Abstracts

Rationale: Disruptions of the autonomic nervous system can occur as sequelae of chronic epilepsy or immediate consequences of focal or generalized seizures. Disordered interictal autonomic function can manifest as impaired temperature, cardiac, and respiratory regulations which are prominent comorbidities in DSpatients. However, the full extent of these abnormalities, their associations with the DS-causing SCN1A mutations, and their underlying mechanisms are not fully understood. We examined autonomic regulation of core body temperature, heart rate (HR), and respiration rate in response to moderately elevated ambient temperature or moderate physical exercise in a mouse model of Dravet Syndrome (DS).  Methods: We studied video-EEG, EMG, ECG, respiratory rate, and temperature in mice with global heterozygous Scn1a knockout (KO) (DS mice), interneuron specific Scn1aKO, and wildtype (WT) mice during exposure to increased environmental temperature and moderate treadmill exercise.  Results: Core body temperatures of WT and DS mice were similar during baseline. But after 15 mins of heat exposure, the peak value was lower in DS than WT mice. In following mins of heat exposure, the temperature of WT mice (unlike DS mice) slowly returned close to baseline level. KO of Scn1ain GABAergic neurons caused similar thermoregulatory deficits in mice. During exercise, the HR increase was less prominent in DS than WT mice. After exercise, the HR was significantly more suppressed in DS. The HRV was higher in DS than WT mice.  Conclusions: We found novel abnormalities that expand the spectrum of interictal, ictal, and postictal autonomic dysregulation in DS mice. During mild heat stress, there was significantly less suppression of HR, and a blunted recovery in DS than WT mice. These effects were seen in mice with selective KO of Scn1Ain GABAergic neurons. During exercise stress, there was diminished increase in HR and HRV as well as exaggerated HR suppression during recovery in DS than control mice. These findings suggest that autonomic disturbance can manifest differentially with sympathetic hyperactivity during interictal and ictal periods and parasympathetic hyperactivity postictally. Understanding the spectrum and mechanisms of autonomic disorders in DS may help develop more effective strategies to prevent seizures and SUDEP. Funding: CURE 2017, Sleep and Epilepsy Award.NIH/NINDS R01NS10279602