Mechanisms underlying a critical period of respiratory development in the rat

Respir Physiol Neurobiol. 2019 Jun;264:40-50. doi: 10.1016/j.resp.2019.04.006. Epub 2019 Apr 15.


Twenty-five years ago, Filiano and Kinney (1994) proposed that a critical period of postnatal development constitutes one of the three risk factors for sudden infant death syndrome (SIDS). The underlying mechanism was poorly understood. In the last 17 years, much has been uncovered on this period in the rat. Against several expected trends of development, abrupt neurochemical, metabolic, ventilatory, and electrophysiological changes occur in the respiratory system at P12-13. This results in a transient synaptic imbalance with suppressed excitation and enhanced inhibition, and the response to acute hypoxia is the weakest at this time, both at the cellular and system's levels. The basis for the synaptic imbalance is likely to be contributed by a reduced expression of brain-derived neurotrophic factor (BDNF) and its TrkB receptors in multiple brain stem respiratory-related nuclei during the critical period. Exogenous BDNF or a TrkB agonist partially reverses the synaptic imbalance, whereas a TrkB antagonist accentuates the imbalance. A transient down-regulation of pituitary adenylate cyclase-activating polypeptide (PACAP) at P12 in respiratory-related nuclei also contributes to the vulnerability of this period. Carotid body denervation during this time or perinatal hyperoxia merely delays and sometimes prolongs, but not eliminate the critical period. The rationale for the necessity of the critical period in postnatal development is discussed.

Keywords: BDNF; Hypoxia; KCC2; NKCC1; PACAP; Synaptic imbalance.

Publication types

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

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / metabolism*
  • Hypoxia / metabolism*
  • Pituitary Adenylate Cyclase-Activating Polypeptide / metabolism*
  • Rats
  • Receptor, trkB / agonists
  • Receptor, trkB / antagonists & inhibitors
  • Receptor, trkB / metabolism*
  • Respiratory Physiological Phenomena*
  • Solute Carrier Family 12, Member 2 / metabolism*


  • Bdnf protein, rat
  • Brain-Derived Neurotrophic Factor
  • Pituitary Adenylate Cyclase-Activating Polypeptide
  • Slc12a2 protein, rat
  • Solute Carrier Family 12, Member 2
  • Ntrk2 protein, rat
  • Receptor, trkB