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bioRxiv · 10.1101/048520

Temperature-dependent changes in neuronal dynamics in a patient with an SCN1A mutation and hyperthermia induced seizures

Colin Peters·Richard E Rosch·Elaine Hughes·Peter C Ruben
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Abstract

Dravet syndrome is the prototype of SCN1A-mutation associated epilepsies. It is characterised by prolonged seizures, typically provoked by fever. We describe the evaluation of an SCN1A mutation in a child with early-onset temperature-sensitive seizures.\n\nThe patient carries a heterozygous miss-sense variant (c3818C>T; pAla1273Val) in the NaV1.1 brain sodium channel. We characterised the functional effects of the variant using patch clamp recordings on Chinese Hamster Ovary Cells at different temperatures (32, 37, and 40{degrees}C).\n\nThe variant channels produced a temperature-dependent destabilization of channel activation and fast inactivation. Implementing these empirical abnormalities in a computational model produces a higher threshold for depolarization block in the variant, particularly at 40{degrees}C, suggesting a failure to autoregulate at high-input states.\n\nThese results reveal direct effects of abnormalities in biophysical NaV1.1 channel properties on neuronal dynamics. They illustrate the value of combining cellular measurements with computational models to integrate different scales (gene/channel to patient) of observations.

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Colin Peters, Richard E Rosch, Elaine Hughes, Peter C Ruben. 2016-04-13. Temperature-dependent changes in neuronal dynamics in a patient with an SCN1A mutation and hyperthermia induced seizures. https://doi.org/10.1101/048520

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