Astrocytopathy is associated with CA1 synaptic dysfunction in a mouse model of Down syndrome

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• dc.contributor.author Fernández-Blanco, Álvaro
• dc.contributor.author González-Arias, Candela
• dc.contributor.author Sierra, Cesar
• dc.contributor.author Zamora Moratalla, Alfonsa
• dc.contributor.author Perea, Gertrudis
• dc.contributor.author Dierssen, Mara
• dc.date.accessioned 2025-10-13T13:56:20Z
• dc.date.available 2025-10-13T13:56:20Z
• dc.date.issued 2025
• dc.date.updated 2025-10-13T13:56:20Z
• dc.description.abstract Brain pathophysiology in Down syndrome (DS), the most common genetic cause of intellectual disability, has traditionally been considered a consequence of neuronal dysfunction. However, although it is well documented that astrocytes play a critical role in brain homeostasis, synaptic regulation, and neuronal support, and their malfunction has been associated with the onset and progression of different neurological disorders, only a few studies have addressed whether astrocyte dysfunction can contribute to the DS pathophysiology. Astrocytes are increased in number and size, and show increased levels of expression of astroglial markers like S100ß and GFAP. In this study, we detected a region-specific increase in astrocyte population in CA1 and, to a lesser extent, in the dentate gyrus. Single-nucleus transcriptomic profiling identified markers associated with reactive astroglia, synaptic transmission, and neuroinflammation in trisomic astrocytes. Functional analysis revealed abnormal Ca2+ oscillations in trisomic astrocytes and impaired astrocyte-to-neuron communication in CA1, the most affected subregion, leading to astrocyte-mediated excitatory synaptic depression. Our findings demonstrate that astrocytes play an active and critical role in the pathophysiology of DS, not only as reactive responders to neuronal injury but as key contributors to the disease process itself. This astrocytic dysfunction presents a region-specific distribution within the hippocampus, suggesting localized vulnerability and complex glial involvement in DS-related neuropathology.
• dc.description.sponsorship The lab of MD is supported by the Secretaria d¿Universitats i Recerca del Departament d'Economia I Coneixement de la Generalitat de Catalunya (Grups consolidats 2017 SGR 926). We also acknowledge the support of the Agencia Estatal de Investigación (PID2022-141900OB-I00 INTO-DS funded by MICIU/AEI/10.13039/501100011033/FEDER, UE). This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 848077). The publication is part of the grant PRE2018-084504, funded by MCIN/AEI/10.13039/501100011033 and by the FSE+ (AFB). Additionally, we have been supported by Fundació La Marató TV3 (201620-31 and 225619), and by PID2022-142617NB-I00 and PID2019-106579RB-I00 funded by MCIN/AEI/10.13039/501100011033 to G.P.
• dc.format.mimetype application/pdf
• dc.identifier.citation Fernández-Blanco Á, González-Arias C, Sierra C, Zamora-Moratalla A, Perea G, Dierssen M. Astrocytopathy is associated with CA1 synaptic dysfunction in a mouse model of Down syndrome. Cells. 2025;14(17):1332. DOI: 10.3390/cells14171332
• dc.identifier.doi http://dx.doi.org/10.3390/cells14171332
• dc.identifier.issn 2073-4409
• dc.identifier.uri http://hdl.handle.net/10230/71489
• dc.language.iso eng
• dc.publisher MDPI
• dc.relation.ispartof Cells. 2025;14(17):1332
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2022-141900OB-I00
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/848077
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PRE2018-084504
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2022-142617NB-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-106579RB-I00
• dc.rights © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Down syndrome
• dc.subject.keyword Astrocytes
• dc.subject.keyword Astrocyte-neuron communication
• dc.subject.keyword Astrocytopathy
• dc.subject.keyword Hippocampus
• dc.subject.keyword Intellectual disability
• dc.title Astrocytopathy is associated with CA1 synaptic dysfunction in a mouse model of Down syndrome
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion