholinergic interneurons contributes to the hypercholinergic state of parkinsonism and dyskinesias
title_full Increased activity of D5R-Kv1.3 pathway in cholinergic interneurons contributes to the hypercholinergic state of parkinsonism and dyskinesias
title_fullStr Increased activity of D5R-Kv1.3 pathway in cholinergic interneurons contributes to the hypercholinergic state of parkinsonism and dyskinesias
title_full_unstemmed Increased activity of D5R-Kv1.3 pathway in cholinergic interneurons contributes to the hypercholinergic state of parkinsonism and dyskinesias
title_sort Increased activity of D5R-Kv1.3 pathway in cholinergic interneurons contributes to the hypercholinergic state of parkinsonism and dyskinesias
dc.creator.none.fl_str_mv Tubert, Cecilia
Paz, Rodrigo Manuel
Stahl, Agostina Mónica
Rela, Lorena
Murer, Mario Gustavo
author Tubert, Cecilia
author_facet Tubert, Cecilia
Paz, Rodrigo Manuel
Stahl, Agostina Mónica
Rela, Lorena
Murer, Mario Gustavo
author_role author
author2 Paz, Rodrigo Manuel
Stahl, Agostina Mónica
Rela, Lorena
Murer, Mario Gustavo
author2_role author
author
author
author
dc.subject.none.fl_str_mv ENFERMEDAD DE PARKINSON
DISCINESIAS
INTERNEURONAS COLINÉRGICAS ESTRIATALES
ACTIVIDAD CONSTITUTIVA
topic ENFERMEDAD DE PARKINSON
DISCINESIAS
INTERNEURONAS COLINÉRGICAS ESTRIATALES
ACTIVIDAD CONSTITUTIVA
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Balanced actions of dopamine (DA) and acetylcholine (ACh) shape striatal function. Striatal cholinergic interneurons (ChIs) are the main striatal ACh source. In Parkinson´s disease (PD), DAergic nigrostriatal neurons degenerate, leading to a hypercholinergic state. L-dopa treatment can induce dyskinesias (LID). Previously, we found that ChIs are hyperexcitable in a mouse model of PD as result of a reduced Kv1.3 current, and, recently, that ChIs from LID mice are even more hyperexcitable. Our aim is to identify the mechanisms underlying this hyperexcitability, which are potential new therapeutic targets for Parkinson?s disease and dyskinesias. Since hyperexcitability occurs in the absence of DA or L-dopa treatment, we hypothesize that physiologic activation of D5R, which results in increased excitability, reduces Kv1.3 current. Because the D5R, which has constitutive (ligand-independent) activity, excites ChIs in physiological conditions, we hypothesize that an alteration of D5R signaling causes ChIs hyperexcitability in PD. With ex-vivo electrophysiological recordings, we found that D5R increases ChIs excitability by reducing a Kv1.3 current through a cAMP dependent signaling cascade. Moreover, in PD and LID mouse models, elevated levels of cAMP contribute to ChIs hyperexcitability. Finally, preliminary results suggest that this pathway is overactive due to an increased constitutive activation of D5R that entails an increased cAMP production followed by a reduction in Kv1.3 current, resulting in ChIs hyperexcitability.
Fil: Tubert, Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina
Fil: Paz, Rodrigo Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina
Fil: Stahl, Agostina Mónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina
Fil: Rela, Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina
Fil: Murer, Mario Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina
XXXV Reunión Anual de la Sociedad Argentina de Investigación en Neurociencias
Ciudad Autónoma de Buenos Aires
Argentina
Sociedad Argentina de Investigación en Neurociencias
description Balanced actions of dopamine (DA) and acetylcholine (ACh) shape striatal function. Striatal cholinergic interneurons (ChIs) are the main striatal ACh source. In Parkinson´s disease (PD), DAergic nigrostriatal neurons degenerate, leading to a hypercholinergic state. L-dopa treatment can induce dyskinesias (LID). Previously, we found that ChIs are hyperexcitable in a mouse model of PD as result of a reduced Kv1.3 current, and, recently, that ChIs from LID mice are even more hyperexcitable. Our aim is to identify the mechanisms underlying this hyperexcitability, which are potential new therapeutic targets for Parkinson?s disease and dyskinesias. Since hyperexcitability occurs in the absence of DA or L-dopa treatment, we hypothesize that physiologic activation of D5R, which results in increased excitability, reduces Kv1.3 current. Because the D5R, which has constitutive (ligand-independent) activity, excites ChIs in physiological conditions, we hypothesize that an alteration of D5R signaling causes ChIs hyperexcitability in PD. With ex-vivo electrophysiological recordings, we found that D5R increases ChIs excitability by reducing a Kv1.3 current through a cAMP dependent signaling cascade. Moreover, in PD and LID mouse models, elevated levels of cAMP contribute to ChIs hyperexcitability. Finally, preliminary results suggest that this pathway is overactive due to an increased constitutive activation of D5R that entails an increased cAMP production followed by a reduction in Kv1.3 current, resulting in ChIs hyperexcitability.
publishDate 2021
dc.date.none.fl_str_mv 2021
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info:eu-repo/semantics/conferenceObject
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Book
http://purl.org/coar/resource_type/c_5794
info:ar-repo/semantics/documentoDeConferencia
status_str publishedVersion
format conferenceObject
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/203648
Increased activity of D5R-Kv1.3 pathway in cholinergic interneurons contributes to the hypercholinergic state of parkinsonism and dyskinesias; XXXV Reunión Anual de la Sociedad Argentina de Investigación en Neurociencias; Ciudad Autónoma de Buenos Aires; Argentina; 2020; 1-1
CONICET Digital
CONICET
url http://hdl.handle.net/11336/203648
identifier_str_mv Increased activity of D5R-Kv1.3 pathway in cholinergic interneurons contributes to the hypercholinergic state of parkinsonism and dyskinesias; XXXV Reunión Anual de la Sociedad Argentina de Investigación en Neurociencias; Ciudad Autónoma de Buenos Aires; Argentina; 2020; 1-1
CONICET Digital
CONICET
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language eng
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dc.coverage.none.fl_str_mv Nacional
dc.publisher.none.fl_str_mv Sociedad Argentina de Neurociencias
publisher.none.fl_str_mv Sociedad Argentina de Neurociencias
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repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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