Early EEG and behavioral alterations in Dravet mice

Abstract

Dravet Syndrome (Dravet) is a severe childhood epileptic encephalopathy. The disease begins around the age of six months, with a febrile stage, characterized by febrile seizures with otherwise normal development. By the end of the first year of life, the disease progresses to the worsening stage, featuring recurrent intractable seizures and the appearance of additional comorbidities, including global developmental delay, cognitive deficits, hyperactivity and motor problems. Later, in early school years, Dravet reaches the stabilization stage, in which seizure burden decreases, while Dravet-associated comorbidities persist. Dravet syndrome mouse models (DS) faithfully recapitulate the three stages of the human syndrome. Here, we performed power spectral analyses of background EEG activity in DS and their wild-type (WT) littermates, demonstrating disease stagerelated alterations. Specifically, while the febrile stage activity resembled that of WT mice, we observed a marked reduction in total power during the worsening stage and a smaller reduction during the stabilization stage. Moreover, low EEG power at the worsening stage correlated with increased risk for premature death, suggesting that such measurements can potentially be used as a marker for Dravet severity. With normal development at the febrile stage and the presentation of developmental delay at the worsening stage, the contribution of recurrent seizures to the emergence of Dravet-associated comorbidities is still debated.Thus, we further characterized the behavior of WT and DS mice during the different stages of Dravet. At the febrile stage, despite their normal background EEG patterns, DS mice already demonstrated motor impairment and hyperactivity in the open field, that persisted to the worsening and stabilization stages. Conversely, clear evidence for deficits in working memory emerged later in life, during the worsening stage. These results indicate that despite the mild epilepsy at the febrile stage, DS development is already altered, suggesting that the pathophysiological mechanisms governing the appearance of some Dravet behavioral comorbidities may be independent of the epileptic phenotype. Highlights • Reduction in background EEG power in Dravet• Low EEG power correlates with the risk of premature death• Motor deficits and hyperactivity are evident as early as the febrile stage • Cognitive deficits and detection of increased anxiety begin at the worsening stage 10 min, and were selected from throughout the entire recording. Spikes were detected using LabChart 8 software (ADInstruments, Sydney, Australia). The threshold was set to 7 standard divisions, and their maximal allowed duration was set to 250 ms. Early motor activityWT and DS mice were tested from P8 to P11. Mice were individually placed in the middle of a 13 cm wide circle and the latency to cross the drawn borders of the circle was measured. The test was repeated three times and averaged. If the mouse was unable to cross the border of the circle within 1 min, the test was terminated. ...