Differential Synaptic Remodeling by Dopamine in Direct and Indirect Striatal Projection Neurons in Pitx3-/- Mice, a Genetic Model of Parkinson's Disease

In toxin-based models of Parkinson's disease (PD), striatal projection neurons (SPNs) exhibit dendritic atrophy and spine loss concurrent with an increase in excitability. Chronic l-DOPA treatment that induces dyskinesia selectively restores spine density and excitability in indirect pathway SP...

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Autores: Suarez, Luz M, Alberquilla, Samuel, García-Montes, Jose R, Moratalla, Rosario
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/345024
Acceso en línea:http://hdl.handle.net/10261/345024
https://api.elsevier.com/content/abstract/scopus_id/85050480058
Access Level:acceso abierto
Palabra clave:L-DOPA
Parkinson's disease
aphakia
dyskinesia
striatum
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oai_identifier_str oai:digital.csic.es:10261/345024
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network_name_str España
repository_id_str
dc.title.none.fl_str_mv Differential Synaptic Remodeling by Dopamine in Direct and Indirect Striatal Projection Neurons in Pitx3-/- Mice, a Genetic Model of Parkinson's Disease
title Differential Synaptic Remodeling by Dopamine in Direct and Indirect Striatal Projection Neurons in Pitx3-/- Mice, a Genetic Model of Parkinson's Disease
spellingShingle Differential Synaptic Remodeling by Dopamine in Direct and Indirect Striatal Projection Neurons in Pitx3-/- Mice, a Genetic Model of Parkinson's Disease
Suarez, Luz M
L-DOPA
Parkinson's disease
aphakia
dyskinesia
striatum
title_short Differential Synaptic Remodeling by Dopamine in Direct and Indirect Striatal Projection Neurons in Pitx3-/- Mice, a Genetic Model of Parkinson's Disease
title_full Differential Synaptic Remodeling by Dopamine in Direct and Indirect Striatal Projection Neurons in Pitx3-/- Mice, a Genetic Model of Parkinson's Disease
title_fullStr Differential Synaptic Remodeling by Dopamine in Direct and Indirect Striatal Projection Neurons in Pitx3-/- Mice, a Genetic Model of Parkinson's Disease
title_full_unstemmed Differential Synaptic Remodeling by Dopamine in Direct and Indirect Striatal Projection Neurons in Pitx3-/- Mice, a Genetic Model of Parkinson's Disease
title_sort Differential Synaptic Remodeling by Dopamine in Direct and Indirect Striatal Projection Neurons in Pitx3-/- Mice, a Genetic Model of Parkinson's Disease
dc.creator.none.fl_str_mv Suarez, Luz M
Alberquilla, Samuel
García-Montes, Jose R
Moratalla, Rosario
author Suarez, Luz M
author_facet Suarez, Luz M
Alberquilla, Samuel
García-Montes, Jose R
Moratalla, Rosario
author_role author
author2 Alberquilla, Samuel
García-Montes, Jose R
Moratalla, Rosario
author2_role author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía, Industria y Competitividad (España)
Ministerio de Sanidad, Servicios Sociales e Igualdad (España)
Instituto de Salud Carlos III
Fundación Ramón Areces
Secretaría de Ciencia, Tecnología e Innovación del Distrito Federal (México)
Consejo Nacional de Ciencia y Tecnología (México)
Ministerio de Educación, Cultura y Deporte (España)
Fundación ONCE
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv L-DOPA
Parkinson's disease
aphakia
dyskinesia
striatum
topic L-DOPA
Parkinson's disease
aphakia
dyskinesia
striatum
description In toxin-based models of Parkinson's disease (PD), striatal projection neurons (SPNs) exhibit dendritic atrophy and spine loss concurrent with an increase in excitability. Chronic l-DOPA treatment that induces dyskinesia selectively restores spine density and excitability in indirect pathway SPNs (iSPNs), whereas spine loss and hyperexcitability persist in direct pathway SPNs (dSPNs). These alterations have only been characterized in toxin-based models of PD, raising the possibility that they are an artifact of exposure to the toxin, which may engage compensatory mechanisms independent of the PD-like pathology or due to the loss of dopaminergic afferents. To test all these, we studied the synaptic remodeling in Pitx3-/- or aphakia mice, a genetic model of PD, in which most of the dopamine neurons in the substantia nigra fail to fully differentiate and to innervate the striatum. We made 3D reconstructions of the dendritic arbor and measured excitability in identified SPNs located in dorsal striatum of BAC-Pitx3-/- mice treated with saline or l-DOPA. Both dSPNs and iSPNs from BAC-Pitx3-/- mice had shorter dendritic trees, lower spine density, and more action potentials than their counterparts from WT mice. Chronic l-DOPA treatment restored spine density and firing rate in iSPNs. By contrast, in dSPNs, spine loss and hyperexcitability persisted following l-DOPA treatment, which is similar to what happens in 6-OHDA WT mice. This indicates that dopamine-mediated synaptic remodeling and plasticity is independent of dopamine innervation during SPN development and that Pitx3-/- mice are a good model because they develop the same pathology described in the toxins-based models and in human postmortem studies of advanced PD.SIGNIFICANCE STATEMENT As the only genetic model of Parkinson's disease (PD) that develops dyskinesia, Pitx3-/- mice reproduce the behavioral effects seen in humans and are a good system for studying dopamine-induced synaptic remodeling. The studies we present here establish that the structural and functional synaptic plasticity that occur in striatal projection neurons in PD and in l-DOPA-induced dyskinesia are specifically due to modulation of the neurotransmitter dopamine and are not artifacts of the use of chemical toxins in PD models. In addition, our findings provide evidence that synaptic plasticity in the Pitx3-/- mouse is similar to that seen in toxin models despite its lack of dopaminergic innervation of the striatum during development. Pitx3-/- mice reproduced the alterations described in patients with advanced PD and in well accepted toxin-based models of PD and dyskinesia. These results further consolidate the fidelity of the Pitx3-/- mouse as a PD model in which to study the morphological and physiological remodeling of striatal projection neurons by administration of l-DOPA and other drugs.
