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Modulation der Aktivität des nikotinischen Acetylcholinrezeptors in transgenen Tiermodellen

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Peter,  Christoph
Working Group Witzemann / Koenen, Max Planck Institute for Medical Research, Max Planck Society;

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Citation

Peter, C. (2003). Modulation der Aktivität des nikotinischen Acetylcholinrezeptors in transgenen Tiermodellen. PhD Thesis, Ruprecht-Karls-Universität Heidelberg, Heidelberg.


Cite as: http://hdl.handle.net/11858/00-001M-0000-002A-12BF-6
Abstract
Mutations in the subunits of the nicotinic acetylcholine receptor (AChR) of the neuromuscular junction (NMJ) can lead to changes of receptor properties, like effects on ligand binding and/or channel opening. The resulting changes of the endplate potentials can lead to congenital myasthenic syndromes (CMS), referred to as Slow-Channel or Fast-Channel Congenital Myasthenic Syndrome (SCCMS or FCCMS) respectively. In this work two lines of transgenic knock-in mice were established. In the first mouse line (g/eFC) the influence of the activity of the AChR on the establishment of the NMJ was examined. In these animals the g-subunit, that is expressed during embryogenesis, carries a point mutation, which provokes an amino acid exchange (P121L) and leads to FCCMS in myasthenic-patients. Electrophysiological examinations showed that the activity of the AChR was dramatically reduced by incorporation of this mutated subunit. Homozygous g/eFC-animals die during birth, the establishment and localisation of the NMJ are disturbed and the directed outgrowth of the motor-axon is absent. These results show that the activity of the AChR is needed for the correct establishment of the postsynaptic part of the NMJ and the directed outgrowth of the motor-axon. Another point mutation leading to an amino acid exchange (L269F) and provoking SCCMS in humans was introduced in the postnatally expressed e-subunit of a second line of knock-in mice (eSC). At two weeks of age homozygous eSC-mice show progressive myasthenic syndromes, like reduced strength, reduced body-weight and changes in posture and vocalisation. Massive degenerative changes were observed in the postsynaptic part of the NMJ and muscle-fibers of these animals. Among these is the loss of postsynaptic folds, the enlargement of mitochondria, subsynaptic accumulation of vesicles and vacuoles and signs of degeneration of subsynaptic nuclei. All together these changes are referred to as endplate-myopathy and are also observed in tissue from SCCMS-patients. Besides the endplate-myopathy, both homozygous eSC-mice and SCCMS-patients showed a reduction of AChR in the NMJ. In humans SCCMS is a dominantly inherited disease but could only be observed in homozygous eSC-mice. The reasons for this difference were clarified by breeding-experiments. eSC-animals were interbred with another transgenic mouse line (eTet), which shows a reduced expression of the e-subunit. The offspring showed myasthenic symptoms. This shows that the differences of the inheritance are due to the expression of the eSC-allele, which has a reduced expression in heterozygous eSC-animals compared to the WT-allele. Animals of the eSC-line can serve as a model organism for SCCMS. With their help it will be possible to gain new in vivo insights about physiological and genetic processes which play a role in the establishment of SCCMS. A transfer of these findings to neurodegenerative diseases like stroke or epilepsy may be possible. In addition genetic and morphological comparisons to other mouse-lines, in which the channel properties of the AChR have been changed, can give useful information about the influence of channel activity on structural and functional maintenance of the NMJ.