Dokument: Ammonium-induzierte Veränderungen der Kalium- und Calciumhomöostase in Hirnschnitten der Maus
| Titel: | Ammonium-induzierte Veränderungen der Kalium- und Calciumhomöostase in Hirnschnitten der Maus | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=30031 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20140716-092102-1 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Deutsch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Haack, Nicole [Autor] | |||||||
| Dateien: |
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| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie | |||||||
| Beschreibungen: | Hepatische Enzephalopathie (HE) ist eine komplexe neurologische Störung, die durch Leberversagen induziert wird. Als Ursache für die HE gilt eine Erhöhung des extrazellulären Ammoniums ([NH4+]o). Es gibt Hinweise, dass NH4+ die Ionen-Homöostase beeinflusst und einige der HE-Symptome scheinen nur durch diese Störungen zu entstehen. So induziert NH4+ eine Zunahme der intrazellulären Natriumkonzentration und verändert die pH-Werte in Neuronen und Astrozyten (Kelly und Rose 2010). In der vorliegende Studie wurden die NH4+-induzierten Veränderungen der extrazellulären Kalium-Konzentration ([K+]o), und der intrazellulären Calcium-Konzentration ([Ca2+]i), untersucht.
Die [K+]o wurde mittels K+-sensitiven Mikroelektroden gemessen, doch jeder K+-Sensor detektiert NH4+ ebenfalls. Daher entwickelten wir eine Formel, um dieses NH4+- induzierte Artefakt herauszurechnen. In der Tat, konnten wir so zum ersten Mal die NH4+-induzierten Veränderungen der [K+]o untersuchen. Somit konnten wir zeigen, dass NH4+ einen transienten [K+]o-Anstieg im Hippocampus, in akuten Schnitten des Mäusegehirns, induziert. Nach dem transienten Anstieg sank [K+]o auf den Ruhewert zurück. Das Auswaschen des NH4+ führte zu einem temporären [K+]o-Unterschuss. Pharmakologische Experimente deuten darauf hin, dass der NH4+-induzierte [K+]o-Anstieg auf eine Verringerung des K+-Transportes durch die Na+/K+-ATPase und der [K+]o-Unterschuss durch eine erhöhte Pumpaktivität der Na+/K+-ATPase bedingt ist. Innerhalb der Astrozyten ist Ca2+ ein wichtiger Mediator der Neuro-Glia-Interaktion und der neuronalen Plastizität. Daher untersuchten wir, im zweiten Teil der Studie, mittels Fluoreszenzmessung mit Fura-2, die Wirkung von NH4+ auf [Ca2+]i in Astrozyten der verschiedenen Hirnregionen. Astrozyten des Hippocampus und Kortex wurden durch Färbung mit dem Vitalfarbstoff SR101 identifiziert; Bergmann-Gliazellen des Kleinhirns durch ihre Morphologie. In allen untersuchten Hirnregionen induzierte NH4+ eine kleine, aber anhaltende Erhöhung der [Ca2+]i, die durch eine Öffnung der NMDA-R und Freisetzung von Ca2+ aus intrazellulären Speichern bedingt ist. Zusammengenommen zeigen unsere Experimente, dass NH4+ komplexe Störungen der [K+]o und [Ca2+]i induziert. Die Beeinflussung der K+ bzw. Ca2+-Homöostase, könnte zu der gesteigerten neuronalen Erregung oder zu der Störung der Neurotransmission beitragen, die während der HE beobachtet werden können.Hepatic encephalopathy (HE) is a complex neurological disorder caused by liver failure, which is attributed to an increase of extracellular ammonium ([NH4+]). There is evidence that NH4+ induces disturbance of ion-homeostasis in general and some of the symptoms during the HE seem to arise just by this disturbance. For example NH4+ induces an increase in intracellular sodium concentration and changes in pH in neurons and astrocytes (Kelly and Rose 2010). The aim of this study was to investigate the NH4+-induced changes of extracellular potassium concentration ([K+]o) and intracellular calcium concentration ([Ca2+]i). [K+]o was determined by K+-sensitive microelectrodes, but all available K+-sensor were affected by NH4+. So we developed a formula to calculate this NH4+- induced artifact. In this study we determined for the first time the NH4+-induced dysregulation of [K+]o. We were able to show that NH4+ induced a transient [K+]o-increase in the hippocampus of acute mouse brainslices. After this transient increase, [K+]o slowly declined to the baseline. Upon NH4+ removal, [K+]o temporarily decreased below the baseline. Pharmacological experiments indicate that the NH4+-induced increase in [K+]o is due to a reduction of the Na+/K+-ATPase-mediated inward transport of K+, and that an increased pump activity after NH4+ washout is responsible for the [K+]o undershoot. Astrocyte Ca2+ is an important mediator of neuron-glia interaction and neural plasticity. So in the second part of the study, we analyzed the effect of NH4+ on [Ca2+]i of astrocytes in different brain regions, determined by calcium imaging with the indicator dye Fura-2. Astrocytes of hippocampus and cortex were identified by staining with the vital dye SR101; cerebellar Bergmann glia cells were identified based on their morphology. In all brain regions studied, NH4+ induced a small, but persistent elevation in [Ca2+]i. The major mechanisms of generation of the NH4+-induced [Ca2+]i increase is NMDA receptor activation and release of Ca2+ from intracellular stores. Taken together, our experiments demonstrate that NH4+ evokes complex changes in [K+]o and [Ca2+]i. These changes lead to an impairment of ion-homeostasis, which might contribute to the altered excitability, or to the disturbance of neurotransmission, both are observed during HE. | |||||||
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| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät » WE Biologie » Neurobiologie | |||||||
| Dokument erstellt am: | 16.07.2014 | |||||||
| Dateien geändert am: | 16.07.2014 | |||||||
| Promotionsantrag am: | 21.05.2014 | |||||||
| Datum der Promotion: | 03.07.2014 |
