Inducible ablation of dopamine D2 receptors in adult mice impairs locomotion, motor skill learning and leads to severe parkinsonism

Autores
Bello Gay, Estefania Pilar; Casas Cordero, Rodrigo; Galiñanes, Gregorio Luis; Casey, Eric; Belluscio, Mariano Andres; Rodríguez, V; Noain, Daniela Maria Clara; Murer, Mario Gustavo; Rubinstein, Marcelo
Año de publicación
2016
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Motor execution and planning are tightly regulated by dopamine D1 and D2 receptors present in basal ganglia circuits. Although stimulation of D1 receptors is known to enhance motor function, the global effect of D2 receptor (D2R) stimulation or blockade remains highly controversial, with studies showing increasing, decreasing or no changes in motor activity. Moreover, pharmacological and genetic attempts to block or eliminate D2R have led to controversial results that questioned the importance of D2R in motor function. In this study, we generated an inducible Drd2 null-allele mouse strain that circumvented developmental compensations found in constitutive Drd2−/− mice and allowed us to directly evaluate the participation of D2R in spontaneous locomotor activity and motor learning. We have found that loss of D2R during adulthood causes severe motor impairments, including hypolocomotion, deficits in motor coordination, impaired learning of new motor routines and spontaneous catatonia. Moreover, severe motor impairment, resting tremor and abnormal gait and posture, phenotypes reminiscent of Parkinson’s disease, were evident when the mutation was induced in aged mice. Altogether, the conditional Drd2 knockout model studied here revealed the overall fundamental contribution of D2R in motor functions and explains some of the side effects elicited by D2R blockers when used in neurological and psychiatric conditions, including schizophrenia, bipolar disorder, Tourette’s syndrome, dementia, alcohol-induced delusions and obsessive-compulsive disorder.
Fil: Bello Gay, Estefania Pilar. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; Argentina
Fil: Casas Cordero, Rodrigo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; Argentina
Fil: Galiñanes, Gregorio Luis. 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: Casey, Eric. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; Argentina
Fil: Belluscio, Mariano Andres. 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: Rodríguez, V. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; Argentina
Fil: Noain, Daniela Maria Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; 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
Fil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; Argentina
Materia
Dopamine
Parkinson'S Disease
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:11336/47481
Acceder
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network_name_str CONICET Digital (CONICET)
spelling Inducible ablation of dopamine D2 receptors in adult mice impairs locomotion, motor skill learning and leads to severe parkinsonismBello Gay, Estefania PilarCasas Cordero, RodrigoGaliñanes, Gregorio LuisCasey, EricBelluscio, Mariano AndresRodríguez, VNoain, Daniela Maria ClaraMurer, Mario GustavoRubinstein, MarceloDopamineParkinson'S Diseasehttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Motor execution and planning are tightly regulated by dopamine D1 and D2 receptors present in basal ganglia circuits. Although stimulation of D1 receptors is known to enhance motor function, the global effect of D2 receptor (D2R) stimulation or blockade remains highly controversial, with studies showing increasing, decreasing or no changes in motor activity. Moreover, pharmacological and genetic attempts to block or eliminate D2R have led to controversial results that questioned the importance of D2R in motor function. In this study, we generated an inducible Drd2 null-allele mouse strain that circumvented developmental compensations found in constitutive Drd2−/− mice and allowed us to directly evaluate the participation of D2R in spontaneous locomotor activity and motor learning. We have found that loss of D2R during adulthood causes severe motor impairments, including hypolocomotion, deficits in motor coordination, impaired learning of new motor routines and spontaneous catatonia. Moreover, severe motor impairment, resting tremor and abnormal gait and posture, phenotypes reminiscent of Parkinson’s disease, were evident when the mutation was induced in aged mice. Altogether, the conditional Drd2 knockout model studied here revealed the overall fundamental contribution of D2R in motor functions and explains some of the side effects elicited by D2R blockers when used in neurological and psychiatric conditions, including schizophrenia, bipolar disorder, Tourette’s syndrome, dementia, alcohol-induced delusions and obsessive-compulsive disorder.Fil: Bello Gay, Estefania Pilar. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; ArgentinaFil: Casas Cordero, Rodrigo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; ArgentinaFil: Galiñanes, Gregorio Luis. 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: Casey, Eric. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; ArgentinaFil: Belluscio, Mariano Andres. 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: Rodríguez, V. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; ArgentinaFil: Noain, Daniela Maria Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; 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; ArgentinaFil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; ArgentinaNature Publishing Group2016-07info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/47481Bello Gay, Estefania Pilar; Casas Cordero, Rodrigo; Galiñanes, Gregorio Luis; Casey, Eric; Belluscio, Mariano Andres; et al.; Inducible ablation of dopamine D2 receptors in adult mice impairs locomotion, motor skill learning and leads to severe parkinsonism; Nature Publishing Group; Molecular Psychiatry; 22; 4; 7-2016; 595-6041359-4184CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1038/mp.2016.105info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/mp2016105info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:05:14Zoai:ri.conicet.gov.ar:11336/47481instacron: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:34982025-10-22 11:05:14.685CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Inducible ablation of dopamine D2 receptors in adult mice impairs locomotion, motor skill learning and leads to severe parkinsonism
title Inducible ablation of dopamine D2 receptors in adult mice impairs locomotion, motor skill learning and leads to severe parkinsonism
spellingShingle Inducible ablation of dopamine D2 receptors in adult mice impairs locomotion, motor skill learning and leads to severe parkinsonism
