{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:37:16Z","timestamp":1787027836576,"version":"build-2736575974"},"reference-count":68,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T00:00:00Z","timestamp":1756339200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Secretaria d\u2019Universitats i Recerca del Departament d\u2019Economia I Coneixement de la Generalitat de Catalunya","award":["2017 SGR 926"],"award-info":[{"award-number":["2017 SGR 926"]}]},{"name":"Secretaria d\u2019Universitats i Recerca del Departament d\u2019Economia I Coneixement de la Generalitat de Catalunya","award":["PID2022-141900OB-I00 INTO-DS"],"award-info":[{"award-number":["PID2022-141900OB-I00 INTO-DS"]}]},{"name":"Secretaria d\u2019Universitats i Recerca del Departament d\u2019Economia I Coneixement de la Generalitat de Catalunya","award":["848077"],"award-info":[{"award-number":["848077"]}]},{"name":"Secretaria d\u2019Universitats i Recerca del Departament d\u2019Economia I Coneixement de la Generalitat de Catalunya","award":["PRE2018-084504"],"award-info":[{"award-number":["PRE2018-084504"]}]},{"name":"Secretaria d\u2019Universitats i Recerca del Departament d\u2019Economia I Coneixement de la Generalitat de Catalunya","award":["201620-31"],"award-info":[{"award-number":["201620-31"]}]},{"name":"Secretaria d\u2019Universitats i Recerca del Departament d\u2019Economia I Coneixement de la Generalitat de Catalunya","award":["225619"],"award-info":[{"award-number":["225619"]}]},{"name":"Secretaria d\u2019Universitats i Recerca del Departament d\u2019Economia I Coneixement de la Generalitat de Catalunya","award":["PID2022-142617NB-I00"],"award-info":[{"award-number":["PID2022-142617NB-I00"]}]},{"name":"Secretaria d\u2019Universitats i Recerca del Departament d\u2019Economia I Coneixement de la Generalitat de Catalunya","award":["PID2019-106579RB-I00"],"award-info":[{"award-number":["PID2019-106579RB-I00"]}]},{"DOI":"10.13039\/501100004837","name":"Agencia Estatal de Investigaci\u00f3n","doi-asserted-by":"publisher","award":["2017 SGR 926"],"award-info":[{"award-number":["2017 SGR 926"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Agencia Estatal de Investigaci\u00f3n","doi-asserted-by":"publisher","award":["PID2022-141900OB-I00 INTO-DS"],"award-info":[{"award-number":["PID2022-141900OB-I00 INTO-DS"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Agencia Estatal de Investigaci\u00f3n","doi-asserted-by":"publisher","award":["848077"],"award-info":[{"award-number":["848077"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Agencia Estatal de Investigaci\u00f3n","doi-asserted-by":"publisher","award":["PRE2018-084504"],"award-info":[{"award-number":["PRE2018-084504"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Agencia Estatal de Investigaci\u00f3n","doi-asserted-by":"publisher","award":["201620-31"],"award-info":[{"award-number":["201620-31"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Agencia Estatal de Investigaci\u00f3n","doi-asserted-by":"publisher","award":["225619"],"award-info":[{"award-number":["225619"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Agencia Estatal de Investigaci\u00f3n","doi-asserted-by":"publisher","award":["PID2022-142617NB-I00"],"award-info":[{"award-number":["PID2022-142617NB-I00"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Agencia Estatal de Investigaci\u00f3n","doi-asserted-by":"publisher","award":["PID2019-106579RB-I00"],"award-info":[{"award-number":["PID2019-106579RB-I00"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Union\u2019s Horizon 2020 research and innovation programme","award":["2017 SGR 926"],"award-info":[{"award-number":["2017 SGR 926"]}]},{"name":"European Union\u2019s Horizon 2020 research and innovation programme","award":["PID2022-141900OB-I00 INTO-DS"],"award-info":[{"award-number":["PID2022-141900OB-I00 INTO-DS"]}]},{"name":"European Union\u2019s Horizon 2020 research and innovation programme","award":["848077"],"award-info":[{"award-number":["848077"]}]},{"name":"European Union\u2019s Horizon 2020 research and innovation programme","award":["PRE2018-084504"],"award-info":[{"award-number":["PRE2018-084504"]}]},{"name":"European Union\u2019s Horizon 2020 research and innovation programme","award":["201620-31"],"award-info":[{"award-number":["201620-31"]}]},{"name":"European Union\u2019s Horizon 2020 research and innovation programme","award":["225619"],"award-info":[{"award-number":["225619"]}]},{"name":"European Union\u2019s Horizon 2020 research and innovation programme","award":["PID2022-142617NB-I00"],"award-info":[{"award-number":["PID2022-142617NB-I00"]}]},{"name":"European Union\u2019s Horizon 2020 research and innovation programme","award":["PID2019-106579RB-I00"],"award-info":[{"award-number":["PID2019-106579RB-I00"]}]},{"name":"MCIN\/AEI\/10.13039\/501100011033","award":["2017 SGR 926"],"award-info":[{"award-number":["2017 SGR 926"]}]},{"name":"MCIN\/AEI\/10.13039\/501100011033","award":["PID2022-141900OB-I00 INTO-DS"],"award-info":[{"award-number":["PID2022-141900OB-I00 INTO-DS"]}]},{"name":"MCIN\/AEI\/10.13039\/501100011033","award":["848077"],"award-info":[{"award-number":["848077"]}]},{"name":"MCIN\/AEI\/10.13039\/501100011033","award":["PRE2018-084504"],"award-info":[{"award-number":["PRE2018-084504"]}]},{"name":"MCIN\/AEI\/10.13039\/501100011033","award":["201620-31"],"award-info":[{"award-number":["201620-31"]}]},{"name":"MCIN\/AEI\/10.13039\/501100011033","award":["225619"],"award-info":[{"award-number":["225619"]}]},{"name":"MCIN\/AEI\/10.13039\/501100011033","award":["PID2022-142617NB-I00"],"award-info":[{"award-number":["PID2022-142617NB-I00"]}]},{"name":"MCIN\/AEI\/10.13039\/501100011033","award":["PID2019-106579RB-I00"],"award-info":[{"award-number":["PID2019-106579RB-I00"]}]},{"name":"Fundaci\u00f3 La Marat\u00f3 TV3","award":["2017 SGR 926"],"award-info":[{"award-number":["2017 SGR 926"]}]},{"name":"Fundaci\u00f3 La Marat\u00f3 TV3","award":["PID2022-141900OB-I00 INTO-DS"],"award-info":[{"award-number":["PID2022-141900OB-I00 INTO-DS"]}]},{"name":"Fundaci\u00f3 La Marat\u00f3 TV3","award":["848077"],"award-info":[{"award-number":["848077"]}]},{"name":"Fundaci\u00f3 La Marat\u00f3 TV3","award":["PRE2018-084504"],"award-info":[{"award-number":["PRE2018-084504"]}]},{"name":"Fundaci\u00f3 La Marat\u00f3 TV3","award":["201620-31"],"award-info":[{"award-number":["201620-31"]}]},{"name":"Fundaci\u00f3 La Marat\u00f3 TV3","award":["225619"],"award-info":[{"award-number":["225619"]}]},{"name":"Fundaci\u00f3 La Marat\u00f3 TV3","award":["PID2022-142617NB-I00"],"award-info":[{"award-number":["PID2022-142617NB-I00"]}]},{"name":"Fundaci\u00f3 La Marat\u00f3 TV3","award":["PID2019-106579RB-I00"],"award-info":[{"award-number":["PID2019-106579RB-I00"]}]},{"DOI":"10.13039\/501100004837","name":"MCIN\/AEI\/10.13039\/501100011033","doi-asserted-by":"publisher","award":["2017 SGR 926"],"award-info":[{"award-number":["2017 SGR 926"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"MCIN\/AEI\/10.13039\/501100011033","doi-asserted-by":"publisher","award":["PID2022-141900OB-I00 INTO-DS"],"award-info":[{"award-number":["PID2022-141900OB-I00 INTO-DS"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"MCIN\/AEI\/10.13039\/501100011033","doi-asserted-by":"publisher","award":["848077"],"award-info":[{"award-number":["848077"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"MCIN\/AEI\/10.13039\/501100011033","doi-asserted-by":"publisher","award":["PRE2018-084504"],"award-info":[{"award-number":["PRE2018-084504"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"MCIN\/AEI\/10.13039\/501100011033","doi-asserted-by":"publisher","award":["201620-31"],"award-info":[{"award-number":["201620-31"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"MCIN\/AEI\/10.13039\/501100011033","doi-asserted-by":"publisher","award":["225619"],"award-info":[{"award-number":["225619"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"MCIN\/AEI\/10.13039\/501100011033","doi-asserted-by":"publisher","award":["PID2022-142617NB-I00"],"award-info":[{"award-number":["PID2022-142617NB-I00"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"MCIN\/AEI\/10.13039\/501100011033","doi-asserted-by":"publisher","award":["PID2019-106579RB-I00"],"award-info":[{"award-number":["PID2019-106579RB-I00"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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 S100\u03b2 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.