title: Failed heart rate recovery at a critical age in 5-HT-deficient mice exposed to episodic anoxia: implications for SIDS.
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.
authors.affiliation: Department of Physiology and Neurobiology, Dartmouth Medical School, Lebanon, New Hampshire, USA. crumbings@gmail.com
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Cummings
authors.forename: Kathryn G
authors.initials: KG
authors.lastname: Commons
authors.forename: Julie C
authors.initials: JC
authors.lastname: Hewitt
authors.forename: John A
authors.initials: JA
authors.lastname: Daubenspeck
authors.forename: Aihua
authors.initials: A
authors.lastname: Li
authors.forename: Hannah C
authors.initials: HC
authors.lastname: Kinney
authors.forename: Eugene E
authors.initials: EE
authors.lastname: Nattie
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001049:Apnea / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D001919:Bradycardia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D001933:Brain Stem / Q000254:growth & development / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D005838:Genotype; D006339:Heart Rate; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D007231:Infant, Newborn; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D020127:Recovery of Function; D015656:Respiratory Mechanics; D012701:Serotonin / Q000172:deficiency*; D013398:Sudden Infant Death / Q000209:etiology*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics
chemical_list: C484684:Fev protein, mouse; D014157:Transcription Factors; D012701:Serotonin