Die Rolle der L-Typ-Kalziumkanäle für die Schrittmacherfunktion in Locus coeruleus Neuronen der Maus

Der Locus coeruleus (LC) ist aufgrund seiner bedeutenden Rolle in der Entstehung der Parkinson-Krankheit von großem wissenschaftlichen und therapeutischen Interesse. Im Verlauf der Erkrankung gehen dopaminerge Neurone der Substantia nigra pars compacta (SNpc) aus bisher ungeklärten Ursachen zugrunde...

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Bibliographic Details
Main Author: Schieber, Simon
Contributors: Decher, Niels (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2013
Online Access:PDF Full Text
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The Locus coeruleus (LC) is considered to play an important role in the pathogenesis of Parkinson´s disease (PD) and therefore is of high scientific and therapeutic interest. In PD dopaminergic Substantia nigra pars compacta (SNpc) neurons degenerate for unknown reasons. Even before the SNpc is affected, there are degenerative processes demonstrable in the LC. Noradrenergic LC neurons are known to have neuroprotective influence on the Substantia nigra and promote survival of SNpc cells. Therefore the Locus coeruleus is an important scientific target for research in the field of Parkinson´s disease. Locus coeruleus neurons are autonomous pacemakers. Up to now, the mechanism underlying pacemaker activity is largly unknown. The aim of this study is to investigate this pacemaker mechanism more closely and to clarify the role of L-type calcium channels. Therefore, electrophysiological, molecularbiological and fluorescence microscopy experiments were performed on brain slices of C57BL/6 mice. Single cell patch clamp recordings showed, that applying the calciumchannel blocker isradipine alone has no influence on the firing pattern of LC neurons. In contrast to our initial expectation, our data show that autonomously generated actionpotentials do not rely on continuous depolarizing calcium currents. However, L-type calcium channels are active in these cells. Blocking action potentials in LC neurons using tetrodotoxin reveals slow oscillatory potentials - similar to those in SNpc neurons - effectively blockable by isradipine. According to that, calcium currents contribute to the electrical activity of LC neurons without being essential for maintaining pacemaking. Increased exposition to calcium-induced oxidative stress is thought to play a role in accelerated degeneration of cells within LC and SNpc in Parkinson´s disease. Our study gives evidence that blocking L-type calcium channels in LC neurons may influence the calcium homeostasis and reduce calcium-mediated production of reactive oxygen species without affecting the physiological properties of the cells. We therefore assume that LC may be a promising target for next generation neuroprotective therapeutical approaches.