Central serotonin and autoresuscitation capability in mammalian neonates.

Autoresuscitation is an important cardiorespiratory protective mechanism that allows neonatal mammals to recover from primary apnea. It begins with hypoxia-induced gasping and ends, if successful, with the recovery of rhythmic breathing and normal heart rate. Many factors influence the efficacy of autoresuscitation, including the availability of serotonin (5-HT) in the brain. Since the early 2000's, there has been mounting interest in the role of 5-HT in promoting autoresuscitation, driven in large part by the recognition that both failed autoresuscitation and a deficiency of central 5-HT correlate with Sudden Infant Death Syndrome in humans. Within this timeframe, newly developed animal models with a central 5-HT deficiency have examined experimentally the role of 5-HT in autoresuscitation capability. The purpose of this review is to discuss some of the methodological considerations associated with 5-HT-deficient animal models, to summarize major findings arising from their use, and to highlight several key issues related to 5-HT involvement in gasping and the autoresuscitation response.

Autoresuscitation responses to hypoxia-induced apnea are delayed in newborn 5-HT-deficient Pet-1 homozygous mice.

Autoresuscitation is a critical survival-promoting mechanism in mammals that allows recovery from primary apnea via hypoxia-induced gasping. Here we show, using head-out plethysmography, that gasping behavior is altered during autoresuscitation, and the autoresuscitation response is delayed, in neonatal 5-hydroxytryptamine (5-HT) neuron-deficient Pet-1 homozygous (Pet-1(-/-)) mice. When exposed to 97% N(2)-3% CO(2) on postnatal day 4.5, unanesthetized Pet-1(-/-) mice required over four times longer than age-matched wild-type controls to initiate gasping following primary apnea. When oxygen was made available before the first gasp, allowing autoresuscitation to occur, gasping frequency was decreased and the duration of the gasping period was extended in the Pet-1 mutants compared with wild type, resulting in a nearly threefold increase in the time needed for successful autoresuscitation. However, when the exposure to anoxia was unrelenting, gasping frequency, the form of the gasps, the total number of gasps produced, the duration of the gasping period, and time to last gasp were comparable to controls. Plethysmographic testing of the same mutants on postnatal day 9.5 revealed that their autoresuscitation responses, although improved compared with day 4.5, remained significantly longer than in wild-type controls. Our data indicate that despite a severe deficiency of central 5-HT neurons, Pet-1(-/-) neonatal mice are capable of gasping, but their gasping pattern is altered during autoresuscitation, leading to a prolongation of the time required to recover from hypoxia-induced apnea.

Arrest of 5HT neuron differentiation delays respiratory maturation and impairs neonatal homeostatic responses to environmental challenges.

Serotonin (5HT) is a powerful modulator of respiratory circuitry in vitro but its role in the development of breathing behavior in vivo is poorly understood. Here we show, using 5HT neuron-deficient Pet-1 (Pet-1(-/-)) neonates, that serotonergic function is required for the normal timing of postnatal respiratory maturation. Plethysmographic recordings reveal that Pet-1(-/-) mice are born with a depressed breathing frequency and a higher incidence of spontaneous and prolonged respiratory pauses relative to wild type littermates. The wild type breathing pattern stabilizes by postnatal day 4.5, while breathing remains depressed, highly irregular and interrupted more frequently by respiratory pauses in Pet-1(-/-) mice. Analysis of in vitro hypoglossal nerve discharge indicates that instabilities in the central respiratory rhythm generator contribute to the abnormal Pet-1(-/-) breathing behavior. In addition, the breathing pattern in Pet-1(-/-) neonates is susceptible to environmental conditions, and can be further destabilized by brief exposure to hypoxia. By postnatal day 9.5, however, breathing frequency in Pet-1(-/-) animals is only slightly depressed compared to wild type, and prolonged respiratory pauses are rare, indicating that the abnormalities seen earlier in the Pet-1(-/-) mice are transient. Our findings provide unexpected insight into the development of breathing behavior by demonstrating that defects in 5HT neuron development can extend and exacerbate the period of breathing instability that occurs immediately after birth during which respiratory homeostasis is vulnerable to environmental challenges.