Convulsive seizures and some behavioral comorbidities are uncoupled in the Scn1a^A1783V Dravet syndrome mouse model

Abstract

Objective: Dravet syndrome (Dravet) is a severe childhood epileptic encephalopathy. The disease begins with a febrile stage, characterized by febrile seizures with otherwise normal development. Progression to the worsening stage features recurrent intractable seizures and the presentation of additional nonepileptic comorbidities, including global developmental delay, hyperactivity, and motor deficits. Later in life, at the stabilization stage, seizure burden decreases, whereas Dravet-associated comorbidities persist. To date, it remains debated whether the nonepileptic comorbidities result from severe epilepsy or represent an independent phenotypic feature. Methods: Dravet mice (DS) faithfully recapitulate many clinical aspects of Dravet. Using wild-type (WT) and DS at different ages, we monitored multiple behavioral features as well as background electroencephalogram (EEG) activity during the different stages of Dravet epilepsy. Results: Behavioral tests of WT and DS demonstrated that some deficits manifest already at the pre-epileptic stage, prior to the onset of convulsive seizures. These include motor impairment and hyperactivity in the open field. Deficits in cognitive functions were detected at the onset of severe spontaneous seizures. Power spectral analysis of background EEG activity, measured through development, showed that DS exhibit normal background oscillations at the pre-epileptic stage, a marked reduction in total power during the onset of severe epilepsy, and a subsequent smaller reduction later in life. Importantly, low EEG power at the stage of severe frequent convulsive seizures correlated with increased risk for premature death. Significance: Our data provide a comprehensive developmental trajectory of Dravet epilepsy and Dravet-associated comorbidities in mice, under controlled settings, demonstrating that the convulsive seizures and some nonepileptic comorbidities may be uncoupled. Moreover, we report the existence of an inverse correlation, on average, between the power of background EEG and the severity of epileptic phenotypes, suggesting that such measurements may potentially serve as a biomarker for Dravet severity. K E Y W O R D S background EEG, Dravet syndrome, hyperactivity, motor impairment, power spectral density 2290 | FADILA et AL. SUPPORTING INFORMATION Additional supporting information may be found online in the Supporting Information section. How to cite this article: Fadila S, Quinn S, Turchetti Maia A, et al. Convulsive seizures and some behavioral comorbidities are uncoupled in the Scn1a A1783V Dravet syndrome mouse model.

Sexual dimorphism in epilepsy and comorbidities in Dravet syndrome mice carrying a targeted deletion of exon 1 of the Scn1a gene

“…Accordingly, a DS mouse model carrying the Scn1a A1783V missense mutation showed that low EEG power correlates with the risk of premature death during the worsening stage of DS. 30 Thus, these findings not only characterise the stage 2 of DS in F1.Scn1a(+/-) tm1kea mice but also reinforce that a severe GTCS and low background EEG power may be an immediate risk factor for SUDEP in DS mice.…”

Scn1a gene reactivation after symptom onset rescues pathological phenotypes in a mouse model of Dravet syndrome

“…More recently, other reports suggested that developmental delay may be independent of epilepsy 41 , 42 and subtle developmental changes have been described during the febrile stage 43 , 44 . In line with this, a recent study showed that in DS mice motor impairment and hyperactivity are evident already in the febrile stage (P14-P18) while deficits in working memory emerged during the worsening stage (P21-P27) 45 . While in our model we did not detect any motor alteration at the age of analysis (3–4 months), hyperactivity, and cognitive deficits were evident and Na v 1.1 reactivation at P30 was sufficient to rescue them.…”

Evaluation of spontaneous seizure activity, sex-dependent differences, behavioral comorbidities, and alterations in CA1 neuron firing properties in a mouse model of Dravet Syndrome

“…Evaluation in the open field showed Scn1a A1783V/WT mice had significantly increased hyperactivity and anxiety-like behavior compared to wild type littermates and had poor nest building performance ( Figure 1 ). This has also been shown by others investigating the Scn1a A1783V/WT mice(17, 23) and in the Scn1a RX/+ and the Scn1a tm1Kea mouse models(15, 16, 18). Poor nest building behavior is an early predictor of behavioral deficits and is an indicator of impaired activities of daily living(24).…”