title: Environmental enrichment rescues DYRK1A activity and hippocampal adult neurogenesis in TgDyrk1A.
abstract: Hippocampal adult neurogenesis disruptions have been suggested as one of the neuronal plasticity mechanisms underlying learning and memory impairment in Down syndrome (DS). However, it remains unknown whether specific candidate genes are implicated in these phenotypes in the multifactorial context of DS. Here we report that transgenic mice (TgDyrk1A) with overdosage of Dyrk1A, a DS candidate gene, show important alterations in adult neurogenesis including reduced cell proliferation rate, altered cell cycle progression and reduced cell cycle exit leading to premature migration, differentiation and reduced survival of newly born cells. In addition, less proportion of newborn hippocampal TgDyrk1A neurons are activated upon learning, suggesting reduced integration in learning circuits. Some of these alterations were DYRK1A kinase-dependent since we could rescue those using a DYRK1A inhibitor, epigallocatechin-3-gallate. Environmental enrichment also normalized DYRK1A kinase overdosage in the hippocampus, and rescued adult neurogenesis alterations in TgDyrk1A mice. We conclude that Dyrk1A is a good candidate to explain neuronal plasticity deficits in DS and that normalizing the excess of DYRK1A kinase activity either pharmacologically or using environmental stimulation can correct adult neurogenesis defects in DS.
authors: Systems Biology Program, Centre for Genomic Regulation (CRG), Dr. Aiguader 88, E-08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), Dr. Aiguader 88, E-08003 Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Dr. Aiguader 88, E-08003 Barcelona, Spain.
authors: Meritxell
authors: M
authors: Pons-Espinal
authors: Maria
authors: M
authors: Martinez de Lagran
authors: Mara
authors: M
authors: Dierssen
mesh_terms: D000818:Animals; D004314:Down Syndrome / Q000201:enzymology; D004777:Environment; D006624:Hippocampus / Q000201:enzymology*; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D055495:Neurogenesis; 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
keywords: Adult neurogenesis; DG; DS; Down syndrome; Dyrk1A; EE; EGCG; Environmental enrichment; Hippocampus; Learning and memory; TgDyrk1A; dentate gyrus; environmental enrichment; epigallocatechin-3-gallate; transgenic mice overexpressing Dyrk1A