Impaired response to hypoxia in the respiratory center is a major cause of neonatal death of the PACAP-knockout mouse


Correspondence: Dr Hiroshi Onimaru, as above.



Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide expressed widely in nervous tissues. PACAP-knockout (−/−) mice display a sudden infant death syndrome (SIDS)-like phenotype, although the underlying physiological mechanism to explain this remains unclear. Here, we report on the presence of abnormal respiratory activity in PACAP−/− mice under hypoxic conditions, which provides a basis for the SIDS-like phenotype. PACAP−/− mice display a lowered baseline respiratory activity compared with wild-type animals, and an abnormal response to hypoxia. More specifically, PACAP−/− mice at postnatal day 7 showed respiratory arrest in response to hypoxia. In contrast, their response to hypercapnic conditions was the same as that of wild-type mice. Histological and real-time PCR analyses indicated that the catecholaminergic system in the medulla oblongata was impaired in PACAP−/− mice, suggesting that endogenous PACAP affects respiratory centers in the medulla oblongata via its action on the catecholaminergic system. We propose that disruption of this system is involved in the SIDS-like phenotype of PACAP−/− mice. Thus, disorders of the catecholaminergic system involved with O2 sensing could be implicated in underlying neuronal mechanisms responsible for SIDS.