Hippocampal hyperexcitability and specific epileptiform activity in a mouse model of Dravet syndrome

Authors

  • Camille Liautard,

    1. Institute of Molecular and Cellular Pharmacology (IPMC), CNRS UMR7275, University of Nice-Sophia Antipolis, Valbonne, France
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  • Paolo Scalmani,

    1. Department of Neurophysiopathology, Epilepsy Center, Laboratory of Experimental Epilepsy, IRCCS Foundation Neurological Institute Carlo Besta, Milan, Italy
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  • Giovanni Carriero,

    1. Department of Neurophysiology, IRCCS Foundation Neurological Institute Carlo Besta, Milan, Italy
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  • Marco de Curtis,

    1. Department of Neurophysiology, IRCCS Foundation Neurological Institute Carlo Besta, Milan, Italy
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  • Silvana Franceschetti,

    1. Department of Neurophysiopathology, Epilepsy Center, Laboratory of Experimental Epilepsy, IRCCS Foundation Neurological Institute Carlo Besta, Milan, Italy
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  • Massimo Mantegazza

    Corresponding author
    1. Institute of Molecular and Cellular Pharmacology (IPMC), CNRS UMR7275, University of Nice-Sophia Antipolis, Valbonne, France
    • Address correspondence to Massimo Mantegazza, IPMC, CNRS UMR7275 and UNS, 660 Route des Lucioles, 06560 Valbonne, France. E-mail: mantegazza@ipmc.cnrs.fr

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Summary

Purpose

Dravet syndrome (DS) is caused by dominant mutations of the SCN1A gene, encoding the NaV1.1 sodium channel α subunit. Gene targeted mouse models of DS mutations replicate patients' phenotype and show reduced γ-aminobutyric acid (GABA)ergic inhibition. However, little is known on the properties of network hyperexcitability and on properties of seizure generation in these models. In fact, seizures have been studied thus far with surface electroencephalography (EEG), which did not show if specific brain regions are particularly involved. We have investigated hyperexcitability and epileptiform activities generated in neuronal networks of a mouse model of DS.

Methods

We have studied heterozygous NaV1.1 knock-out mice performing field potential recordings in combined hippocampal/cortical slices in vitro and video/depth electrode intracerebral recordings in vivo during hyperthermia-induced seizures.

Key Findings

In slices, we have disclosed specific signs of hyperexcitability of hippocampal circuits in both the pre-epileptic and epileptic periods, and a specific epileptiform activity was generated in the hippocampus upon application of the convulsant 4-aminopyridine in the epileptic period. During in vivo hyperthermia-induced seizures, we have observed selective hippocampal activity in early preictal phases and pronounced hippocampal activity in the ictal phase.

Significance

We have identified specific epileptiform activities and signs of network hyperexcitability, and disclosed the important role of the hippocampus in seizure generation in this model. These activities may be potentially used as targets for screenings of antiepileptic approaches.

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