Abstract：
Failure to recover from repeated hypercapnia and hypoxemia (HH) challenges caused by severe GCS and postictal apneas may contribute to sudden unexpected death in epilepsy (SUDEP). Our previous studies found orexinergic dysfunction contributes to respiratory abnormalities in a preclinical model of SUDEP, Kcna1-/- mice. Here, we developed two gas challenges consisting of repeated HH exposures and used whole body plethysmography to determine whether Kcna1-/- mice have detrimental ventilatory responses. Kcna1-/- mice exhibited an elevated ventilatory response to a mild repeated hypercapnia-hypoxia (HH) challenge compared to WT. Moreover, 71% of Kcna1-/- mice failed to survive a severe repeated HH challenge, whereas all WT mice recovered. We next determined whether orexin was involved in these differences. Pretreating Kcna1-/- mice with a dual orexin receptor antagonist rescued the ventilatory response during the mild challenge and all subjects survived the severe challenge. In ex vivo extracellular recordings in the lateral hypothalamus of coronal brain slices, we found reducing pH either inhibits or stimulates putative orexin neurons similar to other chemosensitive neurons; however, a significantly greater percentage of putative orexin neurons from Kcna1-/-mice were stimulated and the magnitude of stimulation was increased resulting in augmentation of the calculated chemosensitivity index relative to WT. Collectively, our data suggest that increased chemosensitive activity of orexin neurons may be pathologic in the Kcna1-/- mouse model of SUDEP, and contribute to elevated ventilatory responses. Our preclinical data suggest that those at high risk for SUDEP may be more sensitive to HH challenges, whether induced by seizures or other means; and the depth and length of the HH exposure could dictate the probability of survival.
摘要：
严重的GCS和局部呼吸暂停引起的反复高碳酸血症和低氧血症挑战无法恢复，可能会导致癫痫（SUDEP）突然意外死亡。我们以前的研究发现，在SUDEP的临床前模型中，食欲素功能障碍会导致呼吸异常，Kcna1-/-小鼠。这里,我们开发了两个由反复HH暴露组成的气体挑战，并使用全身体积描记术来确定Kcna1-/-小鼠是否会产生有害的通气反应。与WT相比，Kcnal-/-小鼠对轻度反复的高碳酸血症缺氧（HH）挑战表现出升高的通气反应。此外，71％的Kcna1-/-小鼠未能在严重的反复HH攻击中存活，而所有WT小鼠恢复。我们接下来确定食欲素是否参与这些差异。用双重食欲素受体拮抗剂预处理Kcna1-/-小鼠在轻度攻击期间挽救了通气反应，所有受试者在严峻的攻击中幸存下来。在离体细胞外记录的外侧下丘脑的冠状脑片，我们发现降低pH会抑制或刺激推定的食欲素神经元，与其他化学敏感神经元相似；然而，刺激了来自Kcna1-/-小鼠的推定食欲素神经元的百分比显着增加，刺激的幅度增加，从而相对于WT增加了计算的化学敏感性指数。总的来说，我们的数据表明，食欲素神经元的化学敏感活性的增加可能是病理性的Kcna1-/-小鼠模型的SUDEP，并有助于提高通气反应。我们的数据表明，SUDEP高风险的个体可能对HH挑战更敏感，是否由癫痫发作或其他方式引起;以及HH暴露的深度和长度可以决定生存的可能性。
