{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T04:11:28Z","timestamp":1785471088410,"version":"3.56.0"},"reference-count":51,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T00:00:00Z","timestamp":1737504000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European FP7-HEALTH AgedBrainSysbio and European JPND TransPathND program"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Chromosome 21 DYRK1A kinase is associated with a variety of neuronal diseases including Down syndrome. However, the functional impact of this kinase at the synapse level remains unclear. We studied a mouse model that incorporated YAC 152F7 (570 kb), encoding six chromosome 21 genes including DYRK1A. The 152F7 mice displayed learning difficulties but their N-methyl-D-aspartate (NMDA)-dependent synaptic long-term potentiation is indistinguishable from non-transgenic animals. We have demonstrated that a presynaptic form of NMDA-independent long-term potentiation (LTP) at the hippocampal mossy fiber was impaired in the 152F7 animals. To obtain insights into the molecular mechanisms involved in such synaptic changes, we analyzed the Dyrk1a interactions with chromatin remodelers. We found that the number of DYRK1A-EP300 and DYRK1A-CREBPP increased in 152F7 mice. Moreover, we observed a transcriptional decrease in genes encoding presynaptic proteins involved in glutamate vesicle exocytosis, namely Rims1, Munc13-1, Syn2 and Rab3A.To refine our findings, we used a mouse BAC 189N3 (152 kb) line that only triplicates the gene Dyrk1a. Again, we found that this NMDA-independent form of LTP is impaired in this mouse line. Altogether, our results demonstrate that Dyrk1a up-regulation is sufficient to specifically inhibit the NMDA-independent form of LTP and suggest that this inhibition is linked to chromatin changes that deregulate genes encoding proteins involved in glutamate synaptic release.<\/jats:p>","DOI":"10.3390\/life15020149","type":"journal-article","created":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T05:50:53Z","timestamp":1737525053000},"page":"149","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["DYRK1A Up-Regulation Specifically Impairs a Presynaptic Form of Long-Term Potentiation"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8923-1037","authenticated-orcid":false,"given":"Aude-Marie","family":"Lepagnol-Bestel","sequence":"first","affiliation":[{"name":"Centre Psychiatrie & Neurosciences, INSERM U894, 75014 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5051-8148","authenticated-orcid":false,"given":"Simon","family":"Haziza","sequence":"additional","affiliation":[{"name":"Centre Psychiatrie & Neurosciences, INSERM U894, 75014 Paris, France"},{"name":"Centre National de la Recherche Scientifique, Universit\u00e9 Paris-Saclay, CentraleSup\u00e9lec, \u00c9cole Normale Sup\u00e9rieure Paris-Saclay, LuMIn, 91190 Gif-sur-Yvette, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Viard","sequence":"additional","affiliation":[{"name":"Centre Psychiatrie & Neurosciences, INSERM U894, 75014 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul A.","family":"Salin","sequence":"additional","affiliation":[{"name":"Centre de Recherche en Neuroscience de Lyon CRNL (INSERM U1028), Universit\u00e9 Claude-Bernard Lyon 1, 69100 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3043-702X","authenticated-orcid":false,"given":"Arnaud","family":"Duchon","sequence":"additional","affiliation":[{"name":"Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire (IGBMC), Universit\u00e9 de Strasbourg, CNRS UMR7104, INSERM, U964, 67404 Illkirch, France"},{"name":"Phenomin, Institut Clinique de la Souris (ICS), GIE CERBM, CNRS, INSERM, Universit\u00e9 de Strasbourg, 1 rue Laurent Fries, 67404 Illkirch, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7049-6900","authenticated-orcid":false,"given":"Yann","family":"Herault","sequence":"additional","affiliation":[{"name":"Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire (IGBMC), Universit\u00e9 de Strasbourg, CNRS UMR7104, INSERM, U964, 67404 Illkirch, France"},{"name":"Phenomin, Institut Clinique de la Souris (ICS), GIE CERBM, CNRS, INSERM, Universit\u00e9 de Strasbourg, 1 rue Laurent Fries, 67404 Illkirch, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0857-8619","authenticated-orcid":false,"given":"Michel","family":"Simonneau","sequence":"additional","affiliation":[{"name":"Centre Psychiatrie & Neurosciences, INSERM U894, 75014 Paris, France"},{"name":"Centre National de la Recherche Scientifique, Universit\u00e9 Paris-Saclay, CentraleSup\u00e9lec, \u00c9cole Normale Sup\u00e9rieure Paris-Saclay, LuMIn, 91190 Gif-sur-Yvette, France"},{"name":"D\u00e9partement d\u2019Enseignement et de Recherche en Biologie, \u00c9cole Normale Sup\u00e9rieure Paris-Saclay, 91190 Gif-sur-Yvette, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1038\/nrg.2016.154","article-title":"Down syndrome and the complexity of genome dosage imbalance","volume":"18","author":"Antonarakis","year":"2017","journal-title":"Nat. Rev. