Department of Neurology, University of Iowa, Iowa City, Iowa 52242
Medical Scientist Training Program, University of Iowa, Iowa City, Iowa 52242.
J Neurosci. 2023 Jul 5;43(27):4959-4971. doi: 10.1523/JNEUROSCI.0450-23.2023. Epub 2023 May 9.
Sudden unexpected death in epilepsy (SUDEP) has been linked to respiratory dysfunction, but the mechanisms underlying this association remain unclear. Here we found that both focal and generalized convulsive seizures (GCSs) in epilepsy patients caused a prolonged decrease in the hypercapnic ventilatory response (HCVR; a measure of respiratory CO chemoreception). We then studied (Dravet syndrome; DS) and (D/+) mice of both sexes, two models of SUDEP, and found that convulsive seizures caused a postictal decrease in ventilation and severely depressed the HCVR in a subset of animals. Those mice with severe postictal depression of the HCVR also exhibited transient postictal hypothermia. A combination of blunted HCVR and abnormal thermoregulation is known to occur with dysfunction of the serotonin (5-hydroxytryptamine; 5-HT) system in mice. Depleting 5-HT with -chlorophenylalanine (PCPA) mimicked seizure-induced hypoventilation, partially occluded the postictal decrease in the HCVR, exacerbated hypothermia, and increased postictal mortality in DS mice. Conversely, pretreatment with the 5-HT agonist fenfluramine reduced postictal inhibition of the HCVR and hypothermia. These results are consistent with the previous observation that seizures cause transient impairment of serotonergic neuron function, which would be expected to inhibit the many aspects of respiratory control dependent on 5-HT, including baseline ventilation and the HCVR. These results provide a scientific rationale to investigate the interictal and/or postictal HCVR as noninvasive biomarkers for those at high risk of seizure-induced death, and to prevent SUDEP by enhancing postictal 5-HT tone. There is increasing evidence that seizure-induced respiratory dysfunction contributes to the pathophysiology of sudden unexpected death in epilepsy (SUDEP). However, the cellular basis of this dysfunction has not been defined. Here, we show that seizures impair CO chemoreception in some epilepsy patients. In two mouse models of SUDEP we found that generalized convulsive seizures impaired CO chemoreception, and induced hypothermia, two effects reported with serotonergic neuron dysfunction. The defects in chemoreception and thermoregulation were exacerbated by chemical depletion of serotonin and reduced with fenfluramine, suggesting that seizure-induced respiratory dysfunction may be due to impairment of serotonin neuron function. These findings suggest that impaired chemoreception because of transient inhibition of serotonergic neurons may contribute to the pathophysiology of SUDEP.
癫痫患者的突发性意外死亡 (SUDEP) 与呼吸功能障碍有关，但这种关联的机制仍不清楚。在这里，我们发现癫痫患者的局灶性和全面性惊厥性发作 (GCS) 都会导致高碳酸血症通气反应 (HCVR；呼吸 CO 化学感受的测量) 长时间下降。然后，我们研究了两种 SUDEP 模型，即 Dravet 综合征 (DS) 和 D/+ 雌雄小鼠，发现惊厥性发作会导致发作后通气减少，并严重抑制部分动物的 HCVR。那些 HCVR 发作后严重抑制的小鼠也表现出短暂的发作后体温过低。众所周知，在 5-羟色胺 (5-HT) 系统功能障碍的小鼠中，HCVR 功能障碍和体温调节异常同时发生。用对氯苯丙氨酸 (PCPA) 耗竭 5-HT 可模拟发作引起的通气不足，部分阻断 HCVR 的发作后降低，加重体温过低，并增加 DS 小鼠的发作后死亡率。相反，5-HT 激动剂芬氟拉明的预处理可减少 HCVR 的发作后抑制和体温过低。这些结果与之前的观察结果一致，即发作会导致 5-羟色胺能神经元功能短暂受损，这预计会抑制许多依赖 5-HT 的呼吸控制方面，包括基础通气和 HCVR。这些结果为研究间歇期和/或发作后 HCVR 作为那些有癫痫发作相关死亡风险的非侵入性生物标志物提供了科学依据，并通过增强发作后 5-HT 张力来预防 SUDEP。越来越多的证据表明，发作引起的呼吸功能障碍导致癫痫患者的突发性意外死亡的病理生理学。然而，这种功能障碍的细胞基础尚未确定。在这里，我们表明发作会损害一些癫痫患者的 CO 化学感受。在两种 SUDEP 小鼠模型中，我们发现全面性惊厥性发作会损害 CO 化学感受，并诱导体温过低，这两种效应与 5-羟色胺能神经元功能障碍有关。化学耗竭 5-羟色胺会加剧化学感受和体温调节的缺陷，而芬氟拉明会减轻这些缺陷，这表明发作引起的呼吸功能障碍可能是由于 5-羟色胺能神经元功能障碍。这些发现表明，由于 5-羟色胺能神经元的短暂抑制而导致的化学感受受损可能有助于 SUDEP 的病理生理学。
