L-DOPA treatment selectively restores spine density in dopamine receptor d2-expressing projection neurons in dyskinetic mice

Autores
Suárez, Luz M.; Solís, Oscar; Caramés, Jose M.; Taravini, Irene Rita Eloisa; Solís, Jose M.; Murer, Mario Gustavo; Moratalla, Rosario
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Background: L-3,4-dihydroxyphenylalanine (L-DOPA)–induced dyskinesia is an incapacitating complication of L-DOPA therapy that affects most patients with Parkinson’s disease. Previous work indicating that molecular sensitization to dopamine receptor D1 (D1R) stimulation is involved in dyskinesias prompted us to perform electrophysiological recordings of striatal projection “medium spiny neurons” (MSN). Moreover, because enhanced D1R signaling in drug abuse induces changes in spine density in striatum, we investigated whether the dyskinesia is related to morphological changes in MSNs. Methods: Wild-type and bacterial artificial chromosome transgenic mice (D1R-tomato and D2R–green fluorescent protein) mice were lesioned with 6-hydroxydopamine and subsequently treated with L-DOPA to induce dyskinesia. Functional, molecular, and structural changes were assessed in corticostriatal slices. Individual MSNs injected with Lucifer-Yellow were detected by immunohistochemistry for three-dimensional reconstructions with Neurolucida software. Intracellular current-clamp recordings with high-resistance micropipettes were used to characterize electrophysiological parameters. Results: Both D1R-MSNs and D2R-MSNs showed diminished spine density in totally denervated striatal regions in parkinsonian mice. Chronic L-DOPA treatment, which induced dyskinesia and aberrant FosB expression, restored spine density in D2R-MSNs but not in D1R-MSNs. In basal conditions, MSNs are more excitable in parkinsonian than in sham mice, and excitability decreases toward normal values after L-DOPA treatment. Despite this normalization of basal excitability, in dyskinetic mice, the selective D1R agonist SKF38393 increased the number of evoked action potentials in MSNs, compared with sham animals. Conclusions: Chronic L-DOPA induces abnormal spine re-growth exclusively in D2R-MSNs and robust supersensitization to D1R-activated excitability in denervated striatal MSNs. These changes might constitute the anatomical and electrophysiological substrates of dyskinesia.
Fil: Suárez, Luz M.. Consejo Superior de Investigaciones Cientificas; España
Fil: Solís, Oscar. Consejo Superior de Investigaciones Cientificas; España
Fil: Caramés, Jose M.. Consejo Superior de Investigaciones Cientificas; España
Fil: Taravini, Irene Rita Eloisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas (i); Argentina
Fil: Solís, Jose M.. Hospital Universitario Ramón y Cajal; España
Fil: Murer, Mario Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentina
Fil: Moratalla, Rosario. Consejo Superior de Investigaciones Cientificas; España
Materia
Behavioral Sensitization
Dyskinesia
L-Dopa
Medium Spiny Neuron
Parkinson'S Disease
Striatum
Three-Dimensional Neuronal Recontruction
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/13605
Acceder
id CONICETDig_ef16339f9ffad070bf9308e875e294c6
oai_identifier_str oai:ri.conicet.gov.ar:11336/13605
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling L-DOPA treatment selectively restores spine density in dopamine receptor d2-expressing projection neurons in dyskinetic miceSuárez, Luz M.Solís, OscarCaramés, Jose M.Taravini, Irene Rita EloisaSolís, Jose M.Murer, Mario GustavoMoratalla, RosarioBehavioral SensitizationDyskinesiaL-DopaMedium Spiny NeuronParkinson'S DiseaseStriatumThree-Dimensional Neuronal Recontructionhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Background: L-3,4-dihydroxyphenylalanine (L-DOPA)–induced dyskinesia is an incapacitating complication of L-DOPA therapy that affects most patients with Parkinson’s disease. Previous work indicating that molecular sensitization to dopamine receptor D1 (D1R) stimulation is involved in dyskinesias prompted us to perform electrophysiological recordings of striatal projection “medium spiny neurons” (MSN). Moreover, because enhanced D1R signaling in drug abuse induces changes in spine density in striatum, we investigated whether the dyskinesia is related to morphological changes in MSNs. Methods: Wild-type and bacterial artificial