Active sleep unmasks apnea and delayed arousal in infant rat pups lacking central serotonin

Sudden infant death syndrome (SIDS), occurring during sleep periods, is highly associated with abnormalities within serotonin (5-HT) neurons, including reduced 5-HT. There is evidence that future SIDS cases experience more apnea and have abnormal arousal from sleep. In rodents, a loss of 5-HT neurons is associated with apnea in early life and, in adulthood, delayed arousal. As the activity of 5-HT neurons changes with vigilance state, we hypothesized that the degree of apnea and delayed arousal displayed by rat pups specifically lacking central 5-HT varies with state. Two-week-old tryptophan hydroxylase 2-deficient (TPH2-/-) and wild-type (WT) rat pups were placed in plethysmographic chambers supplied with room air. At the onset of active (AS) or quiet (QS) sleep, separate groups of rats were exposed to hypercapnia (5% CO₂) or mild hypoxia (~17% O₂) or maintained in room air. Upon arousal, rats received room air. Apnea indexes and latencies to spontaneous arousal from AS and QS were determined for pups exposed only to room air. Arousal latencies were also calculated for TPH2-/- and WT pups exposed to hypoxia or hypercapnia. Compared with WT, TPH2-/- pups hypoventilated in all states but were profoundly more apneic solely in AS. TPH2-/- pups had delayed arousal in response to increasing CO₂, and AS selectively delayed the arousal of TPH2-/- pups, irrespective of the gas they breathed. Thus infants who are deficient in CNS 5-HT may be at increased risk for SIDS in AS because of increased apnea and delayed arousal compared with QS.NEW & NOTEWORTHY Sudden infant death syndrome (SIDS) occurs during sleep and is associated with central serotonin (5-HT) deficiency. We report that rat pups deficient in central 5-HT (TPH2-/-) are profoundly more apneic in active sleep (AS) but not quiet sleep (QS). Unlike control pups, the arousal of TPH2-/- pups in air, CO₂, and hypoxia was delayed in AS compared with QS. Thus for infants deficient in central 5-HT, the risk of SIDS may be higher in AS than in QS.