Modulation der synaptischen Plastizität im Rett-Syndrom durch Antioxidantien-Fütterung

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Rett syndrome is a severe neurodevelopmental disorder that almost exclusively affects females. Upon an apparently normal development during the first 6 – 18 months of life, developmental stagnation and especially neurological symptoms including cognitive impairment, loss of speech, motor dysfunction and hand stereotypes manifest. In most cases Rett syndrome arises from spontaneous mutations in the X-chromosomal methyl-CpG binding protein 2 (MECP2) gene, which plays an important role in the regulation of gene expression. Mitochondrial impairment, redox imbalance and oxidative stress are considered as contributing factors in the pathogenesis of Rett syndrome and therefore represent potential targets for possible therapeutic approaches. Along this line, the effect of oral administration of antioxidants (antioxidant nourishment) and its influence on Rett syndrome was investigated in this thesis: The effects of the antioxidant nourishment on synaptic function and plasticity as well as on the general phenotype of the MeCP2-deficient (Mecp2-/y) mice were thoroughly examined in electrophysiological experiments. Detailed phenotyping based on body weight, length, and blood parameters, showed significant differences in all parameters between wild type and Mecp2-/y mice. Antioxidant nourishment resulted in a significant increase in the length of Mecp2-/y mice as well as an improved body weight. Yet, the lowered blood glucose levels did not improve, and the hematocrit unexpectedly showed a further increase. To assess the extent of synaptic plasticity, post-tetanic potentiation (PTP) and long-term potentiation (LTP) were examined in acute corticohippocampal brain slices in an Oslo-style interface chamber by performing extracellular field potential recordings. PTP and LTP were induced by high-frequency stimulation (three 100 Hz trains of 1 s duration each). Modulated evoked field potentials were monitored and analyzed for an additional hour. PTP was significantly reduced in Mecp2-/y mice compared to wild type mice, while this difference was less pronounced in LTP. However, antioxidant nourishment significantly increased PTP in Mecp2-/y mice and also tended to improve LTP. Thus, the antioxidants were capable of restoring successfully both forms of synaptic plasticity in the Mecp2-/y mouse hippocampus to the level of plasticity seen in wild type mice or even beyond, they rescued the substantial changes in PTP and LTP caused by Rett syndrome. Therefore, antioxidant-based treatments could be considered as a therapeutic approach to improve symptoms like neuronal dysfunction and cognitive impairment in Rett syndrome. Since the spectrum of symptoms of Rett syndrome is highly diverse and complex, the effects of the antioxidant food on other typical disease symptoms as well as on heterozygous female mice, who have a significantly milder and more variable phenotype, need to be thoroughly investigated by future research. Furthermore, studies using different starting points or doses of treatment as well as different durations of compound supplementation will also be necessary to allow for a detailed evaluation of the full potential of antioxidant treatment.