chromosome transgenic mice (D1R-tomato and D2R–green fluorescent protein) mice were lesioned with 6-hydroxydopamine and subsequently treated with L-DOPA to induce dyskinesia. Functional, molecular, and structural changes were assessed in corticostriatal slices. Individual MSNs injected with Lucifer-Yellow were detected by immunohistochemistry for three-dimensional reconstructions with Neurolucida software. Intracellular current-clamp recordings with high-resistance micropipettes were used to characterize electrophysiological parameters. Results: Both D1R-MSNs and D2R-MSNs showed diminished spine density in totally denervated striatal regions in parkinsonian mice. Chronic L-DOPA treatment, which induced dyskinesia and aberrant FosB expression, restored spine density in D2R-MSNs but not in D1R-MSNs. In basal conditions, MSNs are more excitable in parkinsonian than in sham mice, and excitability decreases toward normal values after L-DOPA treatment. Despite this normalization of basal excitability, in dyskinetic mice, the selective D1R agonist SKF38393 increased the number of evoked action potentials in MSNs, compared with sham animals. Conclusions: Chronic L-DOPA induces abnormal spine re-growth exclusively in D2R-MSNs and robust supersensitization to D1R-activated excitability in denervated striatal MSNs. These changes might constitute the anatomical and electrophysiological substrates of dyskinesia.Fil: Suárez, Luz M.. Consejo Superior de Investigaciones Cientificas; EspañaFil: Solís, Oscar. Consejo Superior de Investigaciones Cientificas; EspañaFil: Caramés, Jose M.. Consejo Superior de Investigaciones Cientificas; EspañaFil: Taravini, Irene Rita Eloisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas (i); ArgentinaFil: Solís, Jose M.. Hospital Universitario Ramón y Cajal; EspañaFil: Murer, Mario Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Moratalla, Rosario. Consejo Superior de Investigaciones Cientificas; EspañaElsevier2014-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/13605Suárez, Luz M.; Solís, Oscar; Caramés, Jose M.; Taravini, Irene Rita Eloisa; Solís, Jose M.; et al.; L-DOPA treatment selectively restores spine density in dopamine receptor d2-expressing projection neurons in dyskinetic mice; Elsevier; Biological Psychiatry; 75; 9; 5-2014; 711-7220006-3223enginfo:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0006322313004162info:eu-repo/semantics/altIdentifier/doi/10.1016/j.biopsych.2013.05.006info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T12:16:19Zoai:ri.conicet.gov.ar:11336/13605instacron: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 12:16:19.293CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv L-DOPA treatment selectively restores spine density in dopamine receptor d2-expressing projection neurons in dyskinetic mice
title L-DOPA treatment selectively restores spine density in dopamine receptor d2-expressing projection neurons in dyskinetic mice
spellingShingle L-DOPA treatment selectively restores spine density in dopamine receptor d2-expressing projection neurons in dyskinetic mice
Suárez, Luz M.
Behavioral Sensitization
Dyskinesia
L-Dopa
Medium Spiny Neuron
Parkinson'S Disease
Striatum
Three-Dimensional Neuronal Recontruction
title_short L-DOPA treatment selectively restores spine density in dopamine receptor d2-expressing projection neurons in dyskinetic mice
title_full L-DOPA treatment selectively restores spine density in dopamine receptor d2-expressing projection neurons in dyskinetic mice
title_fullStr L-DOPA treatment selectively restores spine density in dopamine receptor d2-expressing projection neurons in dyskinetic mice
title_full_unstemmed L-DOPA treatment selectively restores spine density in dopamine receptor d2-expressing projection neurons in dyskinetic mice
title_sort L-DOPA treatment selectively restores spine density in dopamine receptor d2-expressing projection neurons in dyskinetic mice
dc.creator.none.fl_str_mv Suárez, Luz M.
Solís, Oscar
Caramés, Jose M.
Taravini, Irene Rita Eloisa
Solís, Jose M.
Murer, Mario Gustavo
Moratalla, Rosario
author Suárez, Luz M.
author_facet Suárez, Luz M.
Solís, Oscar
Caramés, Jose M.
Taravini, Irene Rita Eloisa
Solís, Jose M.
Murer, Mario Gustavo
Moratalla, Rosario
author_role author
author2 Solís, Oscar
Caramés, Jose M.
Taravini, Irene Rita Eloisa
Solís, Jose M.
