Early synaptic changes and reduced brain connectivity in PD-like mice with depressive phenotype

Anxiety and depression are common in Parkinson’s disease (PD), affecting quality of life. Aggregates of α-synuclein (α-Syn) are found in serotonergic (5-HT) raphe nuclei early in the disease, but their relationship to brain changes is unclear. We investigated synaptic plasticity, neuronal activity,...

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Detalhes bibliográficos
Autores: Miquel-Rio, Lluís, Jericó-Escolar, Judith, Sarries-Serrano, Unai, Yanes-Castilla, Claudia, Torres-López, María, Argibay, Uxia, Paz, Verónica, Casal, Carme, Muñoz-Moreno, Emma, López-Gil, Xavier, Bortolozzi, Analía
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/402388
Acesso em linha:http://hdl.handle.net/10261/402388
https://api.elsevier.com/content/abstract/scopus_id/105013466595
Access Level:acceso abierto
Palavra-chave:Diseases
Molecular biology
Neurology
Neuroscience
Systems biology
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spelling Early synaptic changes and reduced brain connectivity in PD-like mice with depressive phenotypeMiquel-Rio, LluísJericó-Escolar, JudithSarries-Serrano, UnaiYanes-Castilla, ClaudiaTorres-López, MaríaArgibay, UxiaPaz, VerónicaCasal, CarmeMuñoz-Moreno, EmmaLópez-Gil, XavierBortolozzi, AnalíaDiseasesMolecular biologyNeurologyNeuroscienceSystems biologyAnxiety and depression are common in Parkinson’s disease (PD), affecting quality of life. Aggregates of α-synuclein (α-Syn) are found in serotonergic (5-HT) raphe nuclei early in the disease, but their relationship to brain changes is unclear. We investigated synaptic plasticity, neuronal activity, and functional magnetic resonance imaging (fMRI)-based brain connectivity in a PD-like mouse model with depressive phenotype. AAV-induced human α-Syn accumulation in raphe 5-HT neurons causes progressive synaptic pathology in interconnected brain regions. This is marked by lower MAP-2, PSD95 and higher SV2A, VAMP2, which are key to synaptic structure and function, as confirmed in human brain tissue samples. Abnormalities in Egr-1-dependent neuronal activity and region-specific differences in resting-state functional brain activity were also detected eight weeks post-AAV infusion, before neurodegeneration. This provides evidence for synaptic and fMRI markers associated with α-Syn pathology in emotional brain circuits, and has translational importance for identifying PD patients at risk for depression.This work was supported by MCIU/AEI/FEDER, UE grant (PID2019-105136RB-100, PID2022-141700OB-I00, MCIN/AEI/10.13039/501100011033 to A.B.), and AGAUR 2021-SGR-01358, Catalan Government. CB/07/09/0034 Center for Networked Biomedical Research on Mental Health (CIBERSAM). We also thank the Spanish Stress Research Network, MCIN/AEI/10.13039/501100011033. U.S.S. is a recipient of a fellowship from the Non- Doctor Researcher Formation Pre-doctoral Program of Basque Government, Spain. U.A. is a recipient of a fellowship from the State Research Agency for the training of predoctoral research personnel (PREP2022-000676) associated to a generation of knowledge project (PID2022-141700OB-I00). The authors would like to thank the staff members of the Biobank of the Clinic Hospital Barcelona - IDIBAPS for their collaboration in the study.Peer reviewedNature Publishing GroupAgencia Estatal de Investigación (España)Ministerio de Ciencia, Innovación y Universidades (España)European CommissionAgència de Gestió d'Ajuts Universitaris i de RecercaGeneralitat de CatalunyaCentro de Investigación Biomédica en Red Salud Mental (España)Eusko JaurlaritzaHospital Clínic de BarcelonaMiquel-Rio, Lluís [0000-0002-3547-6004]Torres-López, María [0000-0001-6569-0397]Bortolozzi, Analía [0000-0002-2069-9192]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202520252025info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/402388https://api.elsevier.com/content/abstract/scopus_id/105013466595reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-105136RB-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2022-141700OB-I00The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1038/s41531-025-01073-1https://doi.org/10.1038/s41531-025-01073-1Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/4023882026-05-22T06:33:51Z
