Decreased Serotonergic Receptor Binding in Rhombic Lip-Derived Regions of the Medulla Oblongata in the Sudden Infant Death Syndrome

Abstract

The sudden infant death syndrome (SIDS) is postulated to result from a failure of homeostatic responses to life-threatening challenges (e.g. asphyxia, hypercapnia) during sleep. The ventral medulla participates in sleep-related homeostatic responses, including chemoreception, arousal, airway reflex control, thermoregulation, respiratory drive, and blood pressure regulation, in part via serotonin and its receptors. The ventral medulla in humans contains the arcuate nucleus, in which we have shown isolated defects in muscarinic and kainate receptor binding in SIDS victims. We also have demonstrated that the arcuate nucleus is anatomically linked to the nucleus raphé obscurus, a medullary region with serotonergic neurons. We tested the hypothesis that serotonergic receptor binding is decreased in both the arcuate nucleus and nucleus raphé obscurus in SIDS victims. Using quantitative autoradiography, 3H-lysergic acid diethylamide (3H-LSD binding) to serotonergic receptors (5-HT1A-D and 5-HT2 subtypes) was measured blinded in 19 brainstem nuclei. Cases were classified as SIDS (n = 52), acute controls (infants who died suddenly and in whom a complete autopsy established a cause of death) (n = 15), or chronic cases with oxygenation disorders (n = 17). Serotonergic binding was significantly lowered in the SIDS victims compared with controls in the arcuate nucleus (SIDS, 6 +/- 1 fmol/mg tissue; acutes, 19 +/- 1; and chronics, 16 +/- 1; p = 0.0001) and n. raphé obscurus (SIDS, 28 +/- 3 fmol/mg tissue; acutes, 66 +/- 6; and chronics, 59 +/- 1; p = 0.0001). Binding, however, was also significantly lower (p < 0.05) in 4 other regions that are integral parts of the medullary raphé/serotonergic system, and/or are derived, like the arcuate nucleus and nucleus raphé obscurus, from the same embryonic anlage (rhombic lip). These data suggest that a larger neuronal network than the arcuate nucleus alone is involved in the pathogenesis of SIDS, that is, a network composed of inter-related serotonergic nuclei of the ventral medulla that are involved in homeostatic mechanisms, and/or are derived from a common embryonic anlage.

Transient attenuation of CO2 sensitivity after neurotoxic lesions in the medullary raphe area of awake goats

“…Additionally, we conclude that lesions produced by midline microtubule implantation have a profound effect on respiratory rhythm, ranging from fractionated breathing to central apnea, likely as a result of reduced raphe neuromodulatory inputs into, or disruption of coordination among, rhythm-generating mechanisms. We believe that the present findings support the hypothesis that deficits in raphe modulation of breathing (via respiratory rhythm and/or CO 2 chemoreception) may contribute to and/or underlie human clinical conditions, such as central and obstructive sleep apnea and a subset of sudden infant deaths (30).…”

Widespread depolarization during expiration: A source of respiratory drive?

“…Abnormalities in the arcuate nucleus [89] and medulla oblongata [90] of the brainstem of SIDs victims suggests that they may have delayed development of cardiorespiratory control, arousal, and homeostatic responses. When breathing or other physiologic activity becomes compromised the infant does not arouse sufficiently to abate progression of such activity [91].…”

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.…”

“…[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. The hypothesized mechanisms include ineffective protective responses to airway obstruction or rebreathing of expired gases in the face-down position (compounded by soft bedding) 5,20 and thermal or cardiovascular stress.…”