Serotonergic Brainstem Abnormalities in Northern Plains Indians with the Sudden Infant Death Syndrome

Abstract

The rate of the sudden infant death syndrome (SIDS) among American Indian infants in the Northern Plains is almost 6 times higher than in U.S. white infants. In a study of infant mortality among Northern Plains Indians, we tested the hypothesis that receptor binding abnormalities to the neurotransmitter serotonin (5-HT) in SIDS cases, compared with autopsied controls, occur in regions of the medulla oblongata that contain 5-HT neurons and that are critical for the regulation of cardiorespiration and central chemosensitivity during sleep, i.e. the medullary 5-HT system. Tritiated-lysergic acid diethylamide binding to 5-HT(1A-D) and 5-HT2 receptors was measured in 19 brainstem nuclei in 23 SIDS and 6 control infants using tissue receptor autoradiography. Binding in the arcuate nucleus, a part of the medullary 5-HT system along the ventral surface, in the SIDS infants (mean age-adjusted binding 7.1 +/- 0.8 fmol/mg tissue, n = 23) was significantly lower than in controls (mean age-adjusted binding 13.1 +/- 1.6 fmol/mg tissue, n = 5) (p = 0.003). Binding also demonstrated significant diagnosis x age interactions (p < 0.04) in 4 other nuclei that are components of the 5-HT system. These data suggest that medullary 5-HT dysfunction can lead to sleep-related, sudden death in affected SIDS infants, and confirm the same binding abnormalities reported by us in a larger dataset of non-American Indian SIDS and control infants. This study also links 5-HT abnormalities in the arcuate nucleus with exposure to adverse prenatal exposures, i.e. cigarette smoking (p = 0.011) and alcohol (p = 0.075), during the periconceptional period or throughout pregnancy. Prenatal exposure to cigarette smoke and/or alcohol may contribute to abnormal fetal medullary 5-HT development in SIDS infants.

Seizures, Cerebral Shutdown, and SUDEP

“…Increased polymorphism frequencies have been identified in 25 genes in SIDS infants compared to controls, 3 of which are serotonin genes (31). Tissue receptor autoradiographic studies of brainstem tissue in SIDS patients have shown arcuate nucleus (30,32) and more widespread brainstem reduction in 5HT 1A binding, increased 5HT cells and reduction in 5HT transporter binding (32,33), suggesting abnormalities in a system prominently Additional information on the serotonin theme comes from animal studies: mice with an audiogenic seizure disorder due to a genetic deletion of the 5HT 2c receptor die in the postictal period if unresuscitated (34). DBA/2 strain mice, which suffer audiogenic seizures, have marked susceptibility to postictal respiratory arrest, which can be reduced when pretreated with selective serotonin reuptake inhibitors (SSRIs) (35).…”

Inhibition of Serotonergic Neurons in the Nucleus Paragigantocellularis Lateralis Fragments Sleep and Decreases Rapid Eye Movement Sleep in the Piglet: Implications for Sudden Infant Death Syndrome

“…A major advance in our understanding of the etiology of SIDS has been the finding that many SIDS infants have decreased binding of muscarinic and kainate receptors in the arcuate nucleus at the ventral surface of the medulla (Kinney et al, 1995;Panigrahy et al, 1997) and abnormal binding to serotonergic (5-HT) receptors in the medullary serotonergic nuclei, including the paragigantocellularis lateralis (PGCL) (Panigrahy et al, 2000;Kinney et al, 2003). Dysfunction in these regions may increase the risk for SIDS by altering protective reflexes to stressors encountered during sleep such as hypercapnia, hypoxia, and laryngeal stimulation (Filiano and Kinney, 1994).…”

Potential Asphyxia and Brainstem Abnormalities in Sudden and Unexpected Death in Infants

“…5,29 We hypothesize that at least a subset of SIDS is caused by an underlying brainstem abnormality in neural networks that mediate protective responses to asphyxia, resulting in sleep-related sudden death. [30][31][32][33][34][35] In support of this hypothesis, we have reported deficiencies in infants who died of SIDS in interrelated neurochemical parameters in the medullary serotonergic network that plays a key role in protective respiratory or autonomic responses to homeostatic stressors. [30][31][32][33][34][35] The parameters are related mainly to the neurotransmitters serotonin and g-aminobutyric acid (GABA) and the signal transduction family 14-3-3, involved in serotonin regulation.…”

“…[30][31][32][33][34][35] In support of this hypothesis, we have reported deficiencies in infants who died of SIDS in interrelated neurochemical parameters in the medullary serotonergic network that plays a key role in protective respiratory or autonomic responses to homeostatic stressors. [30][31][32][33][34][35] The parameters are related mainly to the neurotransmitters serotonin and g-aminobutyric acid (GABA) and the signal transduction family 14-3-3, involved in serotonin regulation. [30][31][32][33][34][35] Given a reduction in the overall SIDS rate associated with an increased rate of supine sleep, 5,[8][9][10] it is highly likely that prone sleep position plays a direct role in the chain of events leading to sudden death in some infants.…”