Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down's syndrome

Down's syndrome (DS) is a major cause of mental retardation, hypotonia and delayed development. Murine models of DS carrying large murine or human gen omic fragments show motor alterations and memory deficits. The specific gen es responsible for these phenotypic alterations have not yet been defined. DYRK1A, the human homolog of the Drosophila minibrain gene, maps to the DS critical region of human chromosome 21 and is overexpressed in DS fetal bra in. DYRK1A encodes a serine-threonine kinase, probably involved in neurobla st proliferation. Mutant Drosophila minibrain flies have a reduction in bot h optic lobes and central brain, showing learning deficits and hypoactivity . We have generated transgenic mice (TgDyrk1A) overexpressing the full-leng th cDNA of Dyrk1A. TgDyrk1A mice exhibit delayed craniocaudal maturation wi th functional consequences in neuromotor development. TgDyrk1A mice also sh ow altered motor skill acquisition and hyperactivity, which is maintained t o adulthood. In the Morris water maze, TgDyrk1A mice show a significant imp airment in spatial learning and cognitive flexibility, indicative of hippoc ampal and prefrontal cortex dysfunction. In the more complex repeated rever sal learning paradigm, this defect turned out to be specifically related to reference memory, whereas working memory was almost unimpaired. These alte rations are comparable with those found in the partial trisomy chromosome 1 6 murine models of DS and suggest a causative role of DYRK1A in mental reta rdation and in motor anomalies of DS.