Sudden neonatal death in PACAP-deficient mice is associated with reduced respiratory chemoresponse and susceptibility to apnoea.

Pituitary adenylate cyclase-activating polypeptide (PACAP)-deficient mice are more prone to sudden death during postnatal weeks 1-3 than wild-type littermates. Given that PACAP is localized in brainstem regions associated with respiratory chemosensitivity, we examined whether PACAP-null neonates have reduced respiratory responses to hypoxia and hypercapnia. Using unrestrained, whole-body, flow-through plethysmography we found that, by postnatal day 4, the PACAP-null neonates had significantly reduced ventilation during baseline breathing, and blunted responses to both hypoxia (10% O2-90% N2) and hypercapnia (8% CO2-92% air). To determine whether the respiratory phenotype of the PACAP-null mice may contribute to their greater neonatal mortality, we used ECG to examine respiration and cardiovascular function of littermates. We demonstrate that, under conditions that exacerbate mortality of knockout but not wild-type animals, PACAP-deficient mice experience prolonged apnoeas that precede atrio-ventricular block. Both apnoeas and atrio-ventricular block were absent in wild-type littermates. These data suggest that PACAP-deficiency results in higher neonatal mortality primarily as a result of respiratory control defects and raise the possibility that mutations in genes encoding components of the PACAP signalling pathways may contribute to neonatal breathing disorders in humans.