Motor phenotypic alterations in TgDyrk1a transgenic mice implicate DYRK1A in Down syndrome motor dysfunction

• Published in: Neurobiology of disease Vol. 15; no. 1; pp. 132 - 142
• Main Authors: Martı́nez de Lagrán, M, Altafaj, X, Gallego, X, Martı́, E, Estivill, X, Sahún, I, Fillat, C, Dierssen, M
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2004; Elsevier
• Subjects: Animals; Brain - metabolism; Brain - pathology; Brain - physiopathology; Disease Models, Animal; Down syndrome; Down Syndrome - complications; Dyrk Kinases; Dyrk1a; DYRK1A expression; Female; Gene Expression Regulation - genetics; Lameness, Animal - genetics; Lameness, Animal - metabolism; Lameness, Animal - physiopathology; Learning Disabilities - genetics; Learning Disabilities - metabolism; Learning Disabilities - physiopathology; Locomotion; Male; Mice; Mice, Transgenic; Motor Activity - genetics; Motor dysfunction; Motor learning; Movement Disorders - genetics; Movement Disorders - metabolism; Movement Disorders - physiopathology; Muscle Weakness - genetics; Muscle Weakness - metabolism; Muscle Weakness - physiopathology; Neurons - metabolism; Neurons - pathology; Phenotype; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Transgenic mice; Locomotion; DYRK1A expression; Dyrk1a; Transgenic mice; Down syndrome; Motor learning; Motor dysfunction
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2003.10.002

Motor deficits are among the most frequent impairments in Down syndrome (DS), but their neuropathological and molecular bases remain elusive. Here we investigate the motor profile of transgenic mice overexpressing Dyrk1a, Tg(Dyrk1a)1Cff (hereafter TgDyrk1a), a candidate gene hypothesized to cause some of the neurological defects associated with DS. We have previously shown DYRK1A expression in the cerebellum and functionally related structures, most brainstem motor nuclei and spinal cord, supporting a role for Dyrk1a in controlling motor function. Here we demonstrate that TgDyrk1a mice present DYRK1A overexpression in these areas along with specific motor dysfunction. The main finding that emerged was impairment of motor learning and alteration of the organization of locomotor behavior, which agrees with reported clinical observations in subjects with DS. These results confirm and extend previous data and provide further insight to the functional domains that might be altered in TgDyrk1a mice and underlying molecular mechanisms of DS motor dysfunction.