<\/jats:p>","DOI":"10.3390\/cells14171332","type":"journal-article","created":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T15:03:14Z","timestamp":1756393394000},"page":"1332","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Astrocytopathy Is Associated with CA1 Synaptic Dysfunction in a Mouse Model of Down Syndrome"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6451-1094","authenticated-orcid":false,"given":"\u00c1lvaro","family":"Fern\u00e1ndez-Blanco","sequence":"first","affiliation":[{"name":"Center for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, 08003 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Candela","family":"Gonz\u00e1lez-Arias","sequence":"additional","affiliation":[{"name":"Department of Functional and Systems Neurobiology, Cajal Institute, CSIC, 28006 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4544-9149","authenticated-orcid":false,"given":"Cesar","family":"Sierra","sequence":"additional","affiliation":[{"name":"Center for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, 08003 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfonsa","family":"Zamora-Moratalla","sequence":"additional","affiliation":[{"name":"Center for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, 08003 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gertrudis","family":"Perea","sequence":"additional","affiliation":[{"name":"Department of Functional and Systems Neurobiology, Cajal Institute, CSIC, 28006 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0853-6865","authenticated-orcid":false,"given":"Mara","family":"Dierssen","sequence":"additional","affiliation":[{"name":"Center for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, 08003 Barcelona, Spain"},{"name":"University Pompeu Fabra (UPF), 08005 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras, 28029 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1126\/science.1144640","article-title":"Astrocytes Potentiate Transmitter Release at Single Hippocampal Synapses","volume":"317","author":"Perea","year":"2007","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.cell.2018.05.002","article-title":"Astrocytic Activation Generates De Novo Neuronal Potentiation and Memory Enhancement","volume":"174","author":"Adamsky","year":"2018","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1038\/nn1849","article-title":"Glutamate Exocytosis from Astrocytes Controls Synaptic Strength","volume":"10","author":"Jourdain","year":"2007","journal-title":"Nat. Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Beard, E., Lengacher, S., Dias, S., Magistretti, P.J., and Finsterwald, C. (2022). Astrocytes as Key Regulators of Brain Energy Metabolism: New Therapeutic Perspectives. Front. Physiol., 12.","DOI":"10.3389\/fphys.2021.825816"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Fern\u00e1ndez-blanco, \u00c1., and Dierssen, M. (2020). Rethinking Intellectual Disability from Neuro- to Astro-Pathology. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21239039"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.bbi.2018.10.004","article-title":"Restoring Microglial and Astroglial Homeostasis Using DNA Immunization in a Down Syndrome Mouse Model","volume":"75","author":"Illouz","year":"2019","journal-title":"Brain. Behav. Immun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1093\/hmg\/ddaa003","article-title":"Human iPSC-Derived Down Syndrome Astrocytes Display Genome-Wide Perturbations in Gene Expression, an Altered Adhesion Profile, and Increased Cellular Dynamics","volume":"29","author":"Farmer","year":"2020","journal-title":"Hum. Mol. