Funding outcome

Some infants born prematurely suffer from apnea of prematurity, a condition where breathing is interrupted by periods when breathing slows or stops (apnea) for short periods. This unstable breathing pattern reflects that the brain circuits that produce breathing are immature. Reductions in oxygen levels during these periods can be life-threatening because when oxygen falls (hypoxia), breathing first increases but after a minute or so there is a secondary depression when breathing falls below resting levels. A life-threatening positive feedback loop can develop: apnea causes oxygen levels to fall, which depresses breathing causing further reductions in oxygen. In many infants, the respiratory stimulant caffeine is used to reduce these apneas. However, ~20% of infants do not respond to caffeine so alternate treatments are required. Our research in rodents has revealed that nonneuronal cells in the brain called astrocytes release ATP in response to hypoxia and that this ATP excites neurons in the region of the brainstem the generates breathing. The ATP excites breathing and this reduces the degree to which breathing is depressed. Further we have identified the type of receptor to which ATP binds on neurons to bring about this excitation. We are now in the process of identifying the signaling pathways inside the neurons through which ATP acts. Significant progress has been made in defining the intermediate steps but we do not yet know that final target on which these signaling molecules act to increase breathing. The objective of this summer proposal is to identify this final target. Once identified, the longer-term objective will be to understand how to enhance the activity of this target to increase and stabilize breathing. Any manipulation that can do so would be of significant clinical interest for its potential to attenuate the hypoxic respiratory depression.