Seizures cause prolonged impairment of ventilation, CO 2 chemoreception and thermoregulation.

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 in epilepsy patients caused a prolonged decrease in the hypercapnic ventilatory response (HCVR; a measure of respiratory CO 2 chemoreception). We then studied Scn1a R1407X/+ (Dravet Syndrome, DS) and Scn8a N1768D/+ (D/+) mice of both sexes, two models of SUDEP, and found that convulsive seizures caused a post-ictal decrease in ventilation and severely depressed the HCVR in a subset of animals. Those mice with severe post-ictal depression of the HCVR also exhibited transient post-ictal 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 para -chlorophenylalanine (PCPA) mimicked seizure-induced hypoventilation, partially occluded the post-ictal decrease in the HCVR, exacerbated hypothermia, and increased post-ictal mortality in DS mice. Conversely, pretreatment with the 5-HT agonist fenfluramine reduced post-ictal 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 inter-ictal and/or post-ictal HCVR as noninvasive biomarkers for those at high risk of seizure-induced death, and to prevent SUDEP by enhancing post-ictal 5-HT tone. Significance Statement: 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 2 chemoreception in some epilepsy patients. In two mouse models of SUDEP we found that generalized convulsive seizures impaired CO 2 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 prevented with fenfluramine, suggesting that seizure-induced respiratory dysfunction may be due to impairment of serotonin neuron function. These findings suggest that impaired chemoreception due to transient inhibition of serotonergic neurons may contribute to the pathophysiology of SUDEP.