Abstracts

Rationale: Dravet syndrome (DS) is characterized by a neuronal sodium channel mutation causing epilepsy onset in early infancy, intractable seizures, sudden unexpected death, and various neurobehavioral comorbidities such as hyperactivity, cognitive deficit, and mood disorder. No effective treatment exists to manage seizures and neuropsychological comorbidities in DS. Limited behavioral studies of DS are available. We present the phenotypic characteristics of developing DS mice with the goal of evaluating novel therapies in future studies.Methods: We employed a murine model of DS using Scn1a (Scn1a+/-) mice from a C57BL/6J x 129S6/SvEvTac-Scn1atm1Kea cross. Each mouse was subjected to hyperthermia-induced seizures at P (postnatal day) 31 and again at P60. After P50, long-term video-EEG monitoring was performed to capture EEG correlates of spontaneous behavioral seizures. Behavioral tests were performed and compared between Scn1a+/- mice (n = 13) and wild type littermate controls (n=16). To test for anxiety-like and exploratory behavior, the open field test was performed every 5 days from P20 until P35 and the elevated plus maze was tested at P21 and P36. Spatial learning and memory were assessed via Barnes maze at P37. Social interaction and novelty recognition were evaluated in the three chamber test and Y maze test at P40.Results: Prolonged hyperthermia (30min) caused seizures in 12/13 (92%) DS mice at P31 with a mean temperature of 41.2℃ and in 13/13 (100%) DS mice at P60 with a mean temperature of 41.3℃. None of the littermate controls had hyperthermic seizures below a body temperature of 42℃. Hyperthermia-induced seizures began with myoclonia evolving to generalized tonic-clonic seizures. All 13 (100%) mice survived until the end of observation at P80, and 4 mice (4/13, 31%) developed spontaneous seizures with onset varying from P34 to P52. At P36, DS mice showed increased anxiety-like behavior in the elevated plus maze. DS mice spent less time in the open arms (p<0.05) and more time in the closed arms than wild types (p<0.01). There was no significant difference in anxiety-like and exploratory behavior in the open field, learning, memory, and sociability between DS mice and littermate controls.Conclusions: DS mice showed persistent sensitivity to hyperthermia-induced seizures beyond P60. Elevated plus maze was the most useful test to evaluate behavioral deficits in DS mice. Anxiety-like behavior was not evident prior to seizure induction, indicating that the comorbid anxiety phenotype develops later, following hyperthermia-induced seizures, in this DS model.