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"e Silva, A.L.T., de Oliveira, P.H.P., Yokota-Moreno, B.Y., Avila, J.P., Nakaya, H.I., Fausto, J.d.S., Serti\u00e9, A.L., and Zampieri, B.L. (2024). Complement System Alteration in iPSC-Derived Astrocytes from Individuals with Down Syndrome. Preprint.","DOI":"10.21203\/rs.3.rs-5319960\/v1"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/S0197-4580(98)00074-8","article-title":"Life-Long Overexpression of S100\u03b2 in Down\u2019s Syndrome: Implications for Alzheimer Pathogenesis","volume":"19","author":"Griffin","year":"1998","journal-title":"Neurobiol. Aging"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"7611","DOI":"10.1073\/pnas.86.19.7611","article-title":"Brain Interleukin 1 and S-100 Immunoreactivity Are Elevated in Down Syndrome and Alzheimer Disease","volume":"86","author":"Griffin","year":"1989","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","first-page":"109","article-title":"Astroglia Disturbances during Development of the Central Nervous System in Fetuses with Down\u2019s Syndrome","volume":"49","author":"Zdaniuk","year":"2011","journal-title":"Folia Neuropathol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1006\/exnr.1993.1052","article-title":"Developmental Changes of S-100 Protein and Glial Fibrillary Acidic Protein in the Brain in Down Syndrome","volume":"120","author":"Mito","year":"1993","journal-title":"Exp. Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1111\/j.1750-3639.2007.00113.x","article-title":"Neurogenesis Impairment and Increased Cell Death Reduce Total Neuron Number in the Hippocampal Region of Fetuses with Down Syndrome","volume":"18","author":"Guidi","year":"2008","journal-title":"Brain Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/nature13200","article-title":"Domains of Genome-Wide Gene Expression Dysregulation in Down\u2019s Syndrome","volume":"508","author":"Letourneau","year":"2014","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.celrep.2018.06.033","article-title":"Aberrant Calcium Signaling in Astrocytes Inhibits Neuronal Excitability in a Human Down Syndrome Stem Cell Model","volume":"24","author":"Mizuno","year":"2018","journal-title":"Cell Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"463909","DOI":"10.1155\/2012\/463909","article-title":"Age-Related Neurodegeneration and Memory Loss in down Syndrome","volume":"2012","author":"Lockrow","year":"2012","journal-title":"Curr. Gerontol. Geriatr. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1002\/hipo.20308","article-title":"Cell Cycle Alteration and Decreased Cell Proliferation in the Hippocampal Dentate Gyrus and in the Neocortical Germinal Matrix of Fetuses with down Syndrome and in Ts65Dn Mice","volume":"17","author":"Contestabile","year":"2007","journal-title":"Hippocampus"},{"key":"ref_18","first-page":"923","article-title":"Brain Ventriculomegaly in Down Syndrome Mice Is Caused by Pcp4 Dose-Dependent Cilia Dysfunction","volume":"26","author":"Raveau","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_19","unstructured":"(2024, November 28). Hypothalamic Astrocytes and the Role of Neuroprogesterone in Estrogen Positive Feedback|SpringerLink. Available online: https:\/\/link.springer.com\/chapter\/10.1007\/978-3-030-62383-8_10."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"274","DOI":"10.3390\/neuroglia5030019","article-title":"Sexual Dimorphism and Hypothalamic Astrocytes: Focus on Glioprotection","volume":"5","author":"Thomaz","year":"2024","journal-title":"Neuroglia"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Kuo, J., Hamid, N., Bondar, G., Dewing, P., Clarkson, J., and Micevych, P. (2010). Sex Differences in Hypothalamic Astrocyte Response to Estradiol Stimulation. Biol. Sex Differ., 1.","DOI":"10.1186\/2042-6410-1-7"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Gozlan, E., Lewit-Cohen, Y., and Frenkel, D. (2024). Sex Differences in Astrocyte Activity. Cells, 13.","DOI":"10.3390\/cells13201724"},{"key":"ref_23","unstructured":"Paxinos, G., and Franklin, K.B.J. (2019). Paxinos and Franklin\u2019s the Mouse Brain in Stereotaxic Coordinates, Academic Press."