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Trisomy of the human chromosome 21, commonly referred to as Down syndrome (DS), is the leading genetic cause of mental retardation worldwide. This neurodevelopmental disorder results in altered physical features and affects every organ system, leading to different co-occurring medical conditions. The cognitive deficits, however, affect 100% of the DS individuals resulting in an altered social and emotional behaviour. As such, in the last decade, a lot of research was done in order to find a therapeutic treatment focusing in the neurological aspect of the syndrome. However, as there exists a lot of intervariability, it remains difficult to pin-point the underlying cause. Regarding the cognitive deficits, it is assumed that the excessive activity of DYRK1A, a gene found in the DSCR region of Hsa21, has a key role in brain development and thus in the progress of mental retardation. With the assumption that EGCG, a DYRK1A inhibitor, would bring DYRK1A activity to normal levels at early stages, we hypothesized in this thesis that the cognitive deficits and possible underlying structural brain alterations could be rescued or at least improved. As such, GTE-EGCG treatment with a concentration of 0,09 ml EGCG/mL (estimated dose of 90 mg/kg/day via dam, assuming all EGCG ended up in the milk, and 45 mg/kg/day via pup itself) was administered to a widely used DS mouse model, Ts65Dn, from embryonic day 9 and was continued until 6 months. We analysed trisomy and treatment effects on a functional level by a defined preweaning test battery for somatometry, developmental landmarks, reflexes and sensory-motor responses. Trisomic mice showed especially a delay in sensory-motor reflexes with treatment having variable effects. As these responses can be linked to the cerebellum due to its key role in cognition as well as in motor function, the cerebellar structures, including the white/gray matter ratio, were examined using in vivo longitudinal MRI. No trisomy effects were observed. however, treatment caused a shift in the cerebellar white/gray matter ratio of TS mice by decreasing the white matter volume and increasing the gray matter volume. To evaluate the impact of this effect, more short-term and long-term behavioural tests with a bigger sample size should be performed. In general, the results in this thesis illustrate that a better understanding of DS can achieved by performing and optimizing the methods used, especially in in vivo studies, which provide longitudinally follow-up of development.
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