Brainstem Serotonergic Deficiency in Sudden Infant Death Syndrome

Department of Pathology, Children's Hospital Boston, 300 Longwood Ave, Boston, MA 02115, USA.
JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 02/2010; 303(5):430-7. DOI: 10.1001/jama.2010.45
Source: PubMed


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

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    • "We chose an intermittent hypercapnic stimulus, as chronic hypercapnia is shown to attenuate subsequent hypercapnic sensitivity (Bavis et al., 2006; Dempsey and Forster, 1982; Kondo et al., 2000; Lai et al., 1981; Rezzonico et al., 1990; Rezzonico and Mortola, 1989; Schaefer et al., 1963). Abnormal serotonergic brainstem mechanisms may contribute to infant vulnerability to Sudden Infant Death Syndrome (SIDS), and that vulnerability may result in part from chemosensory dysfunction (Cummings et al., 2009; Duncan et al., 2010; Hodges and Richerson, 2010; Kinney et al., 2009; Paterson et al., 2006; Richerson, 2004). If induced reflex plasticity is sufficient to overcome or reverse ventilatory chemosensitivity dysfunctions similar to those thought to contribute to SIDS, then interventions that induce plasticity could be therapeutic in augmenting chemoresponsiveness and decreasing infant vulnerability to SIDS. "
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    • "nature of diseases believed to result from failures in chemosensitivity, such as sleep apnea, congenital central hypoventilation syndrome (CCHS), sudden unexplained death in epilepsy (SUDEP), and sudden infant death syndrome (SIDS). In particular, vulnerability to SIDS is proposed to occur as a result of brainstem serotonergic dysfunction (Paterson et al. 2006; Kinney et al. 2009; Kinney and Thach 2009; Duncan et al. 2010). However, it is not known how this dysfunction contributes to these pathologies. "
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    • "-HT agonists (especially 5-HT 1A ) are highly effective in stabilizing breathing in both animals and humans (Richter et al., 2003; Dutschmann et al., 2009; Manzke et al., 2009); (2) 5-HT 1A receptors are the most extensively expressed subtype within the central respiratory network (Richter et al., 2003); (3) 5-HT 1A receptors are greatly reduced in the brainstem of SIDS victims (Ozawa and Okado, 2002; Kinney et al., 2009; Duncan et al., 2010); and (4) the male/female difference in 5-HT 1A receptors may explain the increased risk of SIDS in males versus females (Kinney et al., 2009). "
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