Murer, Mario Gustavo
Moratalla, Rosario
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Behavioral Sensitization
Dyskinesia
L-Dopa
Medium Spiny Neuron
Parkinson'S Disease
Striatum
Three-Dimensional Neuronal Recontruction
topic Behavioral Sensitization
Dyskinesia
L-Dopa
Medium Spiny Neuron
Parkinson'S Disease
Striatum
Three-Dimensional Neuronal Recontruction
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Background: L-3,4-dihydroxyphenylalanine (L-DOPA)–induced dyskinesia is an incapacitating complication of L-DOPA therapy that affects most patients with Parkinson’s disease. Previous work indicating that molecular sensitization to dopamine receptor D1 (D1R) stimulation is involved in dyskinesias prompted us to perform electrophysiological recordings of striatal projection “medium spiny neurons” (MSN). Moreover, because enhanced D1R signaling in drug abuse induces changes in spine density in striatum, we investigated whether the dyskinesia is related to morphological changes in MSNs. Methods: Wild-type and bacterial artificial chromosome transgenic mice (D1R-tomato and D2R–green fluorescent protein) mice were lesioned with 6-hydroxydopamine and subsequently treated with L-DOPA to induce dyskinesia. Functional, molecular, and structural changes were assessed in corticostriatal slices. Individual MSNs injected with Lucifer-Yellow were detected by immunohistochemistry for three-dimensional reconstructions with Neurolucida software. Intracellular current-clamp recordings with high-resistance micropipettes were used to characterize electrophysiological parameters. Results: Both D1R-MSNs and D2R-MSNs showed diminished spine density in totally denervated striatal regions in parkinsonian mice. Chronic L-DOPA treatment, which induced dyskinesia and aberrant FosB expression, restored spine density in D2R-MSNs but not in D1R-MSNs. In basal conditions, MSNs are more excitable in parkinsonian than in sham mice, and excitability decreases toward normal values after L-DOPA treatment. Despite this normalization of basal excitability, in dyskinetic mice, the selective D1R agonist SKF38393 increased the number of evoked action potentials in MSNs, compared with sham animals. Conclusions: Chronic L-DOPA induces abnormal spine re-growth exclusively in D2R-MSNs and robust supersensitization to D1R-activated excitability in denervated striatal MSNs. These changes might constitute the anatomical and electrophysiological substrates of dyskinesia.
Fil: Suárez, Luz M.. Consejo Superior de Investigaciones Cientificas; España
Fil: Solís, Oscar. Consejo Superior de Investigaciones Cientificas; España
Fil: Caramés, Jose M.. Consejo Superior de Investigaciones Cientificas; España
Fil: Taravini, Irene Rita Eloisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas (i); Argentina
Fil: Solís, Jose M.. Hospital Universitario Ramón y Cajal; España
Fil: Murer, Mario Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentina
Fil: Moratalla, Rosario. Consejo Superior de Investigaciones Cientificas; España
description Background: L-3,4-dihydroxyphenylalanine (L-DOPA)–induced dyskinesia is an incapacitating complication of L-DOPA therapy that affects most patients with Parkinson’s disease. Previous work indicating that molecular sensitization to dopamine receptor D1 (D1R) stimulation is involved in dyskinesias prompted us to perform electrophysiological recordings of striatal projection “medium spiny neurons” (MSN). Moreover, because enhanced D1R signaling in drug abuse induces changes in spine density in striatum, we investigated whether the dyskinesia is related to morphological changes in MSNs. Methods: Wild-type and bacterial artificial chromosome transgenic mice (D1R-tomato and D2R–green fluorescent protein) mice were lesioned with 6-hydroxydopamine and subsequently treated with L-DOPA to induce dyskinesia. Functional, molecular, and structural changes were assessed in corticostriatal slices. Individual MSNs injected with Lucifer-Yellow were detected by immunohistochemistry for three-dimensional reconstructions with Neurolucida software. Intracellular current-clamp recordings with high-resistance micropipettes were used to characterize electrophysiological parameters. Results: Both D1R-MSNs and D2R-MSNs showed diminished spine density in totally denervated striatal regions in parkinsonian mice. Chronic L-DOPA treatment, which induced dyskinesia and aberrant FosB expression, restored spine density in D2R-MSNs but not in D1R-MSNs. In basal conditions, MSNs are more excitable in parkinsonian than in sham mice, and excitability decreases toward normal values after L-DOPA treatment. Despite this normalization of basal excitability, in dyskinetic mice, the selective D1R agonist SKF38393 increased the number of evoked action potentials in MSNs, compared with sham animals. Conclusions: Chronic L-DOPA induces abnormal spine re-growth exclusively in D2R-MSNs and robust supersensitization to D1R-activated excitability in denervated striatal MSNs. These changes might constitute the anatomical and electrophysiological substrates of dyskinesia.
publishDate 2014
dc.date.none.fl_str_mv 2014-05
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/11336/13605
Suárez, Luz M.; Solís, Oscar; Caramés, Jose M.; Taravini, Irene Rita Eloisa; Solís, Jose M.; et al.; L-DOPA treatment selectively restores spine density in dopamine receptor d2-expressing projection neurons in dyskinetic mice; Elsevier; Biological Psychiatry; 75; 9; 5-2014; 711-722
0006-3223
url http://hdl.handle.net/11336/13605
identifier_str_mv Suárez, Luz M.; Solís, Oscar; Caramés, Jose M.; Taravini, Irene Rita Eloisa; Solís, Jose M.; et al.; L-DOPA treatment selectively restores spine density in dopamine receptor d2-expressing projection neurons in dyskinetic mice; Elsevier; Biological Psychiatry; 75; 9; 5-2014; 711-722
0006-3223
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0006322313004162
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.biopsych.2013.05.006
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
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 12.982451

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