Abstracts

Rationale: Evidence from the multi-center MORTEMUS study on SUDEP indicates that patients experienced a series of events promoting hypoxic and hypercapnic fluctuations in blood gases, including GCS and apnea, from which they were unable to autoresuscitate resulting in terminal apnea. It is unknown why the autoresuscitation response fails in SUDEP, thus representing a critical knowledge gap. The ability to autoresuscitate from apnea requires activation of chemoresponsive regions to synergistically actuate gasping until recovery of eupneic breathing ensues. Like other neuronal networks under neuropeptide modulatory control to promote adaptive changes, orexin is a key neuropeptide that modulates respiratory chemoresponses. In neurological disorders and neuropathology, neuromodulatory changes can be maladaptive. Indeed, we have reported that in the preclinical Kcna1-null mouse model of spontaneous recurrent seizures and SUDEP, seizures propagate to the orexin-rich lateral hypothalamus, and there is an increase in the number of orexin neurons. We have also reported a concomitant increase in orexin’s influence on normal breathing, and when we blocked orexin with a dual orexin receptor antagonist (DORA) acutely, respiratory function was stabilized. This suggests that orexin’s modulatory influence on respiratory regions is increased and maladaptive in Kcna1-null. Here, we tested the hypothesis that excessive orexin influence over key respiratory regions is maladaptive and results in the deterioration of the autoresuscitation response.

Methods: Ex vivo studies examined orexin innervation of brainstem respiratory regions using immunofluorescent histochemistry in wildtype (WT) and Kcna1-null mice. Sections containing the dorsal raphe, raphe magnus, raphe obscurus, retrotrapezoid nucleus, nucleus ambiguous, prebötzinger complex, hypoglossal nucleus and Kölliker-Fuse nucleus were double-labeled for orexin projections and a region-specific protein. Sections were analyzed via binary skeletonization and unbiased stereology. In vivo autoresuscitation was examined using whole-body plethysmography in Kcna1-null, WT and DORA-treated mice. Endpoints (apnea, gasping and ventilation) were used to distinguish those that survived from those that do not survive.

Results: When tested for autoresuscitation, 100% of WT mice survived. In contrast, 5/7 Kcna1-null mice exhibited a gasping response which deteriorated, and autoresuscitation failed. While dense orexin-rich projections were apparent in both Kcna1-null and WT mice, there were elevated levels in specific respiratory nuclei of Kcna1-null mice. Indeed, acute treatment with DORA enabled 100% of Kcna1-null mice to survive.

Conclusions: Maladaptive orexin neuromodulation over respiratory centers promotes autoresuscitation failure in a preclinical SUDEP model. Blocking orexin receptors enables high-SUDEP risk mice to mount a successful autoresuscitation response. Indeed, we have reported that daily treatment with DORA increases the lifespan of Kcna1-null mice.

Funding: Please list any funding that was received in support of this abstract.: NIN NINDS NS111389.