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1177\/0192623310385140","article-title":"Design-Based Stereology: Introduction to Basic Concepts and Practical Approaches for Estimation of Cell Number","volume":"38","author":"Boyce","year":"2010","journal-title":"Toxicol. Pathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.biopsych.2010.04.030","article-title":"Stereological Approaches to Identifying Neuropathology in Psychosis","volume":"69","author":"Lewis","year":"2011","journal-title":"Biol. Psychiatry"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.neuron.2014.02.041","article-title":"Conditions and Constraints for Astrocyte Calcium Signaling in the Hippocampal Mossy Fiber Pathway","volume":"82","author":"Haustein","year":"2014","journal-title":"Neuron"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1038\/s41593-020-00752-x","article-title":"GABAergic Signaling to Astrocytes in the Prefrontal Cortex Sustains Goal-Directed Behaviors","volume":"24","author":"Mederos","year":"2021","journal-title":"Nat. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/978-1-4939-1096-0_14","article-title":"Acute Brain Slice Methods for Adult and Aging Animals: Application of Targeted Patch Clamp Analysis and Optogenetics","volume":"1183","author":"Ting","year":"2014","journal-title":"Methods Mol. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2117","DOI":"10.1038\/s41380-024-02440-9","article-title":"The lncRNA Snhg11, a New Candidate Contributing to Neurogenesis, Plasticity, and Memory Deficits in Down Syndrome","volume":"29","author":"Sierra","year":"2024","journal-title":"Mol. Psychiatry"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1038\/s41593-017-0056-2","article-title":"Conserved Properties of Dentate Gyrus Neurogenesis across Postnatal Development Revealed by Single-Cell RNA Sequencing","volume":"21","author":"Hochgerner","year":"2018","journal-title":"Nat. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1038\/s41592-019-0619-0","article-title":"Fast, Sensitive and Accurate Integration of Single-Cell Data with Harmony","volume":"16","author":"Korsunsky","year":"2019","journal-title":"Nat. Methods"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1038\/s41590-018-0276-y","article-title":"Reference-Based Analysis of Lung Single-Cell Sequencing Reveals a Transitional Profibrotic Macrophage","volume":"20","author":"Aran","year":"2019","journal-title":"Nat. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1016\/j.cell.2018.06.021","article-title":"Molecular Architecture of the Mouse Nervous System","volume":"174","author":"Zeisel","year":"2018","journal-title":"Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1093\/bioinformatics\/btv715","article-title":"Destiny: Diffusion Maps for Large-Scale Single-Cell Data in R","volume":"32","author":"Angerer","year":"2016","journal-title":"Bioinformatics"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Cao, Y., Lin, Y., Ormerod, J.T., Yang, P., Yang, J.Y.H., and Lo, K.K. (2019). scDC: Single Cell Differential Composition Analysis. BMC Bioinform., 20.","DOI":"10.1186\/s12859-019-3211-9"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1186\/s13041-021-00856-w","article-title":"Side-by-Side Comparison of the Effects of Gq- and Gi-DREADD-Mediated Astrocyte Modulation on Intracellular Calcium Dynamics and Synaptic Plasticity in the Hippocampal CA1","volume":"14","author":"Sanderson","year":"2021","journal-title":"Mol. Brain"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1146\/annurev-pharmtox-010814-124803","article-title":"DREADDs (Designer Receptors Exclusively Activated by Designer Drugs): Chemogenetic Tools with Therapeutic Utility","volume":"55","author":"Urban","year":"2015","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1038\/nn.4201","article-title":"Astrocyte Calcium Signaling: The Third Wave","volume":"19","author":"Bazargani","year":"2016","journal-title":"Nat. Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/0896-6273(92)90271-E","article-title":"Neuronal Activity Triggers Calcium Waves in Hippocampal Astrocyte Networks","volume":"8","author":"Dani","year":"1992","journal-title":"Neuron"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Guerra-Gomes, S., Sousa, N., Pinto, L., and Oliveira, J.F. (2018). Functional Roles of Astrocyte Calcium Elevations: From Synapses to Behavior. Front. Cell. Neurosci., 11.","DOI":"10.3389\/fncel.2017.00427"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1016\/j.neuron.2014.02.007","article-title":"Gliotransmitters Travel in Time and Space","volume":"81","author":"Araque","year":"2014","journal-title":"Neuron"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e32237","DOI":"10.7554\/eLife.32237","article-title":"Neuronal Activity Determines Distinct Gliotransmitter Release from a Single Astrocyte","volume":"7","author":"Covelo","year":"2018","journal-title":"eLife"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Fern\u00e1ndez-Blanco, \u00c1., Sierra, C., Tejido, C., and Dierssen, M. (2024). Beyond Quiescent and Active: Intermediate Microglial Transcriptomic States in a Mouse Model of Down Syndrome. Int. J. Mol. Sci., 25.","DOI":"10.20944\/preprints202402.0220.v1"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1038\/s41467-019-14198-8","article-title":"Identification of Region-Specific Astrocyte Subtypes at Single Cell Resolution","volume":"11","author":"Batiuk","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Schitine, C., Nogaroli, L., Costa, M.R., and Hedin-Pereira, C. (2015). Astrocyte Heterogeneity in the Brain: From Development to Disease. Front. Cell. Neurosci., 9.","DOI":"10.3389\/fncel.2015.00076"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1111\/bpa.12605","article-title":"Abnormal Development of the Inferior Temporal Region in Fetuses with Down Syndrome","volume":"28","author":"Guidi","year":"2018","journal-title":"Brain Pathol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Garc\u00eda, O., and Flores-Aguilar, L. (2022). Astroglial and Microglial Pathology in Down Syndrome: Focus on Alzheimer\u2019s Disease. Front. Cell. Neurosci., 16.","DOI":"10.3389\/fncel.2022.987212"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Le Duigou, C., Simonnet, J., Tele\u00f1czuk, M.T., Fricker, D., and Miles, R. (2014). Recurrent Synapses and Circuits in the CA3 Region of the Hippocampus: An Associative Network. Front. Cell. Neurosci., 7.","DOI":"10.3389\/fncel.2013.00262"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"7463","DOI":"10.1523\/JNEUROSCI.20-19-07463.2000","article-title":"The Involvement of Recurrent Connections in Area CA3 in Establishing the Properties of Place Fields: A Model","volume":"20","author":"Dayan","year":"2000","journal-title":"J. Neurosci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3466","DOI":"10.1016\/j.celrep.2020.02.043","article-title":"Local Resting Ca2+ Controls the Scale of Astroglial Ca2+ Signals","volume":"30","author":"King","year":"2020","journal-title":"Cell Rep."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1002\/jnr.10630","article-title":"Altered Astrocyte Calcium Homeostasis and Proliferation in theTs65Dn Mouse, a Model of Down Syndrome","volume":"73","author":"Bambrick","year":"2003","journal-title":"J. Neurosci. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/S0304-3940(97)13406-1","article-title":"Impaired Ca-Signaling in Astrocytes from the Ts16 Mouse Model of Down Syndrome","volume":"223","author":"Heinemann","year":"1997","journal-title":"Neurosci. Lett."