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

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...

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Autores: Suárez, Luz M., Solís, O., Caramés, J.M., Taravini, I.R., Solís, José M., Murer, Mario Gustavo, Moratalla, Rosario
Tipo de recurso: artículo
Fecha de publicación:2014
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/156389
Acceso en línea:http://hdl.handle.net/10261/156389
Access Level:acceso abierto
Palabra clave:three-dimensional neuronal reconstruction
striatum
Medium spiny neurons
Parkinson’s disease
dyskinesia
Behavioral sensitization
L-DOPA
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spelling L-DOPA treatment selectively restores spine density in dopamine receptor d2-expressing projection neurons in dyskinetic miceSuárez, Luz M.Solís, O.Caramés, J.M.Taravini, I.R.Solís, José M.Murer, Mario GustavoMoratalla, Rosariothree-dimensional neuronal reconstructionstriatumMedium spiny neuronsParkinson’s diseasedyskinesiaBehavioral sensitizationL-DOPABackground 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. © 2014 Society of Biological Psychiatry.This work was supported by grants from the Spanish Ministries de Economía y Competitividad and Sanidad y Política Social, ISCIII: BFU2010-20664, PNSD, RedRTA (RD06/0001/1011), CIBERNED ref. CB06/05/0055, and Comunidad de Madrid ref. S2011/BMD-2336 to RM; Spanish Ministries de Ciencia e Innovación (MICINN) PIU081067 to JMS Fondo Nacional para la Investigación Científica y Tecnológica, Argentina, PICT 2008-2205/PICT 2011-521, Consejo Nacional de Investigaciones Científicas y Tecnológicas, Argentina, PIP 2009-77, and Universidad de Buenos Aires, UBACYT M562, to MGM.Peer ReviewedMinisterio de Economía y Competitividad (España)Ministerio de Sanidad y Política Social (España)Instituto de Salud Carlos IIIComunidad de MadridCentro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España)Ministerio de Ciencia e Innovación (España)Fondo para la Investigación Científica y Tecnológica (Argentina)Consejo Nacional de Investigaciones Científicas y Técnicas (Argentina)Universidad de Buenos AiresConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2017201720142017info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501http://hdl.handle.net/10261/156389reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#S2011/BMD-2336/NEUROSTEMSíinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1563892026-05-22T06:33:51Z
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.
three-dimensional neuronal reconstruction
striatum
Medium spiny neurons
Parkinson’s disease
dyskinesia
Behavioral sensitization
L-DOPA
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, O.
Caramés, J.M.
Taravini, I.R.
Solís, José M.
Murer, Mario Gustavo
Moratalla, Rosario
author Suárez, Luz M.
author_facet Suárez, Luz M.
Solís, O.
Caramés, J.M.
Taravini, I.R.
Solís, José M.
Murer, Mario Gustavo
Moratalla, Rosario
author_role author
author2 Solís, O.
Caramés, J.M.
Taravini, I.R.
Solís, José M.
Murer, Mario Gustavo
Moratalla, Rosario
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
Ministerio de Sanidad y Política Social (España)
Instituto de Salud Carlos III
Comunidad de Madrid
Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España)
Ministerio de Ciencia e Innovación (España)
Fondo para la Investigación Científica y Tecnológica (Argentina)
Consejo Nacional de Investigaciones Científicas y Técnicas (Argentina)
Universidad de Buenos Aires
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv three-dimensional neuronal reconstruction
striatum
Medium spiny neurons
Parkinson’s disease
dyskinesia
Behavioral sensitization
L-DOPA
topic three-dimensional neuronal reconstruction
striatum
Medium spiny neurons
Parkinson’s disease
dyskinesia
Behavioral sensitization
L-DOPA
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. © 2014 Society of Biological Psychiatry.
publishDate 2014
dc.date.none.fl_str_mv 2014
2017
2017
2017
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/156389
url http://hdl.handle.net/10261/156389
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
S2011/BMD-2336/NEUROSTEM
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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