Neurophysiologische Charakterisierung von adulten vulnerablen und resistenten Motoneuronen in einem Mausmodell der Amyotrophen Lateralsklerose
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Philipps-Universität Marburg
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Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motoneurons (MN) of the motor cortex, the brainstem and the spinal cord and leads to paralysis and atrophy of the innervated muscles. Patients mostly die within three to five years after symptom onset. There is no curative therapy. Overexcitability, calcium overload and mitochondrial disturbances are discussed as a common final cause of MN degeneration in this multifactorial disease. Because of technicals difficulties, so far excitability and calcium dynamics could only be analyzed in mouse models of ALS on a single cell level up to a postnatal age of ten days (P10), when mice did not show any symptoms. However, to study the direct mechanisms of neurodegeneration and to develop new therapies, analyses of MN during the stage of degeneration are essential. Here, for the first time a characterization of adult MN in acute brainstem slices of the SOD1-G93A ALS mouse model was performed using whole-cell patch-clamp measurements and fluorometric fura-2 calcium-imaging. The properties of the highly vulnerable hypoglossal MN were compared in wildtype and SOD1-G93A mice during disease endstage. The higher excitability and the increased persistent sodium inward currents, published for P10 SOD1-G93A mice, were not present in adult animals. Although electrophysiological properties were not prominently changed, the calcium clearance was significantly impaired in comparison to wildtype during disease endstage when MN were electrically stimulated to load them with high concentrations of calcium. However, with low physiological calcium load there were no differences. By comparing the vulnerable hMN with the resistant oculomotor MN, it was observed that the clearance deficit was specific for hMN and thereby is an explanation for the differential vulnerability. By fura-2 calcium-imaging in combination with mitochondrial uncoupling, specific pharmacological blocking of different calcium transporters and rhodamine123 imaging, a reduced calcium transport through the mitochondrial calcium uniporter was revealed as a cause for the impairment whereas the driving force for calcium into mitochondria was not changed. By blocking both the mitochondrial and the ER calcium uptake an increase of calcium transport by plasma membrane calcium transporters was indirectly shown in hMN of SOD1-G93A mice. From these result one can conclude that in the used ALS mouse model vulnerable MN try to compensate for a mitochondrial calcium uptake failure by upregulating plasma membrane calcium transport. However, with high calcium load during disease endstage this compensatory mechanism fails and a calcium overload might be the final cause of MN degeneration in ALS.
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Created: 2012Issued: 2012-02-16Updated: 2012-03-19
Faculty
Medizin
Publisher
Philipps-Universität Marburg
Language
ger
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DoctoralThesis
Keywords
MotoneuronSOD-1SOD-1CalciumMotoneuronAmyotrophe LateralskleroseAmyotrophic lateral sclerosisPatch clamp
DFG-subjects
Patch-Clamp-MethodeCalcium
DDC-Numbers
610
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Fuchs, Andrea (1019524723): Neurophysiologische Charakterisierung von adulten vulnerablen und resistenten Motoneuronen in einem Mausmodell der Amyotrophen Lateralsklerose. : Philipps-Universität Marburg 2012-02-16. DOI: https://doi.org/10.17192/z2012.0174.
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This item has been published with the following license: In Copyright