Affiliation:
1. Department of Physiology and Neurobiology, Dartmouth Medical School, Lebanon, New Hampshire; and
2. Departments of 2Anesthesiology and
3. Pathology, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts
Abstract
Mice deficient in the transcription factor Pet-1−/− have a ∼70% deficiency of brainstem serotonin [5-hydroxytryptamine (5-HT)] neurons and exhibit spontaneous bradycardias in room air at postnatal day (P)5 and P12 and delayed gasping in response to a single episode of anoxia at P4.5 and P9.5 (Cummings KJ, Li A, Deneris ES, Nattie EE. Am J Physiol Regul Integr Comp Physiol 298: R1333–R1342, 2010; and Erickson JT, Sposato BC. J Appl Physiol 106: 1785–1792, 2009). We hypothesized that at a critical age Pet-1−/− mice will fail to autoresuscitate during episodic anoxia, ultimately dying from a failure of gasping to restore heart rate (HR). We exposed P5, P8, and P12 Pet-1−/− mice and wild-type littermates (WT) to four 30-s episodes of anoxia (97% N2-3% CO2), separated by 5 min of room air. We observed excess mortality in Pet-1−/− only at P8: 43% of Pet-1−/− animals survived past the third episode of anoxia while ∼95% of WT survived all four episodes ( P = 0.004). No deaths occurred at P5 and at P12, and one of six Pet-1−/− mice died after the fourth episode, while all WT animals survived. At P8, dying Pet-1−/− animals had delayed gasping, recovery of HR, and eupnea after the first two episodes of anoxia ( P < 0.001 for each); death ultimately occurred when gasping failed to restore HR. Both high- and low-frequency components of HR variability were abnormally elevated in dying Pet-1−/− animals following the first episode of anoxia. Dying P8 Pet-1−/− animals had significantly fewer 5-HT neurons in the raphe magnus than surviving animals ( P < 0.001). Our data indicate a critical developmental window at which a brainstem 5-HT deficiency increases the risk of death during episodes of anoxia. They may apply to the sudden infant death syndrome, which occurs at a critical age and is associated with 5-HT deficiency.
Publisher
American Physiological Society
Subject
Physiology (medical),Physiology
Cited by
64 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献