Brainstem serotonergic deficiency in sudden infant death syndrome

Abstract

Context: Sudden infant death syndrome (SIDS) is postulated to result from abnormalities in brainstem control of autonomic function and breathing during a critical developmental period. Abnormalities of serotonin (5-hydroxytryptamine [5-HT]) receptor binding in regions of the medulla oblongata involved in this control have been reported in infants dying from SIDS.

Objective: To test the hypothesis that 5-HT receptor abnormalities in infants dying from SIDS are associated with decreased tissue levels of 5-HT, its key biosynthetic enzyme (tryptophan hydroxylase [TPH2]), or both.

Design, setting, and participants: Autopsy study conducted to analyze levels of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA); levels of TPH2; and 5-HT(1A) receptor binding. The data set was accrued between 2004 and 2008 and consisted of 41 infants dying from SIDS (cases), 7 infants with acute death from known causes (controls), and 5 hospitalized infants with chronic hypoxia-ischemia.

Main outcome measures: Serotonin and metabolite tissue levels in the raphé obscurus and paragigantocellularis lateralis (PGCL); TPH2 levels in the raphé obscurus; and 5-HT(1A) binding density in 5 medullary nuclei that contain 5-HT neurons and 5 medullary nuclei that receive 5-HT projections.

Results: Serotonin levels were 26% lower in SIDS cases (n = 35) compared with age-adjusted controls (n = 5) in the raphé obscurus (55.4 [95% confidence interval {CI}, 47.2-63.6] vs 75.5 [95% CI, 54.2-96.8] pmol/mg protein, P = .05) and the PGCL (31.4 [95% CI, 23.7-39.0] vs 40.0 [95% CI, 20.1-60.0] pmol/mg protein, P = .04). There was no evidence of excessive 5-HT degradation assessed by 5-HIAA levels, 5-HIAA:5-HT ratio, or both. In the raphé obscurus, TPH2 levels were 22% lower in the SIDS cases (n = 34) compared with controls (n = 5) (151.2% of standard [95% CI, 137.5%-165.0%] vs 193.9% [95% CI, 158.6%-229.2%], P = .03). 5-HT(1A) receptor binding was 29% to 55% lower in 3 medullary nuclei that receive 5-HT projections. In 4 nuclei, 3 of which contain 5-HT neurons, there was a decrease with age in 5-HT(1A) receptor binding in the SIDS cases but no change in the controls (age x diagnosis interaction). The profile of 5-HT and TPH2 abnormalities differed significantly between the SIDS and hospitalized groups (5-HT in the raphé obscurus: 55.4 [95% CI, 47.2-63.6] vs 85.6 [95% CI, 61.8-109.4] pmol/mg protein, P = .02; 5-HT in the PGCL: 31.4 [95% CI, 23.7-39.0] vs 71.1 [95% CI, 49.0-93.2] pmol/mg protein, P = .002; TPH2 in the raphé obscurus: 151.2% [95% CI, 137.5%-165.0%] vs 102.6% [95% CI, 58.7%-146.4%], P = .04).

Conclusion: Compared with controls, SIDS was associated with lower 5-HT and TPH2 levels, consistent with a disorder of medullary 5-HT deficiency.

Figure 1. Medullary Serotonin (5-Hydroxytryptamine [5-HT]) System in the Human Infant

A, Medullary 5-HT system in the human infant at the rostral levels (level of the PGCL and GC) for neuroanatomical reference. The medullary 5-HT system is divided into 3 components based on the location of the nuclei containing 5-HT cell bodies: (1) raphé (midline), including the ROb; (2) extraraphé (lateral), including the PGCL, GC, and IRZ; and (3) ventral surface, including 5-HT neurons embedded within the ARC.^, B, Example of micropunched regions at the rostral medulla level for high-performance liquid chromatography and Western blot analysis in SIDS cases and controls. The regions for chromatographic analysis were the ROb and PGCL and for Western blotting was the ROb. C, Representative autoradiogram (pseudocolored computer-based image) of 5-HT_1A receptor binding in a control infant at the same rostral medullary level. High binding (red) is noted in the ROb, intermediate binding (green) in the PGCL, and negligible binding (blue-black) in the PIO.

Figure 2. Age × Diagnosis Interaction in the Intermediate Reticular Zone of Sudden Infant Death Syndrome (SIDS) Cases and Controls

The intermediate reticular zone is a key extraraphé component of the medullary serotonin (5-hydroxytryptamine [5-HT]) system that contains 5-HT cell bodies. In this nucleus, 5-HT_1A receptor binding decreases with age in the SIDS cases but does not change with age in the controls. A, There is a significant difference in the slopes of binding with age in the 2006 and 2010 data sets combined for all SIDS cases and controls (37–90 postconceptional weeks) (P = .002). Sloped solid lines indicate linear regression fit. B, The significant difference between the SIDS cases and controls persists when the analysis is restricted to cases and controls that overlap in age (37–64 weeks’ postconceptional age) (P = .004). Sloped solid lines indicate linear regression fit.

Figure 3

Positive Correlation of 5-HT_1A Receptor Binding Levels in the Gigantocellularis (GC) vs the Raphé Obscurus and Paragigantocellularis Lateralis (PGCL) in Sudden Infant Death Syndrome (SIDS) Cases (N = 40)