Autonomic reflex plasticity associates with time-dependent SUDEP susceptibility in a murine model with hyperactive stress circuits

Sudden unexpected death in Epilepsy (SUDEP) is the leading cause of death in patients with Epilepsy. Although SUDEP results from cardiorespiratory arrest, its underlying mechanisms are poorly understood. Considering the significant association between stress-related disorders and Epilepsy, we hypothesized that stress exaggerates autonomic reflexes critical in cardiorespiratory function and that these exaggerated reflexes increase susceptibility to SUDEP. Experiments were performed using a novel mouse model of SUDEP where chronic hyperactivity of central corticotropin-releasing hormone (CRH) neurons (Kcc2/Crh) predisposes mice to SUDEP in the weeks following seizure induction based on the ventral intrahippocampal kainate (vIHKA) model of chronic Epilepsy. In our study, the vIHKA model was employed in both wild-type (WT) and Kcc2/Crh mice while they were monitored with EEG and ECG using in vivo telemetry and underwent terminal autonomic reflex testing at time points when mortality peaked and plateaued. A resting tachycardia developed by one week following vIHKA injection but subsided by day 30 in both WT and Kcc2/Crh mice. During spontaneous seizures, Kcc2/Crh mice had more pronounced reflex-like ictal bradycardias compared to WT controls that notably occurred prior ([~]10 sec) to seizure termination. vIHKA injection promoted time-dependent exaggeration of autonomic reflexes, with Kcc2/Crh mice exhibiting robust autonomic disturbances compared to WT controls, including a pronounced serotonin-mediated Bezold Jarisch reflex. Taken together, our findings indicate that increased autonomic disturbance burden parallels time-dependent SUDEP susceptibility in mice with hyperactive stress circuits.