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1016\/j.neuron.2017.07.035","article-title":"Human Astrocyte Maturation Captured in 3D Cerebral Cortical Spheroids Derived from Pluripotent Stem Cells","volume":"95","author":"Sloan","year":"2017","journal-title":"Neuron"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/s41587-019-0035-0","article-title":"NFIA Is a Gliogenic Switch Enabling Rapid Derivation of Functional Human Astrocytes from Pluripotent Stem Cells","volume":"37","author":"Tchieu","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1093\/jnen\/64.2.163","article-title":"Proliferative Potential of Human Astrocytes","volume":"64","author":"Colodner","year":"2005","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"5139","DOI":"10.1038\/s41467-018-07528-9","article-title":"A Non-Canonical BRD9-Containing BAF Chromatin Remodeling Complex Regulates Naive Pluripotency in Mouse Embryonic Stem Cells","volume":"9","author":"Gatchalian","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"8372","DOI":"10.1038\/s41467-023-44081-6","article-title":"BRD9 Determines the Cell Fate of Hematopoietic Stem Cells by Regulating Chromatin State","volume":"14","author":"Xiao","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/1750-1172-9-43","article-title":"Expanding the Phenotypic Spectrum of ARID1B-Mediated Disorders and Identification of Altered Cell-Cycle Dynamics Due to ARID1B Haploinsufficiency","volume":"9","author":"Sim","year":"2014","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1093\/hmg\/ddp047","article-title":"DYRK1A Interacts with the REST\/NRSF-SWI\/SNF Chromatin Remodelling Complex to Deregulate Gene Clusters Involved in the Neuronal Phenotypic Traits of Down Syndrome","volume":"18","author":"Zvara","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"6742","DOI":"10.1038\/s41467-024-50626-0","article-title":"Multi-Omic Analysis of Huntington\u2019s Disease Reveals a Compensatory Astrocyte State","volume":"15","author":"Paryani","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2384","DOI":"10.1038\/s41593-024-01791-4","article-title":"Astrocyte Transcriptomic Changes along the Spatiotemporal Progression of Alzheimer\u2019s Disease","volume":"27","author":"Li","year":"2024","journal-title":"Nat. Neurosci."},{"key":"ref_62","first-page":"199","article-title":"Genetic Targeting of Astrocytes to Combat Neurodegenerative Disease","volume":"15","author":"Chen","year":"2019","journal-title":"Neural Regen. Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1002\/glia.22924","article-title":"Gap Junction Coupling Confers Isopotentiality on Astrocyte Syncytium","volume":"64","author":"Ma","year":"2016","journal-title":"Glia"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/S1569-2558(03)31007-0","article-title":"The Astrocytic Syncytium","volume":"31","author":"Scemes","year":"2003","journal-title":"Adv. Mol. Cell Biol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"12880","DOI":"10.1073\/pnas.97.23.12880","article-title":"Effects of Environmental Enrichment on Gene Expression in the Brain","volume":"97","author":"Rampon","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1046\/j.1460-9568.2003.02784.x","article-title":"Connexin30-Deficient Mice Show Increased Emotionality and Decreased Rearing Activity in the Open-Field along with Neurochemical Changes","volume":"18","author":"Dere","year":"2003","journal-title":"Eur. J. Neurosci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1038\/nn.3662","article-title":"Connexin 30 Sets Synaptic Strength by Controlling Astroglial Synapse Invasion","volume":"17","author":"Pannasch","year":"2014","journal-title":"Nat. Neurosci."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Liu, J., Feng, X., Wang, Y., Xia, X., and Zheng, J.C. (2022). Astrocytes: GABAceptive and GABAergic Cells in the Brain. Front. Cell. Neurosci., 16.","DOI":"10.3389\/fncel.2022.892497"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/17\/1332\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:34:40Z","timestamp":1760034880000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/17\/1332"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,28]]},"references-count":68,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["cells14171332"],"URL":"https:\/\/doi.org\/10.3390\/cells14171332","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,28]]}}}