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1038\/s41582-018-0132-6","article-title":"Dementia in Down syndrome: Unique insights for Alzheimer disease research","volume":"15","author":"Lott","year":"2019","journal-title":"Nat. Rev. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1038\/nrn3314","article-title":"Down syndrome: The brain in trisomic mode","volume":"13","author":"Dierssen","year":"2012","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1038\/nrn3983","article-title":"A genetic cause of Alzheimer disease: Mechanistic insights from Down syndrome","volume":"16","author":"Wiseman","year":"2015","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.nbd.2005.12.006","article-title":"DYRK1A BAC transgenic mice show altered synaptic plasticity with learning and memory defects","volume":"22","author":"Ahn","year":"2006","journal-title":"Neurobiol. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.nbd.2012.01.007","article-title":"DYRK1A: A master regulatory protein controlling brain growth","volume":"46","author":"Guedj","year":"2012","journal-title":"Neurobiol. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1523\/JNEUROSCI.2852-13.2014","article-title":"Prefrontal Deficits in a Murine Model Overexpressing the Down Syndrome Candidate Gene Dyrk1a","volume":"34","author":"Thomazeau","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"6540","DOI":"10.1093\/hmg\/ddv364","article-title":"Genetic dissection of the Down syndrome critical region","volume":"24","author":"Jiang","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.pharmthera.2018.09.010","article-title":"DYRK1A and cognition: A lifelong relationship","volume":"194","author":"Arbones","year":"2019","journal-title":"Pharmacol. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1126\/science.1067020","article-title":"The molecular biology of memory storage: A dialogue between genes and synapses","volume":"294","author":"Kandel","year":"2001","journal-title":"Science"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.neuron.2016.12.015","article-title":"A Brief History of Long-Term Potentiation","volume":"93","author":"Nicoll","year":"2017","journal-title":"Neuron"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Castillo, P.E. (2012). Presynaptic LTP and LTD of Excitatory and Inhibitory Synapses. Cold Spring Harb. Perspect. Biol., 4.","DOI":"10.1101\/cshperspect.a005728"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1146\/annurev-neuro-080317-062155","article-title":"Long-Term Plasticity of Neurotransmitter Release: Emerging Mechanisms and Contributions to Brain Function and Disease","volume":"41","author":"Monday","year":"2018","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1038\/ng0597-28","article-title":"Functional screening of 2 Mb of human chromosome 21q22.2 in transgenic mice implicates minibrain in learning defects associated with Down syndrome","volume":"16","author":"Smith","year":"1997","journal-title":"Nat. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1093\/dnares\/9.3.89","article-title":"Identification of Two Novel Primate-Specific Genes in DSCR","volume":"9","author":"Takamatsu","year":"2002","journal-title":"DNA Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s40246-018-0133-y","article-title":"Identify Down syndrome transcriptome associations using integrative analysis of microarray database and correlation-interaction network","volume":"12","author":"Chen","year":"2018","journal-title":"Hum. Genom."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.nbd.2014.04.016","article-title":"Excitation\/inhibition balance and learning are modified by Dyrk1a gene dosage","volume":"69","author":"Souchet","year":"2014","journal-title":"Neurobiol. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"dmm035634","DOI":"10.1242\/dmm.035634","article-title":"Correction of cognitive deficits in mouse models of Down syndrome by a pharmacological inhibitor of DYRK1A","volume":"11","author":"Nguyen","year":"2018","journal-title":"Dis. Models Mech."