Royeck, Michael Winfried: The contribution of the sodium channel subunit NaV1.6 to neuronal excitability. - Bonn, 2010. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5N-20960
@phdthesis{handle:20.500.11811/4559,
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5N-20960,
author = {{Michael Winfried Royeck}},
title = {The contribution of the sodium channel subunit NaV1.6 to neuronal excitability},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2010,
month = apr,

note = {The focus of this work was to elucidate the contribution of a single Na+ channel a-subunit, namely NaV1.6, to the discharge properties of CA1 pyramidal neurons. In the first part of this work, we show that NaV1.6 is strongly aggregated at the axon initial segment. Interestingly, in the absence of NaV1.6 overall Na+ channel density at the axon initial segment remains unchanged, indicating compensation. We find that NaV1.6 displays a hyperpolarized voltage dependence of activation and contributes to persistent and resurgent Na+ currents. As a consequence, loss of NaV1.6 increases action potential threshold and affects spike initiation at the axon initial segment. Furthermore, the absence of NaV1.6 significantly reduces spike gain and spontaneous action potential firing. Utilizing a computational model we characterize the interplay between Na+ channel density and voltage dependence at the axon initial segment in shaping initiation and threshold of action potentials.
In the second part, we concentrated on the role of NaV1.6 during status epilepticus induced epileptogenesis in rats. We show that in epileptic CA1 pyramidal neurons the spike afterdepolarization is augmented due to an upregulation of the persistent Na+ current. Utilizing mRNA expression analysis, Western blotting, and immunohistochemistry we demonstrate that the increased excitability is not mediated by upregulation of Na+ channel a-subunits, including NaV1.6. Furthermore, our immunolabellings show that NaV1.6 and total Na+ channel density at axon initial segments are unchanged. In additional experiments, we find that the increased persistent Na+ current in CA1 pyramidal neurons from pilocarpine treated rats is sensitive to high concentrations of the intracellular polyamine spermine. Therefore, we suggest that the generation of a de novo portion of persistent Na+ current, which contributes to the augmented excitability in epilepsy, is mediated by altered polyamine modulation instead of increased Na+ channel expression.},

url = {http://hdl.handle.net/20.500.11811/4559}
}

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