Preictal dysfunctions of inhibitory interneurons paradoxically lead to their rebound hyperactivity and to Low-Voltage-Fast onset seizures in Dravet syndrome.

Abstract

Epilepsies have numerous specific mechanisms. Understanding neural dynamics leading to seizures is important for disclosing pathological mechanisms and developing targeted therapeutic approaches. We investigated electrographic activities and neural dynamics leading to convulsive seizures in patients and mouse models of Dravet syndrome (DS), a developmental and epileptic encephalopathy in which hypoexcitability of GABAergic neurons is considered to be the main dysfunction. We analyzed EEGs from DS patients carrying a SCN1A pathogenic variant, as well as epidural electrocorticograms, hippocampal local field potentials and hippocampal single-unit neuronal activities in Scn1a+/- knock-out and Scn1aRH/+ knock-in DS mice. Strikingly, most seizures had low-voltage-fast onset in both patients and mice, which is thought to be generated by hyperactivity of GABAergic interneurons, the opposite of the main pathological mechanism of DS. Analyzing single unit recordings, we observed that temporal disorganization of the firing of putative interneurons in the period immediately before the seizure (preictal period) precedes the increase of their activity at seizure onset, together with the entire neuronal network. Moreover, we found early signatures of the preictal period in the spectral features of hippocampal and cortical field potential of Scn1a mice and of patients EEG, which are consistent with the dysfunctions that we observed in single neurons. Therefore, the perturbed preictal activity of interneurons leads to their hyperactivity at the onset of generalized seizures, which have low-voltage-fast features that are similar to those observed in other epilepsies and are triggered by hyperactivity of GABAergic neurons. Spectral features may be used as predictive seizure biomarker. Significance statementDravet syndrome (DS) is caused by mutations of the NaV1.1 sodium channel (SCN1A gene) leading to hypoexcitability of GABAergic interneurons. We found that most of the seizures in both DS patients and mouse models have low-voltage-fast onset, which is instead thought to be generated by hyperactivity of GABAergic neurons. We disclosed a disorganization in the temporal pattern of the firing of single interneurons before the seizure (preictal period), and a rebound hyperactivity at seizure onset. Consistently, the electrographic signal showed a decrease of fast oscillations in the preictal period. Thus, perturbed interneurons preictal activity, consistent with the main mechanism of DS, leads to their hyperactivity at seizure onset and induces specific electrographic signatures that may be exploited for seizure prediction.