title: Time- and age-dependent effects of serotonin on gasping and autoresuscitation in neonatal mice.
abstract: The role of brain stem serotonin (5-hydroxytryptamine, 5-HT) in autoresuscitation in neonatal life is unclear. We hypothesized that a specific loss of 5-HT would compromise gasping and autoresuscitation mainly in the second postnatal week and that acute restoration of 5-HT would reverse the defects. We exposed postnatal day (P)4-5, P8-9, and P11-12 tryptophan-hydroxylase-2 knockout (TPH2(-/-)) and wild-type littermates (WT) to 10 episodes of anoxia (97% N2, 3% CO2), measuring survival, gasp latency, gasp frequency (fB), and the time required to restore eupnea and heart rate. We also tested P8-9 TPH2(-/-) mice after restoring 5-HT with a single injection of 5-hydroxytryptophan (5-HTP) 1-2 h before testing or with multiple injections beginning 24 h before testing. At P4-5 and P8-9, but not at P11-12, gasp latency and the recovery of eupnea were delayed ~2- to 3-fold in TPH2(-/-) pups compared with WT (P < 0.001). At all ages, TPH2(-/-) pups displayed reduced gasp fB (~20-30%; P < 0.001) and delayed heart rate recovery (~60%; P = 0.002) compared with WT littermates. TPH2(-/-) survival was reduced compared with WT (P < 0.001), especially at P8-9 and P11-12 (P = 0.004). Whereas 1-2 h of 5-HTP treatment improved the gasp latency and fB of P8-9 TPH2(-/-) pups, improved cardiorespiratory recovery and survival required 24 h of treatment. Our data suggest that 5-HT operates over a long time span (24 h) to improve survival during episodic severe hypoxia. Early in development (P4-9), 5-HT is critical for both respiratory and cardiovascular components of autoresuscitation; later (P11-12), it is critical mainly for cardiovascular components. Nevertheless, the effect of 5-HT deficiency on survival is most striking from P8 to P12.
authors.affiliation: Department of Biomedical Sciences, University of Missouri, Columbia, Missouri 65211, USA.
authors.forename: Jianping
authors.initials: J
authors.lastname: Chen
authors.forename: Jennifer
authors.initials: J
authors.lastname: Magnusson
authors.forename: Gerard
authors.initials: G
authors.lastname: Karsenty
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Cummings
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001049:Apnea / Q000378:metabolism / Q000503:physiopathology; D001933:Brain Stem / Q000378:metabolism / Q000502:physiology*; D006339:Heart Rate / Q000502:physiology; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012119:Respiration; D012137:Respiratory System / Q000503:physiopathology*; D012701:Serotonin / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D014365:Tryptophan Hydroxylase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D012701:Serotonin; C487802:Tph2 protein, mouse; D014365:Tryptophan Hydroxylase
keywords: SIDS; autoresuscitation; development; gasping; heart rate; hypoxia; serotonin