Abstracts

Rationale: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related death, likely stemming from seizure activity disrupting vital brain centers controlling heart and breathing function. However, understanding of SUDEP's anatomical bases and mechanisms remains limited, hampering risk evaluation and prevention strategies. Prior studies using a neuron-specific Kcna1 conditional knockout (cKO) mouse model of SUDEP identified the primary importance of brain-driven mechanisms contributing to sudden death and cardiorespiratory dysregulation, yet the underlying neurocircuits have not been identified.


Methods: Using the Emx1-Cre driver, we generated a new cKO mouse model lacking Kcna1 in excitatory neurons of the cortex, hippocampus, amygdala, and select vagal afferents. To test whether the absence of Kv1.1 in forebrain corticolimbic circuits is sufficient to induce spontaneous seizures, premature mortality, and cardiorespiratory dysfunction, we performed survival studies and electroencephalography, electrocardiography, and plethysmography (EEG-ECG-Pleth) recordings.


Results: We demonstrate premature death and epilepsy in corticolimbic cKO mice. During monitoring, we fortuitously captured one SUDEP event, which showed a generalized tonic-clonic seizure that initiated respiratory dysfunction culminating in cardiorespiratory failure. In addition, we observe that cardiorespiratory abnormalities are common during non-fatal seizures in cKO mice, but mostly absent during interictal periods, implying ictal, not interictal, cardiorespiratory impairment as a more reliable indicator of SUDEP risk.


Conclusions: These results pinpoint corticolimbic excitatory neurons as critical neural substrates in SUDEP and affirm seizure-related respiratory and cardiac failure as a likely cause of death.


Funding: This work was supported by the National Institutes of Health (R01NS100954, R01NS099188, R01NS129643 to E.G.) and an American Epilepsy Society predoctoral fellowship (to K.P.).