Die zentrale Kontrolle der Atmung in Mäusen mit Natriumkanalmutationen, die Epilepsie verursachen und die Implikationen für sudden unexpected death in epilepsy (SUDEP)
Molekulare Biologie und Physiologie von Nerven- und Gliazellen
Zusammenfassung der Projektergebnisse
The goal of the proposal “Exploring the function of the central control of breathing in mice with sodium-channel mutations causing epilepsy, implication for the sudden unexpected death in epilepsy (SUDEP)” was to investigate the underlying deficits in autonomic brainstem centers in transgenic mice and due to the treatment with AED targeting sodium channels. We found indeed a sodium dependent dysfunction of the rhythm generating kernel (PreBötC) in the combination with severe hypoxia and could link this to direct inhibition of the persistent sodium current (Inap) in PreBötzinger Complex neurons. The results of this study are therefore an important addition to the basic understanding of the function of the PreBötzinger Complex as the critical rhythm generating kernel for inspiratory respiration. Moreover, the finding that the treatment with specific AED affecting sodium channels in the PreBötzinger is severely inhibiting the gasping activity generated in the PreBötC is clinically relevant, since it is a common feature of GTCSs to be combined by severe hypoxemia and respiratory disturbances. Treatment with these drugs might therefore be beneficial to supress the seizure activity, but could potentially have as a side effect the subsequent effects on the respiration and should be considered with caution in patients that have increased risk for SUDEP, such as nightly occurring seizures and a high frequency of GTCSs. In addition, the investigated substances doxapram and ProstaglandinE2 can potentially counteract the suppression of the sodium channel dysfunction mediated breathing disturbances and might therefore be a potential new treatment option to prevent SUDEP. The investigation of the transgenic mice showed a surprising result in vivo an in vitro. While mice carrying a mutation in the SCN1A gene, which has been shown to lead to a loss of function, showed a disturbed breathing in normal conditions, but a robust response to hypoxia, the mice carrying a mutation in SCN2A showed no abnormalities compared to their wildtype littermates. This finding indicates that mutations in SCN1A might not only increase the risk of SUDEP by the occurrence of seizures, but also by direct modifications in the respiratory centers in the brainstem. This outcome is possibly explained by a distinct expression and compensation of the different sodium channel subunits in the cells of the PreBötzinger Complex and this is currently investigated by single cell RNA-Sequencing experiments of the SCN1A mice. This ongoing work will build on the results of this grant proposal and is funded by the FACES foundation and will be jointly published as coherent study. In addition to the Single cell RNA-Seq experiments we also proposed to investigate the interplay between the cortical and subcortical areas in the follow-up studies of this grant in the coming years.
Projektbezogene Publikationen (Auswahl)
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Human Cerebrospinal fluid promotes long-term neuronal viability and network function in human neocortical organotypic brain slice cultures. Sci Rep. 2017 Sep 25;7(1):12249
Schwarz N, Hedrich U.B. S., Schwarz H, P.A. H., Dammeier N., Auffenberg E, Bedogni F, Honegger J. B., Lerche H., Wuttke T.V. & Koch H
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2019. Long-term adult human brain slice cultures as a model system to study human CNS circuitry and disease. eLife 2019;8:e48417
Schwarz N, Uysal B, Welzer M, Bahr JC, Layer N, Löffler H, Stanaitis K, PA H, Weber YG, Hedrich UB, Honegger JB, Skodras A, Becker AJ, Wuttke T V, Koch H
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Doxapram stimulates respiratory activity through distinct activation of neurons in the Nucleus Hypoglossus and the PreBötzinger Complex. J Neurophysiol. 2019 Jan 30
Krusynski S, Brandes J, Poets CF and Koch H