publishDate 2018
dc.date.none.fl_str_mv 2018
2024
2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/345024
https://api.elsevier.com/content/abstract/scopus_id/85050480058
url http://hdl.handle.net/10261/345024
https://api.elsevier.com/content/abstract/scopus_id/85050480058
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv The Journal of neuroscience : the official journal of the Society for Neuroscience
https://doi.org/10.1016/j.nbd.2023.106278
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Society for Neuroscience
publisher.none.fl_str_mv Society for Neuroscience
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
_version_ 1869423624076656640
spelling Differential Synaptic Remodeling by Dopamine in Direct and Indirect Striatal Projection Neurons in Pitx3-/- Mice, a Genetic Model of Parkinson's DiseaseSuarez, Luz MAlberquilla, SamuelGarcía-Montes, Jose RMoratalla, RosarioL-DOPAParkinson's diseaseaphakiadyskinesiastriatumIn toxin-based models of Parkinson's disease (PD), striatal projection neurons (SPNs) exhibit dendritic atrophy and spine loss concurrent with an increase in excitability. Chronic l-DOPA treatment that induces dyskinesia selectively restores spine density and excitability in indirect pathway SPNs (iSPNs), whereas spine loss and hyperexcitability persist in direct pathway SPNs (dSPNs). These alterations have only been characterized in toxin-based models of PD, raising the possibility that they are an artifact of exposure to the toxin, which may engage compensatory mechanisms independent of the PD-like pathology or due to the loss of dopaminergic afferents. To test all these, we studied the synaptic remodeling in Pitx3-/- or aphakia mice, a genetic model of PD, in which most of the dopamine neurons in the substantia nigra fail to fully differentiate and to innervate the striatum. We made 3D reconstructions of the dendritic arbor and measured excitability in identified SPNs located in dorsal striatum of BAC-Pitx3-/- mice treated with saline or l-DOPA. Both dSPNs and iSPNs from BAC-Pitx3-/- mice had shorter dendritic trees, lower spine density, and more action potentials than their counterparts from WT mice. Chronic l-DOPA treatment restored spine density and firing rate in iSPNs. By contrast, in dSPNs, spine loss and hyperexcitability persisted following l-DOPA treatment, which is similar to what happens in 6-OHDA WT mice. This indicates that dopamine-mediated synaptic remodeling and plasticity is independent of dopamine innervation during SPN development and that Pitx3-/- mice are a good model because they develop the same pathology described in the toxins-based models and in human postmortem studies of advanced PD.SIGNIFICANCE STATEMENT As the only genetic model of Parkinson's disease (PD) that develops dyskinesia, Pitx3-/- mice reproduce the behavioral effects seen in humans and are a good system for studying dopamine-induced synaptic remodeling. The studies we present here establish that the structural and functional synaptic plasticity that occur in striatal projection neurons in PD and in l-DOPA-induced dyskinesia are specifically due to modulation of the neurotransmitter dopamine and are not artifacts of the use of chemical toxins in PD models. In addition, our findings provide evidence that synaptic plasticity in the Pitx3-/- mouse is similar to that seen in toxin models despite its lack of dopaminergic innervation of the striatum during development. Pitx3-/- mice reproduced the alterations described in patients with advanced PD and in well accepted toxin-based models of PD and dyskinesia. These results further consolidate the fidelity of the Pitx3-/- mouse as a PD model in which to study the morphological and physiological remodeling of striatal projection neurons by administration of l-DOPA and other drugs.This work was supported by grants from the Spanish Ministries of Economía, Industria y Competitividad (SAF2016-78207-R and PCIN-2015-098) and of Sanidad Servicios Sociales e Igualdad, Instituto de Salud Carlos III (ISCIII), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas [CIBERNED] (CB06/05/0055, PNSD2016I033), the Ramón Areces Foundation (172275), and from Secretaría de Ciencia, Tecnología e Innovacíon [SECITI] from Ciudad de Mexico (037/2016) to R.M., J.R.G.-M. received scholarships from Consejo Nacional de Ciencia y Tecnología and SECITI of Ciudad de México. L.M.S., S.A., and R.M. were awarded the First Prize and Special Prize at the XV Archimedes University Competition from the Spanish Ministry of Educación Cultura y Deporte and ONCE Foundation. We thank Beatriz Pro and Emilia Rubio for technical assistance and Dr. J. DeFelipe for providing the Lucifer yellow antibody.Peer reviewedSociety for NeuroscienceMinisterio de Economía, Industria y Competitividad (España)Ministerio de Sanidad, Servicios Sociales e Igualdad (España)Instituto de Salud Carlos IIIFundación Ramón ArecesSecretaría de Ciencia, Tecnología e Innovación del Distrito Federal (México)Consejo Nacional de Ciencia y Tecnología (México)Ministerio de Educación, Cultura y Deporte (España)Fundación ONCEConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202420242018info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/345024https://api.elsevier.com/content/abstract/scopus_id/85050480058reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)InglésThe Journal of neuroscience : the official journal of the Society for Neurosciencehttps://doi.org/10.1016/j.nbd.2023.106278Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3450242026-05-22T06:33:51Z
score 15.81155

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