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"R1116","DOI":"10.1016\/j.cub.2015.10.049","article-title":"The hippocampus","volume":"25","author":"Knierim","year":"2015","journal-title":"Curr. Biol."},{"key":"ref_20","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_21","doi-asserted-by":"crossref","first-page":"e202101205","DOI":"10.26508\/lsa.202101205","article-title":"Chr21 protein-protein interactions: Enrichment in proteins involved in intellectual disability, autism, and late-onset Alzheimer\u2019s disease","volume":"5","author":"Viard","year":"2022","journal-title":"Life Sci. Alliance"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1038\/nmeth947","article-title":"Direct observation of individual endogenous protein complexes in situ by proximity ligation","volume":"3","author":"Gullberg","year":"2006","journal-title":"Nat. Methods"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4014","DOI":"10.1523\/JNEUROSCI.4717-06.2007","article-title":"Presynaptic FMR1 genotype influences the degree of synaptic connectivity in a mosaic mouse model of fragile X syndrome","volume":"27","author":"Hanson","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Garc\u00eda-Cerro, S., Mart\u00ednez, P., Vidal, V., Corrales, A., Fl\u00f3rez, J., Vidal, R., Rueda, N., Arbon\u00e9s, M.L., and Mart\u00ednez-Cu\u00e9, C. (2014). Overexpression of Dyrk1A is implicated in several cognitive, electrophysiological and neuromorphological alterations found in a mouse model of Down syndrome. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0106572"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1038\/nrn1786","article-title":"Synaptic plasticity at hippocampal mossy fibre synapses","volume":"6","author":"Nicoll","year":"2005","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1016\/j.celrep.2013.03.027","article-title":"The protein interaction landscape of the human CMGC kinase group","volume":"3","author":"Varjosalo","year":"2013","journal-title":"Cell Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"100064","DOI":"10.1016\/j.mcpro.2021.100064","article-title":"Proximity-dependent Mapping of the Androgen Receptor Identifies Kruppel-like Factor 4 as a Functional Partner","volume":"20","author":"Lessard","year":"2021","journal-title":"Mol. Cell. Proteom."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1038\/cr.2010.155","article-title":"A switch from hBrm to Brg1 at IFN\u03b3-activated sequences mediates the activation of human genes","volume":"20","author":"Zhang","year":"2010","journal-title":"Cell Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/j.neuron.2013.10.022","article-title":"Neurotransmitter release: The last millisecond in the life of a synaptic vesicle","volume":"80","year":"2013","journal-title":"Neuron"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1016\/j.neuron.2014.04.020","article-title":"Microsecond dissection of neurotransmitter release: SNARE-complex assembly dictates speed and Ca2+ sensitivity","volume":"82","author":"Acuna","year":"2014","journal-title":"Neuron"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1038\/41574","article-title":"Rab3A is essential for mossy fibre long-term potentiation in the hippocampus","volume":"388","author":"Castillo","year":"1997","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1016\/S0896-6273(00)80631-5","article-title":"Mechanism of action of rab3A in mossy fiber LTP","volume":"21","author":"Lonart","year":"1998","journal-title":"Neuron"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1038\/415327a","article-title":"RIM1alpha is required for presynaptic long-term potentiation","volume":"415","author":"Castillo","year":"2002","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"12053","DOI":"10.1523\/JNEUROSCI.2276-11.2011","article-title":"Munc13-1 is required for presynaptic long-term potentiation","volume":"31","author":"Yang","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1016\/0028-3908(95)00107-H","article-title":"Long-term potentiation in mice lacking synapsins","volume":"34","author":"Spillane","year":"1995","journal-title":"Neuropharmacology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"D672","DOI":"10.1093\/nar\/gkad1025","article-title":"The Reactome Pathway Knowledgebase 2024","volume":"52","author":"Milacic","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1007\/s00335-016-9661-8","article-title":"Mouse models of Down syndrome: Gene content and consequences","volume":"27","author":"Gupta","year":"2016","journal-title":"Mamm. Genome"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1242\/dmm.029728","article-title":"Rodent models in Down syndrome research: Impact and future opportunities","volume":"10","author":"Herault","year":"2017","journal-title":"Dis. Models Mech."