Brainstem Maturation in the Sudden Infant Death Syndrome

The sudden infant death syndrome (SIDS) is a leading cause of postneonatal infant mortality, with an overall incidence of 0.7/1000 live births. Its cause(s) is unknown. We have found a serotonergic defect in the raphe and extra-raphe reticular formation and the ventral region of the medulla in the majority of SIDS cases. These regions contain the serotonergic neurons of the medulla that form a system involved in the control of breathing, blood pressure, chemosensitivity, upper airway reflexes, and temperature control. We postulate that the abnormality in the medullary serotonergic system results in a failure of protective responses to life-threatening challenges (e.g., asphyxia, hypercapnia, hypoxia) during sleep. In this project, we are characterizing the normal development of the 5-HT medullary network across early human life, the time-period of the pathogenesis of SIDS. For these studies we are utilizing markers for 5-HT cells, terminals, receptor subtypes, and the synthetic enzyme, tryptophan hydroxylase, using tissue receptor autoradiography, immunocytochemistry, western blot analysis, high pressure liquid chromatography, and proteomics in medullae from human fetuses and infants. Using these approaches we are determining how 5-HT development is abnormal in SIDS cases compared to controls adjusted for age. These studies should: elucidate the underlying pathogenesis of the serotonergic defect in the medullary homeostatic system in SIDS; provide insight into the normal development and molecular and chemical anatomy of the human serotonergic medullary network; and suggest clues about abnormal function in SIDS cases for testing in animal models, and for devising specific preventive strategies and diagnostic tests in human infants. We also are testing the relationship of serotonin-related polymorphisms and mutations in the pathogenesis of SIDS, particularly in those infants with serotonergic brainstem abnormalities. The areas of relevance to the mission of the NICHD DevelopmentalDisabilities Centers are: 1 and 2.