title: Overexpression of Dyrk1A is implicated in several cognitive, electrophysiological and neuromorphological alterations found in a mouse model of Down syndrome.
abstract: Down syndrome (DS) phenotypes result from the overexpression of several dosage-sensitive genes. The DYRK1A (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A) gene, which has been implicated in the behavioral and neuronal alterations that are characteristic of DS, plays a role in neuronal progenitor proliferation, neuronal differentiation and long-term potentiation (LTP) mechanisms that contribute to the cognitive deficits found in DS. The purpose of this study was to evaluate the effect of Dyrk1A overexpression on the behavioral and cognitive alterations in the Ts65Dn (TS) mouse model, which is the most commonly utilized mouse model of DS, as well as on several neuromorphological and electrophysiological properties proposed to underlie these deficits. In this study, we analyzed the phenotypic differences in the progeny obtained from crosses of TS females and heterozygous Dyrk1A (+/-) male mice. Our results revealed that normalization of the Dyrk1A copy number in TS mice improved working and reference memory based on the Morris water maze and contextual conditioning based on the fear conditioning test and rescued hippocampal LTP. Concomitant with these functional improvements, normalization of the Dyrk1A expression level in TS mice restored the proliferation and differentiation of hippocampal cells in the adult dentate gyrus (DG) and the density of GABAergic and glutamatergic synapse markers in the molecular layer of the hippocampus. However, normalization of the Dyrk1A gene dosage did not affect other structural (e.g., the density of mature hippocampal granule cells, the DG volume and the subgranular zone area) or behavioral (i.e., hyperactivity/attention) alterations found in the TS mouse. These results suggest that Dyrk1A overexpression is involved in some of the cognitive, electrophysiological and neuromorphological alterations, but not in the structural alterations found in DS, and suggest that pharmacological strategies targeting this gene may improve the treatment of DS-associated learning disabilities.
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, University of Cantabria, Santander, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: García-Cerro
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, University of Cantabria, Santander, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Martínez
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, University of Cantabria, Santander, Spain.
authors.forename: Verónica
authors.initials: V
authors.lastname: Vidal
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, University of Cantabria, Santander, Spain.
authors.forename: Andrea
authors.initials: A
authors.lastname: Corrales
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, University of Cantabria, Santander, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Flórez
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, University of Cantabria, Santander, Spain; Institute of Biomedicine and Biotechnology (IBBITEC), (University of Cantabria- Consejo Superior de Investigaciones Científicas (CSIC) and Investigación, Desarrollo e Investigación Cantabria (IDICAN)), Santander, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Vidal
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, University of Cantabria, Santander, Spain.
authors.forename: Noemí
authors.initials: N
authors.lastname: Rueda
authors.affiliation: Barcelona Institute of Molecular Biology, Centro Superior de Investigaciones Científicas (CSIC) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.
authors.forename: María L
authors.initials: ML
authors.lastname: Arbonés
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, University of Cantabria, Santander, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Martínez-Cué
mesh_terms: D000818:Animals; D003071:Cognition / Q000502:physiology; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D005260:Female; D017774:Long-Term Potentiation / Q000235:genetics / Q000502:physiology; D008297:Male; D008568:Memory / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D000097603:Dyrk Kinases
chemical_list: D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases