Suchergebnisse

The use of mouse models has revolutionized the field of Down syndrome (DS), increasing our knowledge about neuropathology and helping to propose new therapies for cognitive impairment. However, concerns about the reproducibility of results in mice and their translatability to humans have become a major issue, and controlling for moderators of behavior is essential. Social and environmental factors, the experience of the researcher, and the sex and strain of the animals can all have effects on behavior, and their impact on DS mouse models has not been explored. Here we analyzed the influence of a number of social and environmental factors, usually not taken into consideration, on the behavior of male and female wild-type and trisomic mice (the Ts65Dn model) in one of the most used tests for proving drug effects on memory, the novel object recognition (NOR) test. Using principal component analysis and correlation matrices, we show that the ratio of trisomic mice in the cage, the experience of the experimenter, and the timing of the test have a differential impact on male and female and on wild-type and trisomic behavior. We conclude that although the NOR test is quite robust and less susceptible to environmental influences than expected, to obtain useful results, the phenotype expression must be contrasted against the influences of social and environmental factors. ; The lab of MD is supported by the Departament d'Universitats, Recerca i Societat de la Informació de la Generalitat de Catalunya (Grups consolidats 2017 SGR 926, 2017 SGR 138). This research was funded by the Agencia Estatal de Investigación (PID2019-110755RB-I00/AEI/10.13039/501100011033), the European Union's Horizon 2020 Research and Innovation Program under grant agreement No. 848077. Jerôme Lejeune Foundation (Grant number 2002), NIH (Grant Number: 1R01EB 028159-01), Marató TV3 (#2016/20-30), and JPND (Heroes; AC17/00006). The Centre for Genomic Regulation (CRG) acknowledges the support of the Spanish Ministry of Science and Innovation to the EMBL partnership, the Centro de Excelencia Severo Ochoa, and the CERCA Program/Generalitat de Catalunya. The CIBER of Rare Diseases (CIBERER) is an initiative of the ISCIII. CS received the FI grant from Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR) de la Generalitat de Catalunya

Down syndrome (DS), caused by trisomy of chromosome 21, is the most common genetic cause of intellectual disability. We recently discovered that green tea extracts containing epigallocatechin-3-gallate (EGCG) improve cognition in mice transgenic for Dyrk1a (TgDyrk1A) and in a trisomic DS mouse model (Ts65Dn). Interestingly, paired with cognitive stimulation, green tea has beneficial pro-cognitive effects in DS individuals. Dual Specificity Tyrosine-Phosphorylation-Regulated Kinase 1A (DYRK1A) is a major candidate to explain the cognitive phenotypes of DS, and inhibiting its activity is a promising pro-cognitive therapy. DYRK1A kinase activity can be normalized in the hippocampus of transgenic DYRK1A mice administering green tea extracts, but also submitting the animals to environmental enrichment (EE). However, many other mechanisms could also explain the pro-cognitive effects of green tea extracts and EE. To underpin the overall alterations arising upon DYRK1A overexpression and the molecular processes underneath the pro-cognitive effects, we used quantitative proteomics. We investigated the hippocampal (phospho)proteome in basal conditions and after treatment with a green tea extract containing EGCG and/or EE in TgDyrk1A and control mice. We found that Dyrk1A overexpression alters protein and phosphoprotein levels of key postsynaptic and plasticity-related pathways and that these alterations were rescued upon the cognitive enhancer treatments. ; The work has received financial support from MINECO (SAF2016-79956-R), Jerome Lejeune Foundation (Project #1347 "Elucidation of the mechanism of action of epigallocatechin-3-gallate as a therapeutic agent on the cognitive phenotype in Down Syndrome mice models"), and the NIH 1R01EB 028159-01 to MD, the Centre for Genomic Regulation Severo Ochoa excellence grant (SEV-2012-0208), the Centro de Investigación Biomédica en Red Enfermedades Raras (CIBER) of Rare Diseases; "Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement de la Generalitat de Catalunya" (Grups consolidats SGR 2016/1125, and 2017SGR595); and the "Centro para el Desarrollo Tecnológico Industrial CDTI." The CRG/UPF Proteomics Unit is part of the Spanish Infrastructure for Omics Technologies (ICTS OmicsTech) and it is a member of Proteored, PRB3, and is supported by grant PT17/0019, of the PE I+D+i 2013–2016, funded by ISCIII. ID received funding from the People Program (Marie Curie Actions) of the European Union's Seventh Framework Program (FP7/2007-2013) under REA grant agreement n° 608959. MO received an FPI Severo Ochoa Doctoral Fellowship from the Spanish Ministry of Economy and Finance (MINECO) SVP-2013-068022 during the period 2014–2018 and a short research international stay fellowship (EEBB-I-16-11305).