Abstract
The rate of sudden unexpected death in epilepsy (SUDEP) is ~1 per 1000 patients each year. Terminal events reportedly involve repeated and prolonged apnea, suggesting a failure to autoresuscitate. To better understand the mechanisms and identify novel therapeutics, standardized tests to screen for autoresuscitation efficacy are needed in preclinical SUDEP. To investigate the efficacy of the autoresuscitation response and potential contribution to SUDEP susceptibility, we adapted an anoxia-induced autoresuscitation test. The test was optimized to allow for survival of most wild-type (WT) mice, whereas autoresuscitation failure occurred for most Kcna1(-/-) mice, a preclinical model of SUDEP. Using whole-body plethysmography, we assessed ventilatory parameters, gasp-apnea dynamics, and survival in WT, Kcna1(-/-), and Kcna1(+/-) mice. A proof-of-concept pharmacological rescue was performed using a dual orexin receptor antagonist (DORA). WT mice exhibited robust autoresuscitation (80% survival), whereas only 20% of high-risk Kcna1(-/-) mice survived the anoxic challenge, indicating a 4-fold increase in risk for autoresuscitation failure. Kcna1(-/-) mice had disordered ventilatory responses, characterized by increased minute ventilation, tidal volume, and expiratory flow during anoxia. Kcna1(-/-) mice initiated gasping earlier with reduced gasp number, lower gasp frequency, and longer post-gasp apnea durations. In-depth analyses revealed three phases of gasping. Phase III recovery gasping was significantly impaired in Kcna1(-/-) mice, and they were unable to transition to eupnea. In contrast, low-risk Kcna1(-/-) mice and Kcna1(+/-)mice showed intermediate to normal autoresuscitation, respectively. DORA pretreatment improved survival to 80%, restored ventilatory patterns, and normalized gasp-apnea metrics to WT levels. This modified autoresuscitation test provides a reproducible and sensitive approach to probe respiratory vulnerability in preclinical SUDEP models. Our findings identify augmented ventilatory chemosensitivity and impaired autoresuscitation as critical pathophysiological features of SUDEP in Kcna1(-/-) mice and support the utility of this test platform for preclinical therapeutic screening and mechanistic discovery.