Authors :
Presenting Author: Sandy Saunders, PhD – University of Missouri
Kaylie Dow, BS – University of Missouri
Grace Bostic, Undergraduate – University of Missouri
Jamie Maguire, PhD – Tufts University School of Medicine
Carie Boychuk, Ph.D. – University of Missouri
Rationale:
Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with epilepsy and results from seizures that trigger cardiorespiratory arrest. Considering the significant comorbidity between stress-related disorders and epilepsy, we hypothesized that stress exaggerates autonomic reflexes that promote SUDEP.Methods:
Experiments were performed using a novel mouse model where central corticotropin-releasing hormone (CRH) neurons are hyperactive (Kcc2/Crh mice). WT and Kcc2/Crh mice were microinjected with a chemical convulsant, kainic acid, into ventral hippocampus. Mice were chronically monitored with EEG and ECG using in vivo telemetry and/or underwent terminal autonomic reflex testing.
Results:
We found that 41% (9/22) of Kcc2/Crh mice spontaneously died ~11 days after KA injection, with no deaths in WT controls (0/10). Both Kcc2/Crh mice and WT mice had a resting tachycardia 7 days after seizure induction, compared to sham controls. By day 14, HR remained significantly elevated only in KA-injected Kcc2/Crh mice relative to sham controls. During spontaneous seizures, HR fluctuated between periods of tachycardia and bradycardia. Ictal tachycardia was similar between Kcc2/Crh and WT mice. However, Kcc2/Crh mice had significantly longer duration and greater magnitude ictal bradycardia than WT mice. All KA injected mice had an exaggerated hypotension-mediated paradoxical bradycardia (HPB) at 10 days compared to saline controls. However, by day 30, only WT mice had blunted HPB compared to WTs at day 10. Baroreflex was unaffected in Kcc2/Crh compared to any group while WT KA-injected mice had blunted baroreflex at day 30 relative to day 10. Kcc2/Crh mice, but not WT, had an exaggerated Bezold-Jarisch reflex (BJR) at day 10 compared to saline controls, but this was ameliorated by day 30. Finally, the magnitude of BJR in KA-injected Kcc2/Crh mice was decreased compared to Kcc2/Crh mice at day 10 yet remained elevated compared to KA-injected WT mice at day 30.Conclusions:
KA injection promotes a resting tachycardia that subsides in both groups, albeit with a slower recovery in Kcc2/Crh mice. Kcc2/Crh mice have more severe bradycardias during spontaneous seizures than WT. Finally, KA injection promotes time-dependent plasticity of autonomic reflexes, with Kcc2/Crh mice having additional autonomic disturbances (BJR reflex) compared to WT mice and an apparent diminished capacity to mount compensatory responses that dampen autonomic reflexes. Taken together, we propose that increased autonomic disturbance burden and weakened capacity to mount compensatory responses drive time-dependent SUDEP susceptibility in our model. Funding:
R01NS102937 NINDS to CRB/JLM and NextGen Precision Health Postdoctoral Fellowship (SS)