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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/13605
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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 Técnicas2025-09-29T10:43:27Zoai: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:34982025-09-29 10:43:27.321CONICET 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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1844614470077251584 |
score |
13.070432 |