Bello Gay, Estefania Pilar
Dopamine
Parkinson'S Disease
title_short Inducible ablation of dopamine D2 receptors in adult mice impairs locomotion, motor skill learning and leads to severe parkinsonism
title_full Inducible ablation of dopamine D2 receptors in adult mice impairs locomotion, motor skill learning and leads to severe parkinsonism
title_fullStr Inducible ablation of dopamine D2 receptors in adult mice impairs locomotion, motor skill learning and leads to severe parkinsonism
title_full_unstemmed Inducible ablation of dopamine D2 receptors in adult mice impairs locomotion, motor skill learning and leads to severe parkinsonism
title_sort Inducible ablation of dopamine D2 receptors in adult mice impairs locomotion, motor skill learning and leads to severe parkinsonism
dc.creator.none.fl_str_mv Bello Gay, Estefania Pilar
Casas Cordero, Rodrigo
Galiñanes, Gregorio Luis
Casey, Eric
Belluscio, Mariano Andres
Rodríguez, V
Noain, Daniela Maria Clara
Murer, Mario Gustavo
Rubinstein, Marcelo
author Bello Gay, Estefania Pilar
author_facet Bello Gay, Estefania Pilar
Casas Cordero, Rodrigo
Galiñanes, Gregorio Luis
Casey, Eric
Belluscio, Mariano Andres
Rodríguez, V
Noain, Daniela Maria Clara
Murer, Mario Gustavo
Rubinstein, Marcelo
author_role author
author2 Casas Cordero, Rodrigo
Galiñanes, Gregorio Luis
Casey, Eric
Belluscio, Mariano Andres
Rodríguez, V
Noain, Daniela Maria Clara
Murer, Mario Gustavo
Rubinstein, Marcelo
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Dopamine
Parkinson'S Disease
topic Dopamine
Parkinson'S Disease
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Motor execution and planning are tightly regulated by dopamine D1 and D2 receptors present in basal ganglia circuits. Although stimulation of D1 receptors is known to enhance motor function, the global effect of D2 receptor (D2R) stimulation or blockade remains highly controversial, with studies showing increasing, decreasing or no changes in motor activity. Moreover, pharmacological and genetic attempts to block or eliminate D2R have led to controversial results that questioned the importance of D2R in motor function. In this study, we generated an inducible Drd2 null-allele mouse strain that circumvented developmental compensations found in constitutive Drd2−/− mice and allowed us to directly evaluate the participation of D2R in spontaneous locomotor activity and motor learning. We have found that loss of D2R during adulthood causes severe motor impairments, including hypolocomotion, deficits in motor coordination, impaired learning of new motor routines and spontaneous catatonia. Moreover, severe motor impairment, resting tremor and abnormal gait and posture, phenotypes reminiscent of Parkinson’s disease, were evident when the mutation was induced in aged mice. Altogether, the conditional Drd2 knockout model studied here revealed the overall fundamental contribution of D2R in motor functions and explains some of the side effects elicited by D2R blockers when used in neurological and psychiatric conditions, including schizophrenia, bipolar disorder, Tourette’s syndrome, dementia, alcohol-induced delusions and obsessive-compulsive disorder.
Fil: Bello Gay, Estefania Pilar. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; Argentina
Fil: Casas Cordero, Rodrigo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; Argentina
Fil: Galiñanes, Gregorio Luis. 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: Casey, Eric. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; Argentina
Fil: Belluscio, Mariano Andres. 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: Rodríguez, V. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; Argentina
Fil: Noain, Daniela Maria Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; 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
Fil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; Argentina
description Motor execution and planning are tightly regulated by dopamine D1 and D2 receptors present in basal ganglia circuits. Although stimulation of D1 receptors is known to enhance motor function, the global effect of D2 receptor (D2R) stimulation or blockade remains highly controversial, with studies showing increasing, decreasing or no changes in motor activity. Moreover, pharmacological and genetic attempts to block or eliminate D2R have led to controversial results that questioned the importance of D2R in motor function. In this study, we generated an inducible Drd2 null-allele mouse strain that circumvented developmental compensations found in constitutive Drd2−/− mice and allowed us to directly evaluate the participation of D2R in spontaneous locomotor activity and motor learning. We have found that loss of D2R during adulthood causes severe motor impairments, including hypolocomotion, deficits in motor coordination, impaired learning of new motor routines and spontaneous catatonia. Moreover, severe motor impairment, resting tremor and abnormal gait and posture, phenotypes reminiscent of Parkinson’s disease, were evident when the mutation was induced in aged mice. Altogether, the conditional Drd2 knockout model studied here revealed the overall fundamental contribution of D2R in motor functions and explains some of the side effects elicited by D2R blockers when used in neurological and psychiatric conditions, including schizophrenia, bipolar disorder, Tourette’s syndrome, dementia, alcohol-induced delusions and obsessive-compulsive disorder.
publishDate 2016
dc.date.none.fl_str_mv 2016-07
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/11336/47481
Bello Gay, Estefania Pilar; Casas Cordero, Rodrigo; Galiñanes, Gregorio Luis; Casey, Eric; Belluscio, Mariano Andres; et al.; Inducible ablation of dopamine D2 receptors in adult mice impairs locomotion, motor skill learning and leads to severe parkinsonism; Nature Publishing Group; Molecular Psychiatry; 22; 4; 7-2016; 595-604
1359-4184
CONICET Digital
CONICET
url http://hdl.handle.net/11336/47481
identifier_str_mv Bello Gay, Estefania Pilar; Casas Cordero, Rodrigo; Galiñanes, Gregorio Luis; Casey, Eric; Belluscio, Mariano Andres; et al.; Inducible ablation of dopamine D2 receptors in adult mice impairs locomotion, motor skill learning and leads to severe parkinsonism; Nature Publishing Group; Molecular Psychiatry; 22; 4; 7-2016; 595-604
1359-4184
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1038/mp.2016.105
info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/mp2016105
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
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
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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