IMPACT OF SEIZURE REPETITION ON THE MECHANISMS OF SUDDEN UNEXPECTED DEATH IN EPILEPSY (SUDEP) IN A MOUSE MODEL OF DRAVET SYNDROME

We are using the Scn1a R1648H/+ Knock-In (KI) mouse model, which reproduces the Dravet Syndrome (DS) phenotype and increases the risk of SUDEP after induction of repeated short seizures by a convulsant agent (fluoroethyl). Our model is appropriate for studying whether repeated seizures have an impact on the control of the autonomic nervous system (ANS), leading to cardio-ventilatory dysfunctions and increasing the risk of SUDEP. We are studying these dysfunctions at several levels: i) on the characteristics of cardiomyocytes (calcium homeostasis) using calcium imaging, and ii) by conducting an in vivo pathophysiological study with multimodal recordings of behavioural characteristics (video), brain activity (electrocorticogram, ECoG), ventilation (nasal thermistor), and heart rate/rhythm parameters (electrocardiogram, ECG) in relation to SUDEP events. We observed that on the day before SUDEP, the duration of postictal generalized electroencephalographic suppression (PGES) is increased and that heart rate variability (HRV), which is used to assess the influence of the ANS on the heart, is low. During SUDEP, we observed terminal apnea beginning during PGES as well as progressive bradycardia. In addition, the parasympathetic component of the ANS decreased on the day of SUDEP compared to surviving KI mice, possibly promoting SUDEP. Repeated seizures in the mouse model of Dravet syndrome aggravate cardio-ventilatory dysfunctions, particularly through prolonged PGES and impaired autonomic modulation. These abnormalities precede and accompany SUDEP events. However, calcium homeostasis in cardiomyocytes is not directly affected. These observations reinforce the hypothesis of a functional link between repeated seizures, autonomic nervous system disruption, and SUDEP.