Failed heart rate recovery at a critical age in 5-HT-deficient mice exposed to episodic anoxia: implications for SIDS

J Appl Physiol (1985). 2011 Sep;111(3):825-33. doi: 10.1152/japplphysiol.00336.2011. Epub 2011 Jun 16.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Apnea / genetics
  • Apnea / metabolism*
  • Apnea / physiopathology
  • Bradycardia / genetics
  • Bradycardia / metabolism*
  • Bradycardia / physiopathology
  • Brain Stem / growth & development
  • Brain Stem / metabolism*
  • Brain Stem / physiopathology
  • Disease Models, Animal
  • Genotype
  • Heart Rate*
  • Humans
  • Hypoxia / genetics
  • Hypoxia / metabolism*
  • Hypoxia / physiopathology
  • Infant, Newborn
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phenotype
  • Recovery of Function
  • Respiratory Mechanics*
  • Serotonin / deficiency*
  • Sudden Infant Death / etiology*
  • Transcription Factors / deficiency
  • Transcription Factors / genetics


  • Fev protein, mouse
  • Transcription Factors
  • Serotonin