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"dmm046243","DOI":"10.1242\/dmm.046243","article-title":"Longitudinal neuroanatomical and behavioral analyses show phenotypic drift and variability in the Ts65Dn mouse model of Down syndrome","volume":"13","author":"Shaw","year":"2020","journal-title":"Dis. Model Mech."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Tom\u00e1s Ahumada Saavedra, J., Chevalier, C., Zupan, A.B., and Herault, Y. (2024). Ripply3 overdosage induces mid-face shortening through Tbx1 downregulation in Down syndrome models. bioRxiv, Available online: https:\/\/www.biorxiv.org\/content\/10.1101\/2024.09.13.612914v1.","DOI":"10.1101\/2024.09.13.612914"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"6384","DOI":"10.1038\/s41467-022-34200-0","article-title":"Rescue of deficits by Brwd1 copy number restoration in the Ts65Dn mouse model of Down syndrome","volume":"13","author":"Fulton","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"De Toma, I., Ortega, M., Aloy, P., Sabid\u00f3, E., and Dierssen, M. (2019). DYRK1A Overexpression Alters Cognition and Neural-Related Proteomic Pathways in the Hippocampus That Are Rescued by Green Tea Extract and\/or Environmental Enrichment. Front. Mol. Neurosci., 12.","DOI":"10.3389\/fnmol.2019.00272"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Ortega, M., De Toma, I., Fern\u00e1ndez-Blanco, \u00c1., Calder\u00f3n, A., Barahona, L., Trull\u00e0s, R., Sabid\u00f3, E., and Dierssen, M. (2022). Proteomic profiling reveals mitochondrial dysfunction in the cerebellum of transgenic mice overexpressing DYRK1A, a Down syndrome candidate gene. Front. Mol. Neurosci., 15.","DOI":"10.3389\/fnmol.2022.1015220"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"bhad431","DOI":"10.1093\/cercor\/bhad431","article-title":"Deficits in neuronal architecture but not over-inhibition are main determinants of reduced neuronal network activity in a mouse model of overexpression of Dyrk1A","volume":"34","author":"Gener","year":"2024","journal-title":"Cereb. Cortex"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1016\/j.molcel.2014.12.026","article-title":"Chromatin-wide profiling of DYRK1A reveals a role as a gene-specific RNA polymerase II CTD kinase","volume":"57","author":"Vona","year":"2015","journal-title":"Mol. Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"11202","DOI":"10.1093\/nar\/gky754","article-title":"DYRK1A interacts with histone acetyl transferase p300 and CBP and localizes to enhancers","volume":"46","author":"Li","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1016\/j.neuron.2004.05.021","article-title":"Chromatin Acetylation, Memory, and LTP Are Impaired in CBP+\/\u2212 Mice","volume":"42","author":"Malleret","year":"2004","journal-title":"Neuron"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/S0092-8674(02)01074-7","article-title":"Integration of Long-Term-Memory-Related Synaptic Plasticity Involves Bidirectional Regulation of Gene Expression and Chromatin Structure","volume":"111","author":"Guan","year":"2002","journal-title":"Cell"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"19186","DOI":"10.1073\/pnas.0509735102","article-title":"CREB-binding protein controls response to cocaine by acetylating histones at the fosB promoter in the mouse striatum","volume":"102","author":"Levine","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1136\/jmg-2023-109438","article-title":"Diagnosis and management in Rubinstein-Taybi syndrome: First international consensus statement","volume":"61","author":"Lacombe","year":"2024","journal-title":"J. Med. Genet."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1038\/s41586-023-06569-5","article-title":"Spatial atlas of the mouse central nervous system at molecular resolution","volume":"622","author":"Shi","year":"2023","journal-title":"Nature"}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/15\/2\/149\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:33:36Z","timestamp":1759919616000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/15\/2\/149"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,22]]},"references-count":51,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["life15020149"],"URL":"https:\/\/doi.org\/10.3390\/life15020149","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/645200","asserted-by":"object"}]},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,22]]}}}