dc.title.none.fl_str_mv Early synaptic changes and reduced brain connectivity in PD-like mice with depressive phenotype
title Early synaptic changes and reduced brain connectivity in PD-like mice with depressive phenotype
spellingShingle Early synaptic changes and reduced brain connectivity in PD-like mice with depressive phenotype
Miquel-Rio, Lluís
Diseases
Molecular biology
Neurology
Neuroscience
Systems biology
title_short Early synaptic changes and reduced brain connectivity in PD-like mice with depressive phenotype
title_full Early synaptic changes and reduced brain connectivity in PD-like mice with depressive phenotype
title_fullStr Early synaptic changes and reduced brain connectivity in PD-like mice with depressive phenotype
title_full_unstemmed Early synaptic changes and reduced brain connectivity in PD-like mice with depressive phenotype
title_sort Early synaptic changes and reduced brain connectivity in PD-like mice with depressive phenotype
dc.creator.none.fl_str_mv Miquel-Rio, Lluís
Jericó-Escolar, Judith
Sarries-Serrano, Unai
Yanes-Castilla, Claudia
Torres-López, María
Argibay, Uxia
Paz, Verónica
Casal, Carme
Muñoz-Moreno, Emma
López-Gil, Xavier
Bortolozzi, Analía
author Miquel-Rio, Lluís
author_facet Miquel-Rio, Lluís
Jericó-Escolar, Judith
Sarries-Serrano, Unai
Yanes-Castilla, Claudia
Torres-López, María
Argibay, Uxia
Paz, Verónica
Casal, Carme
Muñoz-Moreno, Emma
López-Gil, Xavier
Bortolozzi, Analía
author_role author
author2 Jericó-Escolar, Judith
Sarries-Serrano, Unai
Yanes-Castilla, Claudia
Torres-López, María
Argibay, Uxia
Paz, Verónica
Casal, Carme
Muñoz-Moreno, Emma
López-Gil, Xavier
Bortolozzi, Analía
author2_role author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Agencia Estatal de Investigación (España)
Ministerio de Ciencia, Innovación y Universidades (España)
European Commission
Agència de Gestió d'Ajuts Universitaris i de Recerca
Generalitat de Catalunya
Centro de Investigación Biomédica en Red Salud Mental (España)
Eusko Jaurlaritza
Hospital Clínic de Barcelona
Miquel-Rio, Lluís [0000-0002-3547-6004]
Torres-López, María [0000-0001-6569-0397]
Bortolozzi, Analía [0000-0002-2069-9192]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Diseases
Molecular biology
Neurology
Neuroscience
Systems biology
topic Diseases
Molecular biology
Neurology
Neuroscience
Systems biology
description Anxiety and depression are common in Parkinson’s disease (PD), affecting quality of life. Aggregates of α-synuclein (α-Syn) are found in serotonergic (5-HT) raphe nuclei early in the disease, but their relationship to brain changes is unclear. We investigated synaptic plasticity, neuronal activity, and functional magnetic resonance imaging (fMRI)-based brain connectivity in a PD-like mouse model with depressive phenotype. AAV-induced human α-Syn accumulation in raphe 5-HT neurons causes progressive synaptic pathology in interconnected brain regions. This is marked by lower MAP-2, PSD95 and higher SV2A, VAMP2, which are key to synaptic structure and function, as confirmed in human brain tissue samples. Abnormalities in Egr-1-dependent neuronal activity and region-specific differences in resting-state functional brain activity were also detected eight weeks post-AAV infusion, before neurodegeneration. This provides evidence for synaptic and fMRI markers associated with α-Syn pathology in emotional brain circuits, and has translational importance for identifying PD patients at risk for depression.
publishDate 2025
dc.date.none.fl_str_mv 2025
2025
2025
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/10261/402388
https://api.elsevier.com/content/abstract/scopus_id/105013466595
url http://hdl.handle.net/10261/402388
https://api.elsevier.com/content/abstract/scopus_id/105013466595
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-105136RB-I00
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2022-141700OB-I00
The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1038/s41531-025-01073-1
https://doi.org/10.1038/s41531-025-01073-1
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 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: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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