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

Abstract

Dravet syndrome (DS) is a rare childhood epilepsy disorder resulting in spontaneous, recurrent seizures and behavioral co-morbidities. A successful drug screening model should recapitulate the phenotypes observed in a clinical setting. To facilitate the discovery and development of anti-seizure drugs for DS, the contract site of the NINDS Epilepsy Therapy Screening Program (ETSP) has continued to evaluate a mouse model of DS with a focus on evaluating behavioral phenotypes, spontaneous seizure activity, and sex-dependent differences. Scn1aA1783V/WT mice exhibited increased hyperactivity, thigmotaxis, and deficits in nest-building behavior. Ex-vivo brain slice electrophysiology experiments revealed increased excitability of hippocampal CA1 neurons specifically due to increased action potential firing frequency in response to brief depolarizations and decreased frequency of spontaneous GABAergic synaptic events. A video-EEG study revealed mice had on average, 1 seizure per day, with males seizing significantly more frequently than females. Increased proportion of seizure activity occurred during the dark phase of the light/dark cycle in both sexes. While clobazam, a drug commonly prescribed to patients with DS, had no effect on spontaneous seizure activity at the tested doses, the seizure history and frequency observed in this study aids in determining the sample sizes and experimental timeline needed for adequately powered preclinical drug studies. Overall, this study provides a broad description of the Scn1aA1783V/WT mouse and highlights the utility of this model in therapy discovery.

Breathing dysfunction and alveolar damage in a mouse model of Dravet syndrome

“…A mutation such as the Scn1a A1783V/WT heterozygous (Het) knock-in mutation has been identified in human DS patients and recapitulates the human disease in mice [Ricobaraza, et al 2019]. Het mice experience febrile and spontaneous seizures and have a higher mortality rate than wild-type (WT) littermates [Pernici, et al 2021, Pernici, et al bioRxiv]. Death most frequently occurs during post-natal day 15 (P15) to P30 [Pernici, et al 2021].…”